Tips for treating patients with late-life depression

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Tips for treating patients with late-life depression

Late-life depression is the onset of a major depressive disorder in an individual ≥ 60 years of age. Depressive illness compromises quality of life and is especially troublesome for older people. The prevalence of depression among individuals > 65 years of age is about 4% in women and 3% in men.1 The estimated lifetime prevalence is approximately 24% for women and 10% for men.2 Three factors account for this disparity: women exhibit greater susceptibility to depression; the illness persists longer in women than it does in men; and the probability of death related to depression is lower in women.2

Beyond its direct mental and emotional impacts, depression takes a financial toll; health care costs are higher for those with depression than for those without depression.3 Unpaid caregiver expense is the largest indirect financial burden with late-life depression.4 Additional indirect costs include less work productivity, early retirement, and diminished financial security.4

Many individuals with depression never receive treatment. Fortunately, there are many interventions in the primary care arsenal that can be used to treat older patients with depression and dramatically improve mood, comfort, and function.

The interactions of emotional and physical health

The pathophysiology of depression remains unclear. However, numerous factors are known to contribute to, exacerbate, or prolong depression among elderly populations. Insufficient social engagement and support is strongly associated with depressive mood.5 The loss of independence in giving up automobile driving can compromise self-confidence.6 Sleep difficulties predispose to, and predict, the emergence of a mood disorder, independent of other symptoms.7 Age-related hearing deficits also are associated with depression.8

There is a close relationship between emotional and physical health.9 Depression adds to the likelihood of medical illness, and somatic pathology increases the risk for mood disorders.9 Depression has been linked with obesity, frailty, diabetes, cognitive impairment, and terminal illness.9 Other conditions associated with depression include Parkinson disease, alcohol dependence,and chronic pain.10-12 Cerebrovascular disease may predispose to, precipitate, or perpetuate this mood disorder.13

Inflammatory markers and depression may also be related. Plasma levels of interleukin­-6 and C-reactive protein were measured in a longitudinal aging study.14 A high level of interleukin-6, but not C-reactive protein, correlated with an increased prevalence of depression in older people.

Escitalopram is often better tolerated than paroxetine and has fewer pharmaceutical interactions, compared with sertraline.

Chronic cerebral ischemia can result in a “vascular depression”13 in which disruption of prefrontal systems by ischemic lesions is hypothesized to be an important factor in developing despair. Psychomotor retardation, executive dysfunction, severe disability, and a heightened risk for relapse are common features of vascular depression.15 Poststroke depression often follows a cerebrovascular episode16; the exact pathogenic mechanism is unknown.17

Continue to: A summation of common risk factors

 

 

A summation of common risk factors. A personal or family history of depression increases the risk for late-life depression. Other risk factors are female gender, bereavement, sleep disturbance, and disability.18 Poor general health, chronic pain, cognitive impairment, poor social support, and medical comorbidities with impaired functioning increase the likelihood of resultant mood disorders.18

Somatic complaints may overshadow diagnostic symptoms

Manifestations of depression include disturbed sleep and reductions in appetite, concentration, activity, and energy for daily function.19 These features, of course, may accompany medical disorders and some normal physiologic changes among elderly people. We find that while older individuals may report a sad mood, disturbed sleep, or other dysfunctions, they frequently emphasize their somatic complaints much more prominently than their emotions. This can make it difficult to recognize clinical depression.

For a diagnosis of major depression, ­5 of the following 9 symptoms must be present for most of the day or nearly every day over a period of at least 2 weeks19: depressed mood; diminished interest in most activities; significant weight loss or decreased appetite; insomnia or hypersomnia; agitation or retardation; fatigue or loss of energy; feelings of worthlessness or guilt; diminished concentration; and recurrent thoughts of death or suicide.19

Planning difficulties, apathy, disability, and anhedonia frequently occur. Executive dysfunction and inefficacy of antidepressant pharmacotherapy are related to compromised frontal-striatal-limbic pathways.20 Since difficulties with planning and organization are associated with suboptimal response to antidepressant medications, a psychotherapeutic focus on these executive functions can augment drug-induced benefit.

Rule out these alternative diagnoses

Dementias can manifest as depression. Other brain pathologies, particularly Parkinson disease or stroke, also should be ruled out. Overmedication can simulate depression, so be sure to review the prescription and over-the-counter agents a patient is taking. Some medications can occasionally precipitate a clinical depression; these include stimulants, steroids, methyldopa, triptans, chemotherapeutic agents, and immunologic drugs, to name a few.19

Continue to: Pharmacotherapy, Yes, but first, consider these factors

 

 

Pharmacotherapy, Yes, but first, consider these factors

Maintaining a close patient–doctor relationship augments all therapeutic interventions. Good eye contact when listening to and counseling patients is key, as is providing close follow-up appointments.

Encourage social interactions with family and friends, which can be particularly productive. Encouraging spiritual endeavors, such as attendance at religious services, can be beneficial.21

Recommend exercise. Physical exercise yields positive outcomes22; it can enhance mood, improve sleep, and help to diminish anxiety. Encourage patients with depression to take a daily walk during the day; doing so can enhance emotional outlook, health, and even socialization.

What treatment will best serve your patient?

It’s important when caring for patients with depression to assess and address suicidal ideation. Depression with a previous suicide attempt is a strong risk factor for suicide. Inquire about suicidal intent or death wishes, access to guns, and other life-ending behaviors. Whenever suicide is an active issue, immediate crisis management is required. Psychiatric referral is an option, and hospitalization may be indicated. Advise family members to remove firearms or restrict access, be with the patient as much as possible, and assist at intervention planning and implementation.

It is worth mentioning, here, the connection between chronic pain and suicidal ideation. Pain management reduces suicidal ideation, regardless of depression severity.23 

Continue to: Psychotherapy and pharmacotherapies...

 

 

Psychotherapy and pharmacotherapies offered for the treatment of depression in geriatric practices are both effective, without much difference seen in efficacy.24 Psychotherapy might include direct physician and family support to the patient or referral to a mental health professional. Base treatment choices on clinical access, patient preference, and medical contraindications and other illnesses.

Pros and cons of various pharmacotherapies

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed first for elderly patients with depression.25 Escitalopram is often better tolerated than paroxetine, which exhibits muscarinic antagonism and enzyme inhibition of cytochrome P450-2D6.26 Escitalopram also has fewer pharmaceutical interactions compared with sertraline.26

Generally, when prescribing an antidepressant drug, stay with the initial choice, gradually increasing the dose as clinically needed to its maximum limit. Suicidal ideation may be worsened by too quickly switching from one antidepressant to another or by co-prescribing anxiolytic or hypnotic medicines. Benzodiazepines have addictive and disinhibiting properties and should be avoided, if possible.27 For patients withinsomnia, consider initially selecting a sedating antidepressant medication such as paroxetine or mirtazapine to augment sleep.

Alternatives to SSRIs. Nonselective serotonin reuptake inhibitors have similar efficacy as SSRIs. However, escitalopram is as effective as venlafaxine (a selective serotonin and norepinephrine reuptake inhibitor [SSNRI]) and is better tolerated.28 Duloxetine, another SSNRI, improves mood and often diminishes chronic pain.29 Mirtazapine, an alpha-2 antagonist, might cause fewer drug-drug interactions and is effective, well tolerated, and especially helpful for patients with anxiety or insomnia.30 Dry mouth, sedation, and weight gain are common adverse effects of mirtazapine. Obesity precautions are often necessary during mirtazapine therapy; this includes monitoring body weight and metabolic profiles, instituting dietary changes, and recommending an exercise regimen. In contrast to SSRIs, mirtazapine might induce less sexual dysfunction.31

Suicidal ideation may be worsened by too quickly switching from one antidepressant to another or by co-prescribing anxiolytic or hypnotic medicines.

Tricyclic antidepressant drugs can also be effective but may worsen cardiac conduction abnormalities, prostatic hypertrophy, or narrow angle glaucoma. Tricyclic antidepressants may be useful in patients without cardiac disease who have not responded to an SSRI or an SSNRI.

Continue to: The role of aripiprazole

 

 

The role of aripiprazole. Elderly patients not achieving remission from depression with antidepressant agents alone may benefit from co-prescribing aripiprazole.32 As an adjunct, aripiprazole is effective in achieving and sustaining remission, but it has the potential for less tolerability by inducing akathisia and parkinsonism.32

Minimize risks and maximize ­benefits of antidepressants by following these recommendations:

  1. Ascertain whether any antidepressant treatments have worked well in the past.
  2. Start with an SSRI if no other antidepressant treatment has worked in the past.
  3. Counsel patients about the need for treatment adherence. Antidepressants may take 2 weeks to 2 months to provide noticeable improvement.
  4. Prescribe up to the maximum drug dose if needed to enhance benefit.
  5. Use a mood measurement tool (eg, the Patient Health Questionnaire-9) to help evaluate treatment response.

Try a different class of drugs for patients who do not respond to treatment. For patients who have a partial response, augment with bupropion XL, mirtazapine, aripiprazole, or quetiapine.33 Sertraline and nortriptyline are similarly effective on a population-wide basis, with sertraline having less-problematic adverse effects.34 Trial-and-error treatments in practice may find one patient responding only to sertraline and another patient only to nortriptyline.

Transcranial magnetic stimulation is a promising, relatively new therapeutic option for treating refractory cases of depressive mood disorders.

Combinations of different drug classes may provide benefit for patients not responding to a single antidepressant. In geriatric patients, combined treatment with methylphenidate and citalopram enhances mood and well-being.35 Compared with either drug alone, the combination yielded an augmented clinical response profile and a higher rate of remission. Cognitive functioning, energy, and mood improve even with methylphenidate alone, especially when fatigue is an issue. However, addictive properties limit its use to cases in which conventional antidepressant medications are not effective or indicated, and only when drug refills are closely monitored.

The challenges of advancing age. Antidepressant treatment needs increase with advanced age.36 As mentioned earlier, elderly people often have medical illnesses complicating their depression and frequently are dealing with pain from the medical illness. When dementia coexists with depression, the efficacy of pharmacotherapies is compromised.

Continue to: When drug-related interventions fail

 

 

When drug-related interventions fail, therapy ought to be more psychologically focused.37 Psychotherapy is usually helpful and is particularly indicated when recovery is suboptimal. Counseling might come from the treating physician or referral to a psychotherapist.

Nasal esketamine can be efficacious when supplementing antidepressant pharmacotherapy among older patients with treatment-resistant depression.38 Elderly individuals responding to antidepressants do not benefit from adjunctive donepezil to correct mild cognitive impairment.39 There is no advantage to off-label cholinesterase inhibitor prescribing for patients with both depression and dementia.

Other options. Electroconvulsive therapy (ECT) does not cause long-term cognitive problems and is reserved for ­treatment-resistant cases.40 Patients with depression who also have had previous cognitive impairment often improve in mental ability following ECT.41

A promising new option. Transcranial magnetic stimulation (TMS) is a promising, relatively new therapeutic option for treating refractory cases of depressive mood disorders. In TMS, an electromagnetic coil that creates a magnetic field is placed over the left dorsolateral prefrontal cortex (which is responsible for mood regulation). Referral for TMS administration may offer new hope for older patients with treatment-resistant depression.42

Keep comorbidities in mind as you address depression

Coexisting psychiatric illnesses worsen emotions. Geriatric patients are susceptible to psychiatric comorbidities that include substance abuse, obsessive-compulsive characteristics, dysfunctional eating, and panic disorder.19 Myocardial and cerebral infarctions are detrimental to mental health, especially soon after such events.43 Poststroke depression magnifies the risk for disability and mortality,16,17 yet antidepressant pharmacotherapy often enhances prognoses. Along with early intervention algorithm-based plans and inclusion of a depression care manager, antidepressants often diminish poststroke depression severity.44 Even when cancer is present, depression care reduces mortality.44 So with this in mind, persist with antidepressant treatment, which will often benefit an elderly individual with depression.

Continue to: When possible, get ahead of depression before it sets in

 

 

When possible, get ahead of depression before it sets in

Social participation and employment help to sustain an optimistic, euthymic mood.45 Maintaining good physical health, in part through consistent activity levels (including exercise), can help prevent depression. Since persistent sleep disturbance predicts depression among those with a depression history, optimizing sleep among geriatric adults can avoid or alleviate depression.46

Low vitamin D levels can contribute to depression, yet vitamin D supplementation may not improve mood.

Sleep hygiene education for patients is also helpful. A regular waking time often promotes a better sleeping schedule. Restful sleep also is more likely when an individual avoids excess caffeine, exercises during the day, and uses the bed only for sleeping (not for listening to music or watching television).

Because inflammation may precede ­depression, anti-inflammatory medications have been proposed as potential treatment, but such pharmacotherapies are often ineffective. Older adults generally do not benefit from low-dose aspirin administration to prevent depression.47 Low vitamin D levels can contribute to depression, yet vitamin D supplementation may not improve mood.48

Offering hope. Tell your patients that if they are feeling depressed, they should make an appointment with you, their primary care physician, because there are medications they can take and counseling they can avail themselves of that could help.

CORRESPONDENCE
Steven Lippmann, MD, University of Louisville-Psychiatry, 401 East Chestnut Street, Suite 610, Louisville, KY 40202; steven.lippmann@louisville.edu.

References

1. Steffens DC, Skoog I, Norton MC, et al. Prevalence of depression and its treatment in an elderly population: the Cache County study. Arch Gen Psych. 2000;57:601-607. doi: 10.1001/ archpsyc.57.6.601

2. Barry LC, Allore HG, Guo Z, et al. Higher burden of depression among older women: the effect of onset, persistence, and mortality over time. Arch Gen Psych. 2008;65:172-178. doi: 10.1001/archgenpsychiatry.2007.17

3. Katon WJ, Lin E, Russo J, et al. Increased medical costs of a ­population-based sample of depressed elderly patients. Arch Gen Psych. 2003;60:897-903. doi: 10.1001/archpsyc.60.9.897

4. Snow CE, Abrams RC. The indirect costs of late-life depression in the United States: a literature review and perspective. Geriatrics. 2016;1,30. doi.org/10.3390/geriatrics/1040030 

5. George LK, Blazer DG, Hughes D, et al. Social support and the outcome of major depression.  Br J Psych. 1989;154:478-485. doi: 10.1192/bjp.154.4.478

6. Fonda SJ, Wallace RB, Herzog AR. Changes in driving patterns and worsening depressive symptoms among older adults. ­­ J Gerontol Psychol Soc Sci. 2001;56:S343-S351. doi: 10.1093/geronb/56.6.s343

7. Cho HJ, Lavretsky H, Olmstead R, et al. Sleep disturbance and depression recurrence in community dwelling older adults—a prospective study. Am J Psych. 2008;165:1543-1550. doi: 10.1176/appi.ajp.2008.07121882

8. Golub JS, Brewster KK, Brickman AM, et al. Subclinical hearing loss is associated with depressive symptoms. Am J Geriatr Psychiatry. 2020;28:545-556. doi: 10.1016/j.jagp.2019.12.008

9. Alexopoulos GS. Mechanisms and treatment of late-life depression.  Focus (Am Psychiatr Publ). 2021;19:340-354. doi: 10.1176/appi.focus.19304

10. Starkstein SE, Preziosi TJ, Bolduc PL, et al. Depression in Parkinson’s disease.  J Nerv Ment Disord. 1990;178:27-31. doi: 10.1097/00005053-199001000-00005

11. Gilman SE, Abraham HE. A longitudinal study of the order of onset of alcohol dependence and major depression. Drug Alco Depend. 2001;63:277-286. doi: 10.1016/s0376-8716(00)00216-7

12. Parmelee PA, Katz IR, Lawton MP. The relation of pain to depression among institutionalized aged. J Gerontol. 1991;46:P15-P21. doi: 10.1093/geronj/46.1.p15

13. Alexopoulos GS, Meyers BS, Young RC, et al. ‘Vascular depression’ hypothesis. Arch Gen Psych. 1997;54:915-922. doi: 10.1001/archpsyc.1997.01830220033006

14. Bremmer MA, Beekman AT, Deeg DJ, et al. Inflammatory markers in late-life depression: results from a population-based study. J Affect Disord. 2008;106:249-255. doi: 10.1016/j.jad.2007.07.002

15. Taylor WD, Aizenstein HJ, Alexopoulos GS. The vascular depression hypothesis: mechanisms linking vascular disease with depression. Mol Psych. 2013;18:963-974. doi: 10.1038/mp.2013.20

16. Robinson RG, Jorge RE. Post-stroke depression: a review. Am J Psych. 2016;173:221-231. doi: 10.1176/appi.ajp.2015.15030363

17. Cai W, Mueller C, Li YJ, et al. Post stroke depression and risk of stroke recurrence and mortality: a systematic review and meta-analysis. Ageing Res Rev. 2019;50:102-109. doi: 10.1016/ j.arr.2019.01.013

18. Cole MG, Dendukuri N. Risk factors for depression among elderly community subjects: a systematic review and meta-analysis. Am J Psych. 2003;160:1147-1156. doi: 10.1176/appi.ajp.160.6.1147

19. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). 2013:160-168.

20. Pimontel MA, Rindskopf D, Rutherford BR, et al. A meta-analysis of executive dysfunction and antidepressant treatment response in late-life depression. Am J Geriatr Psych. 2016;24:31-34. doi: 10.1016/j.jagp.2015.05.010

21. Koenig HG, Cohen HJ, Blazer DG, et al. Religious coping and depression in elderly hospitalized medically ill men. Am J Psychiatry. 1992;149:1693-1700. doi: 10.1176/ajp.149.12.1693

22. Blake H, Mo P, Malik S, et al. How effective are physical activity interventions for alleviating depressive symptoms in older people? A systematic review. Clin Rehabil. 2009;10:873-887. doi: 10.1177/0269215509337449

23. Bruce ML, Ten Have TR, Reynolds CF, et al. Reducing suicidal and depressive symptoms in depressed older primary care patients: a randomized controlled trial. JAMA. 2004;291:1081-1091. doi: 10.1001/jama.291.9.1081

24. Pinquart M, Duberstein PR, Lyness JM. Treatments for later-life depressive conditions: a meta-analytic comparison of pharmacotherapy and psychotherapy. Am J Psychiatry. 2006;163:1493-1501. doi: 10.1176/ajp.2006.163.9.1493

25. Solai LK, Mulsant BH, Pollack BG. Selective serotonin reuptake inhibitors for late-life depression: a comparative review. Drugs Aging. 2001;18:355-368. doi: 10.2165/00002512-200118050-00006

26. Sanchez C, Reines EH, Montgomery SA. A comparative review of escitalopram, paroxetine, and sertraline. Are they all alike? Int Clin Psychopharmacol. 2014;29:185-196. doi: 10.1097/YIC.0000000000000023

27. Hedna K, Sundell KA, Hamidi A, et al. Antidepressants and suicidal behaviour in late life: a prospective population-based study of use patterns in new users aged 75 and above. Eur J Clin ­Pharmacol. 2018;74:201-208. doi: 10.1007/s00228-017-2360-x

28. Bielski RJ, Ventura D, Chang CC. A double-blind comparison of escitalopram and venlafaxine extended release in the treatment of major depressive disorder. J Clin Psychiatry. 2004;65:1190-1196. doi: 10.4088/jcp.v65n0906

29. Robinson M, Oakes TM, Raskin J, et al. Acute and long-term treatment of late-life major depressive disorder: duloxetine versus placebo. Am J Geriatr Psychiatry. 2014;22:34-45. doi: 10.1016/ j.jagp.2013.01.019

30. Holm KJ, Markham A. Mirtazapine: a review of its use in major depression. Drugs. 1999;57:607-631. doi: 10.2165/00003495-199957040-00010

31. Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev. 2001;7:249-264. doi: 10.1111/j.1527-3458.2001.tb00198.x

32. Lenze EJ, Mulsant BH, Blumberger DM, et al. Efficacy, safety and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised ­double-blind, placebo-controlled trial. Lancet. 2015;386:2404-2412. doi: 10.1016/S0140-6736(15)00308-6

33. Lenze EJ, Oughli HA. Antidepressant treatment for late-life depression: considering risks and benefits. J Am Geriatr Soc. 2019;67:1555-1556. doi: 10.1111/jgs.15964

34. Bondareff W, Alpert M, Friedhoff AJ, et al: Comparison of sertraline and nortriptyline in the treatment of major depressive disorder in late life. Am J Psychiatry. 2000;157:729-736. doi: 10.1176/appi.ajp.157.5.729

35. Lavretsky H, Reinlieb M, St Cyr N. Citalopram, methylphenidate, or their combination in geriatric depression: a randomized, ­double-blind, placebo controlled trial. Am J Psych. 2015;72:561-569. doi: 10.1176/appi.ajp.2014.14070889

36. Arthur A, Savva GM, Barnes LE, et al. Changing prevalence and treatment of depression among older people over two decades. Br J Psychiatry. 2020;21:49-54. doi: 10.1192/bjp.2019.193

37. Zuidersma M, Chua K-C, Hellier J, et al. Sertraline and mirtazapine versus placebo in subgroups of depression in dementia: findings from the HTA-SADD randomized controlled trial. Am J Geriatr Psychiatry. 2019;27:920-931. doi: 10.1016/­ j.jagp.2019.03.021

38. Ochs-Ross R, Wajs E, Daly EJ, et al. Comparison of long-term efficacy and safety of esketamine nasal spray plus oral antidepressant in younger versus older patients with treatment-resistant depression: post-hoc analysis of SUSTAIN-2, a long-term open-label phase 3 safety and efficacy study. Am J Geriatr Psychiatry. 2022;30:541-556. doi: 10.1016/j.jagp.2021.09.014

39. Devanand DP, Pelton GH, D’Antonio K, et al. Donepezil treatment in patients with depression and cognitive impairment on stable antidepressant treatment: a randomized controlled trial. Am J Geriatr Psychiatry. 2018;26:1050-1060. doi: 10.1016/ j­.jagp.2018.05.008

40. Obbels J, Vansteelandt K, Verwijk E, et al. MMSE changes during and after ECT in late life depression: a prospective study. Am J Geriatr Psychiatry. 2019;27:934-944. doi: 10.1016/ j.jagp.2019.04.006

41. Wagenmakers MJ, Vansteelandt K, van Exel E, et al. Transient cognitive impairment and white matter hyperintensities in severely depressed older patients treated with electroconvulsive therapy. Am J Geriatr Psychiatry. 2021:29:1117-1128. doi: 10.1016/j.jagp.2020.12.028

42. Trevizol AP, Goldberger KW, Mulsant BH, et al. Unilateral and bilateral repetitive transcranial magnetic stimulation for treatment-resistant late-life depression. Int J Ger Psychiatry. 2019;34:822-827. doi: 10.1002/gps.5091

43. Aben I, Verhey F, Stik J, et al. A comparative study into the one year cumulative incidence of depression after stroke and myocardial infarction.  J Neurol Neurosurg Psychiatry. 2003;74:581-585. doi: 10.1136/jnnp.74.5.581

44. Gallo JJ, Bogner HR, Morales KH, et al. The effect of a primary care practice-based depression intervention on mortality in older adults: a randomized trial. Ann Intern Med. 2007;146:689-698. doi: 10.7326/0003-4819-146-10-200705150-00002

45. Lee J, Jang SN, Cho SL. Gender differences in the trajectories and the risk factors of depressive symptoms in later life. Int ­Psychogeriatr. 2017;29:1495-1505. doi: 10.1017/S1041610217000709

46. Lee E, Cho HJ, Olmstead R, et al. Persistent sleep disturbance: a risk factor for recurrent depression in community-dwelling older adults. Sleep. 2013;36:1685-1691. doi: 10.5665/sleep.3128

47. Berk M, Woods RL, Nelson MR, et al. Effect of aspirin vs placebo on the prevention of depression in older people: a randomized clinical trial.  J Am Med A Psych. 2020;77:1012-1020. doi: 10.1001/jamapsychiatry.2020.1214

48. Okereke OI, Reynolds CF, Mischoulon D, et al. Effect of long-term vitamin D3 supplementation vs placebo on risk of depression or clinically relevant depressive symptoms and on change in mood scores: a randomized clinical trial. JAMA. 2020;324:471-480. doi: 10.1001/jama.2020.10224

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Late-life depression is the onset of a major depressive disorder in an individual ≥ 60 years of age. Depressive illness compromises quality of life and is especially troublesome for older people. The prevalence of depression among individuals > 65 years of age is about 4% in women and 3% in men.1 The estimated lifetime prevalence is approximately 24% for women and 10% for men.2 Three factors account for this disparity: women exhibit greater susceptibility to depression; the illness persists longer in women than it does in men; and the probability of death related to depression is lower in women.2

Beyond its direct mental and emotional impacts, depression takes a financial toll; health care costs are higher for those with depression than for those without depression.3 Unpaid caregiver expense is the largest indirect financial burden with late-life depression.4 Additional indirect costs include less work productivity, early retirement, and diminished financial security.4

Many individuals with depression never receive treatment. Fortunately, there are many interventions in the primary care arsenal that can be used to treat older patients with depression and dramatically improve mood, comfort, and function.

The interactions of emotional and physical health

The pathophysiology of depression remains unclear. However, numerous factors are known to contribute to, exacerbate, or prolong depression among elderly populations. Insufficient social engagement and support is strongly associated with depressive mood.5 The loss of independence in giving up automobile driving can compromise self-confidence.6 Sleep difficulties predispose to, and predict, the emergence of a mood disorder, independent of other symptoms.7 Age-related hearing deficits also are associated with depression.8

There is a close relationship between emotional and physical health.9 Depression adds to the likelihood of medical illness, and somatic pathology increases the risk for mood disorders.9 Depression has been linked with obesity, frailty, diabetes, cognitive impairment, and terminal illness.9 Other conditions associated with depression include Parkinson disease, alcohol dependence,and chronic pain.10-12 Cerebrovascular disease may predispose to, precipitate, or perpetuate this mood disorder.13

Inflammatory markers and depression may also be related. Plasma levels of interleukin­-6 and C-reactive protein were measured in a longitudinal aging study.14 A high level of interleukin-6, but not C-reactive protein, correlated with an increased prevalence of depression in older people.

Escitalopram is often better tolerated than paroxetine and has fewer pharmaceutical interactions, compared with sertraline.

Chronic cerebral ischemia can result in a “vascular depression”13 in which disruption of prefrontal systems by ischemic lesions is hypothesized to be an important factor in developing despair. Psychomotor retardation, executive dysfunction, severe disability, and a heightened risk for relapse are common features of vascular depression.15 Poststroke depression often follows a cerebrovascular episode16; the exact pathogenic mechanism is unknown.17

Continue to: A summation of common risk factors

 

 

A summation of common risk factors. A personal or family history of depression increases the risk for late-life depression. Other risk factors are female gender, bereavement, sleep disturbance, and disability.18 Poor general health, chronic pain, cognitive impairment, poor social support, and medical comorbidities with impaired functioning increase the likelihood of resultant mood disorders.18

Somatic complaints may overshadow diagnostic symptoms

Manifestations of depression include disturbed sleep and reductions in appetite, concentration, activity, and energy for daily function.19 These features, of course, may accompany medical disorders and some normal physiologic changes among elderly people. We find that while older individuals may report a sad mood, disturbed sleep, or other dysfunctions, they frequently emphasize their somatic complaints much more prominently than their emotions. This can make it difficult to recognize clinical depression.

For a diagnosis of major depression, ­5 of the following 9 symptoms must be present for most of the day or nearly every day over a period of at least 2 weeks19: depressed mood; diminished interest in most activities; significant weight loss or decreased appetite; insomnia or hypersomnia; agitation or retardation; fatigue or loss of energy; feelings of worthlessness or guilt; diminished concentration; and recurrent thoughts of death or suicide.19

Planning difficulties, apathy, disability, and anhedonia frequently occur. Executive dysfunction and inefficacy of antidepressant pharmacotherapy are related to compromised frontal-striatal-limbic pathways.20 Since difficulties with planning and organization are associated with suboptimal response to antidepressant medications, a psychotherapeutic focus on these executive functions can augment drug-induced benefit.

Rule out these alternative diagnoses

Dementias can manifest as depression. Other brain pathologies, particularly Parkinson disease or stroke, also should be ruled out. Overmedication can simulate depression, so be sure to review the prescription and over-the-counter agents a patient is taking. Some medications can occasionally precipitate a clinical depression; these include stimulants, steroids, methyldopa, triptans, chemotherapeutic agents, and immunologic drugs, to name a few.19

Continue to: Pharmacotherapy, Yes, but first, consider these factors

 

 

Pharmacotherapy, Yes, but first, consider these factors

Maintaining a close patient–doctor relationship augments all therapeutic interventions. Good eye contact when listening to and counseling patients is key, as is providing close follow-up appointments.

Encourage social interactions with family and friends, which can be particularly productive. Encouraging spiritual endeavors, such as attendance at religious services, can be beneficial.21

Recommend exercise. Physical exercise yields positive outcomes22; it can enhance mood, improve sleep, and help to diminish anxiety. Encourage patients with depression to take a daily walk during the day; doing so can enhance emotional outlook, health, and even socialization.

What treatment will best serve your patient?

It’s important when caring for patients with depression to assess and address suicidal ideation. Depression with a previous suicide attempt is a strong risk factor for suicide. Inquire about suicidal intent or death wishes, access to guns, and other life-ending behaviors. Whenever suicide is an active issue, immediate crisis management is required. Psychiatric referral is an option, and hospitalization may be indicated. Advise family members to remove firearms or restrict access, be with the patient as much as possible, and assist at intervention planning and implementation.

It is worth mentioning, here, the connection between chronic pain and suicidal ideation. Pain management reduces suicidal ideation, regardless of depression severity.23 

Continue to: Psychotherapy and pharmacotherapies...

 

 

Psychotherapy and pharmacotherapies offered for the treatment of depression in geriatric practices are both effective, without much difference seen in efficacy.24 Psychotherapy might include direct physician and family support to the patient or referral to a mental health professional. Base treatment choices on clinical access, patient preference, and medical contraindications and other illnesses.

Pros and cons of various pharmacotherapies

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed first for elderly patients with depression.25 Escitalopram is often better tolerated than paroxetine, which exhibits muscarinic antagonism and enzyme inhibition of cytochrome P450-2D6.26 Escitalopram also has fewer pharmaceutical interactions compared with sertraline.26

Generally, when prescribing an antidepressant drug, stay with the initial choice, gradually increasing the dose as clinically needed to its maximum limit. Suicidal ideation may be worsened by too quickly switching from one antidepressant to another or by co-prescribing anxiolytic or hypnotic medicines. Benzodiazepines have addictive and disinhibiting properties and should be avoided, if possible.27 For patients withinsomnia, consider initially selecting a sedating antidepressant medication such as paroxetine or mirtazapine to augment sleep.

Alternatives to SSRIs. Nonselective serotonin reuptake inhibitors have similar efficacy as SSRIs. However, escitalopram is as effective as venlafaxine (a selective serotonin and norepinephrine reuptake inhibitor [SSNRI]) and is better tolerated.28 Duloxetine, another SSNRI, improves mood and often diminishes chronic pain.29 Mirtazapine, an alpha-2 antagonist, might cause fewer drug-drug interactions and is effective, well tolerated, and especially helpful for patients with anxiety or insomnia.30 Dry mouth, sedation, and weight gain are common adverse effects of mirtazapine. Obesity precautions are often necessary during mirtazapine therapy; this includes monitoring body weight and metabolic profiles, instituting dietary changes, and recommending an exercise regimen. In contrast to SSRIs, mirtazapine might induce less sexual dysfunction.31

Suicidal ideation may be worsened by too quickly switching from one antidepressant to another or by co-prescribing anxiolytic or hypnotic medicines.

Tricyclic antidepressant drugs can also be effective but may worsen cardiac conduction abnormalities, prostatic hypertrophy, or narrow angle glaucoma. Tricyclic antidepressants may be useful in patients without cardiac disease who have not responded to an SSRI or an SSNRI.

Continue to: The role of aripiprazole

 

 

The role of aripiprazole. Elderly patients not achieving remission from depression with antidepressant agents alone may benefit from co-prescribing aripiprazole.32 As an adjunct, aripiprazole is effective in achieving and sustaining remission, but it has the potential for less tolerability by inducing akathisia and parkinsonism.32

Minimize risks and maximize ­benefits of antidepressants by following these recommendations:

  1. Ascertain whether any antidepressant treatments have worked well in the past.
  2. Start with an SSRI if no other antidepressant treatment has worked in the past.
  3. Counsel patients about the need for treatment adherence. Antidepressants may take 2 weeks to 2 months to provide noticeable improvement.
  4. Prescribe up to the maximum drug dose if needed to enhance benefit.
  5. Use a mood measurement tool (eg, the Patient Health Questionnaire-9) to help evaluate treatment response.

Try a different class of drugs for patients who do not respond to treatment. For patients who have a partial response, augment with bupropion XL, mirtazapine, aripiprazole, or quetiapine.33 Sertraline and nortriptyline are similarly effective on a population-wide basis, with sertraline having less-problematic adverse effects.34 Trial-and-error treatments in practice may find one patient responding only to sertraline and another patient only to nortriptyline.

Transcranial magnetic stimulation is a promising, relatively new therapeutic option for treating refractory cases of depressive mood disorders.

Combinations of different drug classes may provide benefit for patients not responding to a single antidepressant. In geriatric patients, combined treatment with methylphenidate and citalopram enhances mood and well-being.35 Compared with either drug alone, the combination yielded an augmented clinical response profile and a higher rate of remission. Cognitive functioning, energy, and mood improve even with methylphenidate alone, especially when fatigue is an issue. However, addictive properties limit its use to cases in which conventional antidepressant medications are not effective or indicated, and only when drug refills are closely monitored.

The challenges of advancing age. Antidepressant treatment needs increase with advanced age.36 As mentioned earlier, elderly people often have medical illnesses complicating their depression and frequently are dealing with pain from the medical illness. When dementia coexists with depression, the efficacy of pharmacotherapies is compromised.

Continue to: When drug-related interventions fail

 

 

When drug-related interventions fail, therapy ought to be more psychologically focused.37 Psychotherapy is usually helpful and is particularly indicated when recovery is suboptimal. Counseling might come from the treating physician or referral to a psychotherapist.

Nasal esketamine can be efficacious when supplementing antidepressant pharmacotherapy among older patients with treatment-resistant depression.38 Elderly individuals responding to antidepressants do not benefit from adjunctive donepezil to correct mild cognitive impairment.39 There is no advantage to off-label cholinesterase inhibitor prescribing for patients with both depression and dementia.

Other options. Electroconvulsive therapy (ECT) does not cause long-term cognitive problems and is reserved for ­treatment-resistant cases.40 Patients with depression who also have had previous cognitive impairment often improve in mental ability following ECT.41

A promising new option. Transcranial magnetic stimulation (TMS) is a promising, relatively new therapeutic option for treating refractory cases of depressive mood disorders. In TMS, an electromagnetic coil that creates a magnetic field is placed over the left dorsolateral prefrontal cortex (which is responsible for mood regulation). Referral for TMS administration may offer new hope for older patients with treatment-resistant depression.42

Keep comorbidities in mind as you address depression

Coexisting psychiatric illnesses worsen emotions. Geriatric patients are susceptible to psychiatric comorbidities that include substance abuse, obsessive-compulsive characteristics, dysfunctional eating, and panic disorder.19 Myocardial and cerebral infarctions are detrimental to mental health, especially soon after such events.43 Poststroke depression magnifies the risk for disability and mortality,16,17 yet antidepressant pharmacotherapy often enhances prognoses. Along with early intervention algorithm-based plans and inclusion of a depression care manager, antidepressants often diminish poststroke depression severity.44 Even when cancer is present, depression care reduces mortality.44 So with this in mind, persist with antidepressant treatment, which will often benefit an elderly individual with depression.

Continue to: When possible, get ahead of depression before it sets in

 

 

When possible, get ahead of depression before it sets in

Social participation and employment help to sustain an optimistic, euthymic mood.45 Maintaining good physical health, in part through consistent activity levels (including exercise), can help prevent depression. Since persistent sleep disturbance predicts depression among those with a depression history, optimizing sleep among geriatric adults can avoid or alleviate depression.46

Low vitamin D levels can contribute to depression, yet vitamin D supplementation may not improve mood.

Sleep hygiene education for patients is also helpful. A regular waking time often promotes a better sleeping schedule. Restful sleep also is more likely when an individual avoids excess caffeine, exercises during the day, and uses the bed only for sleeping (not for listening to music or watching television).

Because inflammation may precede ­depression, anti-inflammatory medications have been proposed as potential treatment, but such pharmacotherapies are often ineffective. Older adults generally do not benefit from low-dose aspirin administration to prevent depression.47 Low vitamin D levels can contribute to depression, yet vitamin D supplementation may not improve mood.48

Offering hope. Tell your patients that if they are feeling depressed, they should make an appointment with you, their primary care physician, because there are medications they can take and counseling they can avail themselves of that could help.

CORRESPONDENCE
Steven Lippmann, MD, University of Louisville-Psychiatry, 401 East Chestnut Street, Suite 610, Louisville, KY 40202; steven.lippmann@louisville.edu.

Late-life depression is the onset of a major depressive disorder in an individual ≥ 60 years of age. Depressive illness compromises quality of life and is especially troublesome for older people. The prevalence of depression among individuals > 65 years of age is about 4% in women and 3% in men.1 The estimated lifetime prevalence is approximately 24% for women and 10% for men.2 Three factors account for this disparity: women exhibit greater susceptibility to depression; the illness persists longer in women than it does in men; and the probability of death related to depression is lower in women.2

Beyond its direct mental and emotional impacts, depression takes a financial toll; health care costs are higher for those with depression than for those without depression.3 Unpaid caregiver expense is the largest indirect financial burden with late-life depression.4 Additional indirect costs include less work productivity, early retirement, and diminished financial security.4

Many individuals with depression never receive treatment. Fortunately, there are many interventions in the primary care arsenal that can be used to treat older patients with depression and dramatically improve mood, comfort, and function.

The interactions of emotional and physical health

The pathophysiology of depression remains unclear. However, numerous factors are known to contribute to, exacerbate, or prolong depression among elderly populations. Insufficient social engagement and support is strongly associated with depressive mood.5 The loss of independence in giving up automobile driving can compromise self-confidence.6 Sleep difficulties predispose to, and predict, the emergence of a mood disorder, independent of other symptoms.7 Age-related hearing deficits also are associated with depression.8

There is a close relationship between emotional and physical health.9 Depression adds to the likelihood of medical illness, and somatic pathology increases the risk for mood disorders.9 Depression has been linked with obesity, frailty, diabetes, cognitive impairment, and terminal illness.9 Other conditions associated with depression include Parkinson disease, alcohol dependence,and chronic pain.10-12 Cerebrovascular disease may predispose to, precipitate, or perpetuate this mood disorder.13

Inflammatory markers and depression may also be related. Plasma levels of interleukin­-6 and C-reactive protein were measured in a longitudinal aging study.14 A high level of interleukin-6, but not C-reactive protein, correlated with an increased prevalence of depression in older people.

Escitalopram is often better tolerated than paroxetine and has fewer pharmaceutical interactions, compared with sertraline.

Chronic cerebral ischemia can result in a “vascular depression”13 in which disruption of prefrontal systems by ischemic lesions is hypothesized to be an important factor in developing despair. Psychomotor retardation, executive dysfunction, severe disability, and a heightened risk for relapse are common features of vascular depression.15 Poststroke depression often follows a cerebrovascular episode16; the exact pathogenic mechanism is unknown.17

Continue to: A summation of common risk factors

 

 

A summation of common risk factors. A personal or family history of depression increases the risk for late-life depression. Other risk factors are female gender, bereavement, sleep disturbance, and disability.18 Poor general health, chronic pain, cognitive impairment, poor social support, and medical comorbidities with impaired functioning increase the likelihood of resultant mood disorders.18

Somatic complaints may overshadow diagnostic symptoms

Manifestations of depression include disturbed sleep and reductions in appetite, concentration, activity, and energy for daily function.19 These features, of course, may accompany medical disorders and some normal physiologic changes among elderly people. We find that while older individuals may report a sad mood, disturbed sleep, or other dysfunctions, they frequently emphasize their somatic complaints much more prominently than their emotions. This can make it difficult to recognize clinical depression.

For a diagnosis of major depression, ­5 of the following 9 symptoms must be present for most of the day or nearly every day over a period of at least 2 weeks19: depressed mood; diminished interest in most activities; significant weight loss or decreased appetite; insomnia or hypersomnia; agitation or retardation; fatigue or loss of energy; feelings of worthlessness or guilt; diminished concentration; and recurrent thoughts of death or suicide.19

Planning difficulties, apathy, disability, and anhedonia frequently occur. Executive dysfunction and inefficacy of antidepressant pharmacotherapy are related to compromised frontal-striatal-limbic pathways.20 Since difficulties with planning and organization are associated with suboptimal response to antidepressant medications, a psychotherapeutic focus on these executive functions can augment drug-induced benefit.

Rule out these alternative diagnoses

Dementias can manifest as depression. Other brain pathologies, particularly Parkinson disease or stroke, also should be ruled out. Overmedication can simulate depression, so be sure to review the prescription and over-the-counter agents a patient is taking. Some medications can occasionally precipitate a clinical depression; these include stimulants, steroids, methyldopa, triptans, chemotherapeutic agents, and immunologic drugs, to name a few.19

Continue to: Pharmacotherapy, Yes, but first, consider these factors

 

 

Pharmacotherapy, Yes, but first, consider these factors

Maintaining a close patient–doctor relationship augments all therapeutic interventions. Good eye contact when listening to and counseling patients is key, as is providing close follow-up appointments.

Encourage social interactions with family and friends, which can be particularly productive. Encouraging spiritual endeavors, such as attendance at religious services, can be beneficial.21

Recommend exercise. Physical exercise yields positive outcomes22; it can enhance mood, improve sleep, and help to diminish anxiety. Encourage patients with depression to take a daily walk during the day; doing so can enhance emotional outlook, health, and even socialization.

What treatment will best serve your patient?

It’s important when caring for patients with depression to assess and address suicidal ideation. Depression with a previous suicide attempt is a strong risk factor for suicide. Inquire about suicidal intent or death wishes, access to guns, and other life-ending behaviors. Whenever suicide is an active issue, immediate crisis management is required. Psychiatric referral is an option, and hospitalization may be indicated. Advise family members to remove firearms or restrict access, be with the patient as much as possible, and assist at intervention planning and implementation.

It is worth mentioning, here, the connection between chronic pain and suicidal ideation. Pain management reduces suicidal ideation, regardless of depression severity.23 

Continue to: Psychotherapy and pharmacotherapies...

 

 

Psychotherapy and pharmacotherapies offered for the treatment of depression in geriatric practices are both effective, without much difference seen in efficacy.24 Psychotherapy might include direct physician and family support to the patient or referral to a mental health professional. Base treatment choices on clinical access, patient preference, and medical contraindications and other illnesses.

Pros and cons of various pharmacotherapies

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed first for elderly patients with depression.25 Escitalopram is often better tolerated than paroxetine, which exhibits muscarinic antagonism and enzyme inhibition of cytochrome P450-2D6.26 Escitalopram also has fewer pharmaceutical interactions compared with sertraline.26

Generally, when prescribing an antidepressant drug, stay with the initial choice, gradually increasing the dose as clinically needed to its maximum limit. Suicidal ideation may be worsened by too quickly switching from one antidepressant to another or by co-prescribing anxiolytic or hypnotic medicines. Benzodiazepines have addictive and disinhibiting properties and should be avoided, if possible.27 For patients withinsomnia, consider initially selecting a sedating antidepressant medication such as paroxetine or mirtazapine to augment sleep.

Alternatives to SSRIs. Nonselective serotonin reuptake inhibitors have similar efficacy as SSRIs. However, escitalopram is as effective as venlafaxine (a selective serotonin and norepinephrine reuptake inhibitor [SSNRI]) and is better tolerated.28 Duloxetine, another SSNRI, improves mood and often diminishes chronic pain.29 Mirtazapine, an alpha-2 antagonist, might cause fewer drug-drug interactions and is effective, well tolerated, and especially helpful for patients with anxiety or insomnia.30 Dry mouth, sedation, and weight gain are common adverse effects of mirtazapine. Obesity precautions are often necessary during mirtazapine therapy; this includes monitoring body weight and metabolic profiles, instituting dietary changes, and recommending an exercise regimen. In contrast to SSRIs, mirtazapine might induce less sexual dysfunction.31

Suicidal ideation may be worsened by too quickly switching from one antidepressant to another or by co-prescribing anxiolytic or hypnotic medicines.

Tricyclic antidepressant drugs can also be effective but may worsen cardiac conduction abnormalities, prostatic hypertrophy, or narrow angle glaucoma. Tricyclic antidepressants may be useful in patients without cardiac disease who have not responded to an SSRI or an SSNRI.

Continue to: The role of aripiprazole

 

 

The role of aripiprazole. Elderly patients not achieving remission from depression with antidepressant agents alone may benefit from co-prescribing aripiprazole.32 As an adjunct, aripiprazole is effective in achieving and sustaining remission, but it has the potential for less tolerability by inducing akathisia and parkinsonism.32

Minimize risks and maximize ­benefits of antidepressants by following these recommendations:

  1. Ascertain whether any antidepressant treatments have worked well in the past.
  2. Start with an SSRI if no other antidepressant treatment has worked in the past.
  3. Counsel patients about the need for treatment adherence. Antidepressants may take 2 weeks to 2 months to provide noticeable improvement.
  4. Prescribe up to the maximum drug dose if needed to enhance benefit.
  5. Use a mood measurement tool (eg, the Patient Health Questionnaire-9) to help evaluate treatment response.

Try a different class of drugs for patients who do not respond to treatment. For patients who have a partial response, augment with bupropion XL, mirtazapine, aripiprazole, or quetiapine.33 Sertraline and nortriptyline are similarly effective on a population-wide basis, with sertraline having less-problematic adverse effects.34 Trial-and-error treatments in practice may find one patient responding only to sertraline and another patient only to nortriptyline.

Transcranial magnetic stimulation is a promising, relatively new therapeutic option for treating refractory cases of depressive mood disorders.

Combinations of different drug classes may provide benefit for patients not responding to a single antidepressant. In geriatric patients, combined treatment with methylphenidate and citalopram enhances mood and well-being.35 Compared with either drug alone, the combination yielded an augmented clinical response profile and a higher rate of remission. Cognitive functioning, energy, and mood improve even with methylphenidate alone, especially when fatigue is an issue. However, addictive properties limit its use to cases in which conventional antidepressant medications are not effective or indicated, and only when drug refills are closely monitored.

The challenges of advancing age. Antidepressant treatment needs increase with advanced age.36 As mentioned earlier, elderly people often have medical illnesses complicating their depression and frequently are dealing with pain from the medical illness. When dementia coexists with depression, the efficacy of pharmacotherapies is compromised.

Continue to: When drug-related interventions fail

 

 

When drug-related interventions fail, therapy ought to be more psychologically focused.37 Psychotherapy is usually helpful and is particularly indicated when recovery is suboptimal. Counseling might come from the treating physician or referral to a psychotherapist.

Nasal esketamine can be efficacious when supplementing antidepressant pharmacotherapy among older patients with treatment-resistant depression.38 Elderly individuals responding to antidepressants do not benefit from adjunctive donepezil to correct mild cognitive impairment.39 There is no advantage to off-label cholinesterase inhibitor prescribing for patients with both depression and dementia.

Other options. Electroconvulsive therapy (ECT) does not cause long-term cognitive problems and is reserved for ­treatment-resistant cases.40 Patients with depression who also have had previous cognitive impairment often improve in mental ability following ECT.41

A promising new option. Transcranial magnetic stimulation (TMS) is a promising, relatively new therapeutic option for treating refractory cases of depressive mood disorders. In TMS, an electromagnetic coil that creates a magnetic field is placed over the left dorsolateral prefrontal cortex (which is responsible for mood regulation). Referral for TMS administration may offer new hope for older patients with treatment-resistant depression.42

Keep comorbidities in mind as you address depression

Coexisting psychiatric illnesses worsen emotions. Geriatric patients are susceptible to psychiatric comorbidities that include substance abuse, obsessive-compulsive characteristics, dysfunctional eating, and panic disorder.19 Myocardial and cerebral infarctions are detrimental to mental health, especially soon after such events.43 Poststroke depression magnifies the risk for disability and mortality,16,17 yet antidepressant pharmacotherapy often enhances prognoses. Along with early intervention algorithm-based plans and inclusion of a depression care manager, antidepressants often diminish poststroke depression severity.44 Even when cancer is present, depression care reduces mortality.44 So with this in mind, persist with antidepressant treatment, which will often benefit an elderly individual with depression.

Continue to: When possible, get ahead of depression before it sets in

 

 

When possible, get ahead of depression before it sets in

Social participation and employment help to sustain an optimistic, euthymic mood.45 Maintaining good physical health, in part through consistent activity levels (including exercise), can help prevent depression. Since persistent sleep disturbance predicts depression among those with a depression history, optimizing sleep among geriatric adults can avoid or alleviate depression.46

Low vitamin D levels can contribute to depression, yet vitamin D supplementation may not improve mood.

Sleep hygiene education for patients is also helpful. A regular waking time often promotes a better sleeping schedule. Restful sleep also is more likely when an individual avoids excess caffeine, exercises during the day, and uses the bed only for sleeping (not for listening to music or watching television).

Because inflammation may precede ­depression, anti-inflammatory medications have been proposed as potential treatment, but such pharmacotherapies are often ineffective. Older adults generally do not benefit from low-dose aspirin administration to prevent depression.47 Low vitamin D levels can contribute to depression, yet vitamin D supplementation may not improve mood.48

Offering hope. Tell your patients that if they are feeling depressed, they should make an appointment with you, their primary care physician, because there are medications they can take and counseling they can avail themselves of that could help.

CORRESPONDENCE
Steven Lippmann, MD, University of Louisville-Psychiatry, 401 East Chestnut Street, Suite 610, Louisville, KY 40202; steven.lippmann@louisville.edu.

References

1. Steffens DC, Skoog I, Norton MC, et al. Prevalence of depression and its treatment in an elderly population: the Cache County study. Arch Gen Psych. 2000;57:601-607. doi: 10.1001/ archpsyc.57.6.601

2. Barry LC, Allore HG, Guo Z, et al. Higher burden of depression among older women: the effect of onset, persistence, and mortality over time. Arch Gen Psych. 2008;65:172-178. doi: 10.1001/archgenpsychiatry.2007.17

3. Katon WJ, Lin E, Russo J, et al. Increased medical costs of a ­population-based sample of depressed elderly patients. Arch Gen Psych. 2003;60:897-903. doi: 10.1001/archpsyc.60.9.897

4. Snow CE, Abrams RC. The indirect costs of late-life depression in the United States: a literature review and perspective. Geriatrics. 2016;1,30. doi.org/10.3390/geriatrics/1040030 

5. George LK, Blazer DG, Hughes D, et al. Social support and the outcome of major depression.  Br J Psych. 1989;154:478-485. doi: 10.1192/bjp.154.4.478

6. Fonda SJ, Wallace RB, Herzog AR. Changes in driving patterns and worsening depressive symptoms among older adults. ­­ J Gerontol Psychol Soc Sci. 2001;56:S343-S351. doi: 10.1093/geronb/56.6.s343

7. Cho HJ, Lavretsky H, Olmstead R, et al. Sleep disturbance and depression recurrence in community dwelling older adults—a prospective study. Am J Psych. 2008;165:1543-1550. doi: 10.1176/appi.ajp.2008.07121882

8. Golub JS, Brewster KK, Brickman AM, et al. Subclinical hearing loss is associated with depressive symptoms. Am J Geriatr Psychiatry. 2020;28:545-556. doi: 10.1016/j.jagp.2019.12.008

9. Alexopoulos GS. Mechanisms and treatment of late-life depression.  Focus (Am Psychiatr Publ). 2021;19:340-354. doi: 10.1176/appi.focus.19304

10. Starkstein SE, Preziosi TJ, Bolduc PL, et al. Depression in Parkinson’s disease.  J Nerv Ment Disord. 1990;178:27-31. doi: 10.1097/00005053-199001000-00005

11. Gilman SE, Abraham HE. A longitudinal study of the order of onset of alcohol dependence and major depression. Drug Alco Depend. 2001;63:277-286. doi: 10.1016/s0376-8716(00)00216-7

12. Parmelee PA, Katz IR, Lawton MP. The relation of pain to depression among institutionalized aged. J Gerontol. 1991;46:P15-P21. doi: 10.1093/geronj/46.1.p15

13. Alexopoulos GS, Meyers BS, Young RC, et al. ‘Vascular depression’ hypothesis. Arch Gen Psych. 1997;54:915-922. doi: 10.1001/archpsyc.1997.01830220033006

14. Bremmer MA, Beekman AT, Deeg DJ, et al. Inflammatory markers in late-life depression: results from a population-based study. J Affect Disord. 2008;106:249-255. doi: 10.1016/j.jad.2007.07.002

15. Taylor WD, Aizenstein HJ, Alexopoulos GS. The vascular depression hypothesis: mechanisms linking vascular disease with depression. Mol Psych. 2013;18:963-974. doi: 10.1038/mp.2013.20

16. Robinson RG, Jorge RE. Post-stroke depression: a review. Am J Psych. 2016;173:221-231. doi: 10.1176/appi.ajp.2015.15030363

17. Cai W, Mueller C, Li YJ, et al. Post stroke depression and risk of stroke recurrence and mortality: a systematic review and meta-analysis. Ageing Res Rev. 2019;50:102-109. doi: 10.1016/ j.arr.2019.01.013

18. Cole MG, Dendukuri N. Risk factors for depression among elderly community subjects: a systematic review and meta-analysis. Am J Psych. 2003;160:1147-1156. doi: 10.1176/appi.ajp.160.6.1147

19. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). 2013:160-168.

20. Pimontel MA, Rindskopf D, Rutherford BR, et al. A meta-analysis of executive dysfunction and antidepressant treatment response in late-life depression. Am J Geriatr Psych. 2016;24:31-34. doi: 10.1016/j.jagp.2015.05.010

21. Koenig HG, Cohen HJ, Blazer DG, et al. Religious coping and depression in elderly hospitalized medically ill men. Am J Psychiatry. 1992;149:1693-1700. doi: 10.1176/ajp.149.12.1693

22. Blake H, Mo P, Malik S, et al. How effective are physical activity interventions for alleviating depressive symptoms in older people? A systematic review. Clin Rehabil. 2009;10:873-887. doi: 10.1177/0269215509337449

23. Bruce ML, Ten Have TR, Reynolds CF, et al. Reducing suicidal and depressive symptoms in depressed older primary care patients: a randomized controlled trial. JAMA. 2004;291:1081-1091. doi: 10.1001/jama.291.9.1081

24. Pinquart M, Duberstein PR, Lyness JM. Treatments for later-life depressive conditions: a meta-analytic comparison of pharmacotherapy and psychotherapy. Am J Psychiatry. 2006;163:1493-1501. doi: 10.1176/ajp.2006.163.9.1493

25. Solai LK, Mulsant BH, Pollack BG. Selective serotonin reuptake inhibitors for late-life depression: a comparative review. Drugs Aging. 2001;18:355-368. doi: 10.2165/00002512-200118050-00006

26. Sanchez C, Reines EH, Montgomery SA. A comparative review of escitalopram, paroxetine, and sertraline. Are they all alike? Int Clin Psychopharmacol. 2014;29:185-196. doi: 10.1097/YIC.0000000000000023

27. Hedna K, Sundell KA, Hamidi A, et al. Antidepressants and suicidal behaviour in late life: a prospective population-based study of use patterns in new users aged 75 and above. Eur J Clin ­Pharmacol. 2018;74:201-208. doi: 10.1007/s00228-017-2360-x

28. Bielski RJ, Ventura D, Chang CC. A double-blind comparison of escitalopram and venlafaxine extended release in the treatment of major depressive disorder. J Clin Psychiatry. 2004;65:1190-1196. doi: 10.4088/jcp.v65n0906

29. Robinson M, Oakes TM, Raskin J, et al. Acute and long-term treatment of late-life major depressive disorder: duloxetine versus placebo. Am J Geriatr Psychiatry. 2014;22:34-45. doi: 10.1016/ j.jagp.2013.01.019

30. Holm KJ, Markham A. Mirtazapine: a review of its use in major depression. Drugs. 1999;57:607-631. doi: 10.2165/00003495-199957040-00010

31. Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev. 2001;7:249-264. doi: 10.1111/j.1527-3458.2001.tb00198.x

32. Lenze EJ, Mulsant BH, Blumberger DM, et al. Efficacy, safety and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised ­double-blind, placebo-controlled trial. Lancet. 2015;386:2404-2412. doi: 10.1016/S0140-6736(15)00308-6

33. Lenze EJ, Oughli HA. Antidepressant treatment for late-life depression: considering risks and benefits. J Am Geriatr Soc. 2019;67:1555-1556. doi: 10.1111/jgs.15964

34. Bondareff W, Alpert M, Friedhoff AJ, et al: Comparison of sertraline and nortriptyline in the treatment of major depressive disorder in late life. Am J Psychiatry. 2000;157:729-736. doi: 10.1176/appi.ajp.157.5.729

35. Lavretsky H, Reinlieb M, St Cyr N. Citalopram, methylphenidate, or their combination in geriatric depression: a randomized, ­double-blind, placebo controlled trial. Am J Psych. 2015;72:561-569. doi: 10.1176/appi.ajp.2014.14070889

36. Arthur A, Savva GM, Barnes LE, et al. Changing prevalence and treatment of depression among older people over two decades. Br J Psychiatry. 2020;21:49-54. doi: 10.1192/bjp.2019.193

37. Zuidersma M, Chua K-C, Hellier J, et al. Sertraline and mirtazapine versus placebo in subgroups of depression in dementia: findings from the HTA-SADD randomized controlled trial. Am J Geriatr Psychiatry. 2019;27:920-931. doi: 10.1016/­ j.jagp.2019.03.021

38. Ochs-Ross R, Wajs E, Daly EJ, et al. Comparison of long-term efficacy and safety of esketamine nasal spray plus oral antidepressant in younger versus older patients with treatment-resistant depression: post-hoc analysis of SUSTAIN-2, a long-term open-label phase 3 safety and efficacy study. Am J Geriatr Psychiatry. 2022;30:541-556. doi: 10.1016/j.jagp.2021.09.014

39. Devanand DP, Pelton GH, D’Antonio K, et al. Donepezil treatment in patients with depression and cognitive impairment on stable antidepressant treatment: a randomized controlled trial. Am J Geriatr Psychiatry. 2018;26:1050-1060. doi: 10.1016/ j­.jagp.2018.05.008

40. Obbels J, Vansteelandt K, Verwijk E, et al. MMSE changes during and after ECT in late life depression: a prospective study. Am J Geriatr Psychiatry. 2019;27:934-944. doi: 10.1016/ j.jagp.2019.04.006

41. Wagenmakers MJ, Vansteelandt K, van Exel E, et al. Transient cognitive impairment and white matter hyperintensities in severely depressed older patients treated with electroconvulsive therapy. Am J Geriatr Psychiatry. 2021:29:1117-1128. doi: 10.1016/j.jagp.2020.12.028

42. Trevizol AP, Goldberger KW, Mulsant BH, et al. Unilateral and bilateral repetitive transcranial magnetic stimulation for treatment-resistant late-life depression. Int J Ger Psychiatry. 2019;34:822-827. doi: 10.1002/gps.5091

43. Aben I, Verhey F, Stik J, et al. A comparative study into the one year cumulative incidence of depression after stroke and myocardial infarction.  J Neurol Neurosurg Psychiatry. 2003;74:581-585. doi: 10.1136/jnnp.74.5.581

44. Gallo JJ, Bogner HR, Morales KH, et al. The effect of a primary care practice-based depression intervention on mortality in older adults: a randomized trial. Ann Intern Med. 2007;146:689-698. doi: 10.7326/0003-4819-146-10-200705150-00002

45. Lee J, Jang SN, Cho SL. Gender differences in the trajectories and the risk factors of depressive symptoms in later life. Int ­Psychogeriatr. 2017;29:1495-1505. doi: 10.1017/S1041610217000709

46. Lee E, Cho HJ, Olmstead R, et al. Persistent sleep disturbance: a risk factor for recurrent depression in community-dwelling older adults. Sleep. 2013;36:1685-1691. doi: 10.5665/sleep.3128

47. Berk M, Woods RL, Nelson MR, et al. Effect of aspirin vs placebo on the prevention of depression in older people: a randomized clinical trial.  J Am Med A Psych. 2020;77:1012-1020. doi: 10.1001/jamapsychiatry.2020.1214

48. Okereke OI, Reynolds CF, Mischoulon D, et al. Effect of long-term vitamin D3 supplementation vs placebo on risk of depression or clinically relevant depressive symptoms and on change in mood scores: a randomized clinical trial. JAMA. 2020;324:471-480. doi: 10.1001/jama.2020.10224

References

1. Steffens DC, Skoog I, Norton MC, et al. Prevalence of depression and its treatment in an elderly population: the Cache County study. Arch Gen Psych. 2000;57:601-607. doi: 10.1001/ archpsyc.57.6.601

2. Barry LC, Allore HG, Guo Z, et al. Higher burden of depression among older women: the effect of onset, persistence, and mortality over time. Arch Gen Psych. 2008;65:172-178. doi: 10.1001/archgenpsychiatry.2007.17

3. Katon WJ, Lin E, Russo J, et al. Increased medical costs of a ­population-based sample of depressed elderly patients. Arch Gen Psych. 2003;60:897-903. doi: 10.1001/archpsyc.60.9.897

4. Snow CE, Abrams RC. The indirect costs of late-life depression in the United States: a literature review and perspective. Geriatrics. 2016;1,30. doi.org/10.3390/geriatrics/1040030 

5. George LK, Blazer DG, Hughes D, et al. Social support and the outcome of major depression.  Br J Psych. 1989;154:478-485. doi: 10.1192/bjp.154.4.478

6. Fonda SJ, Wallace RB, Herzog AR. Changes in driving patterns and worsening depressive symptoms among older adults. ­­ J Gerontol Psychol Soc Sci. 2001;56:S343-S351. doi: 10.1093/geronb/56.6.s343

7. Cho HJ, Lavretsky H, Olmstead R, et al. Sleep disturbance and depression recurrence in community dwelling older adults—a prospective study. Am J Psych. 2008;165:1543-1550. doi: 10.1176/appi.ajp.2008.07121882

8. Golub JS, Brewster KK, Brickman AM, et al. Subclinical hearing loss is associated with depressive symptoms. Am J Geriatr Psychiatry. 2020;28:545-556. doi: 10.1016/j.jagp.2019.12.008

9. Alexopoulos GS. Mechanisms and treatment of late-life depression.  Focus (Am Psychiatr Publ). 2021;19:340-354. doi: 10.1176/appi.focus.19304

10. Starkstein SE, Preziosi TJ, Bolduc PL, et al. Depression in Parkinson’s disease.  J Nerv Ment Disord. 1990;178:27-31. doi: 10.1097/00005053-199001000-00005

11. Gilman SE, Abraham HE. A longitudinal study of the order of onset of alcohol dependence and major depression. Drug Alco Depend. 2001;63:277-286. doi: 10.1016/s0376-8716(00)00216-7

12. Parmelee PA, Katz IR, Lawton MP. The relation of pain to depression among institutionalized aged. J Gerontol. 1991;46:P15-P21. doi: 10.1093/geronj/46.1.p15

13. Alexopoulos GS, Meyers BS, Young RC, et al. ‘Vascular depression’ hypothesis. Arch Gen Psych. 1997;54:915-922. doi: 10.1001/archpsyc.1997.01830220033006

14. Bremmer MA, Beekman AT, Deeg DJ, et al. Inflammatory markers in late-life depression: results from a population-based study. J Affect Disord. 2008;106:249-255. doi: 10.1016/j.jad.2007.07.002

15. Taylor WD, Aizenstein HJ, Alexopoulos GS. The vascular depression hypothesis: mechanisms linking vascular disease with depression. Mol Psych. 2013;18:963-974. doi: 10.1038/mp.2013.20

16. Robinson RG, Jorge RE. Post-stroke depression: a review. Am J Psych. 2016;173:221-231. doi: 10.1176/appi.ajp.2015.15030363

17. Cai W, Mueller C, Li YJ, et al. Post stroke depression and risk of stroke recurrence and mortality: a systematic review and meta-analysis. Ageing Res Rev. 2019;50:102-109. doi: 10.1016/ j.arr.2019.01.013

18. Cole MG, Dendukuri N. Risk factors for depression among elderly community subjects: a systematic review and meta-analysis. Am J Psych. 2003;160:1147-1156. doi: 10.1176/appi.ajp.160.6.1147

19. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). 2013:160-168.

20. Pimontel MA, Rindskopf D, Rutherford BR, et al. A meta-analysis of executive dysfunction and antidepressant treatment response in late-life depression. Am J Geriatr Psych. 2016;24:31-34. doi: 10.1016/j.jagp.2015.05.010

21. Koenig HG, Cohen HJ, Blazer DG, et al. Religious coping and depression in elderly hospitalized medically ill men. Am J Psychiatry. 1992;149:1693-1700. doi: 10.1176/ajp.149.12.1693

22. Blake H, Mo P, Malik S, et al. How effective are physical activity interventions for alleviating depressive symptoms in older people? A systematic review. Clin Rehabil. 2009;10:873-887. doi: 10.1177/0269215509337449

23. Bruce ML, Ten Have TR, Reynolds CF, et al. Reducing suicidal and depressive symptoms in depressed older primary care patients: a randomized controlled trial. JAMA. 2004;291:1081-1091. doi: 10.1001/jama.291.9.1081

24. Pinquart M, Duberstein PR, Lyness JM. Treatments for later-life depressive conditions: a meta-analytic comparison of pharmacotherapy and psychotherapy. Am J Psychiatry. 2006;163:1493-1501. doi: 10.1176/ajp.2006.163.9.1493

25. Solai LK, Mulsant BH, Pollack BG. Selective serotonin reuptake inhibitors for late-life depression: a comparative review. Drugs Aging. 2001;18:355-368. doi: 10.2165/00002512-200118050-00006

26. Sanchez C, Reines EH, Montgomery SA. A comparative review of escitalopram, paroxetine, and sertraline. Are they all alike? Int Clin Psychopharmacol. 2014;29:185-196. doi: 10.1097/YIC.0000000000000023

27. Hedna K, Sundell KA, Hamidi A, et al. Antidepressants and suicidal behaviour in late life: a prospective population-based study of use patterns in new users aged 75 and above. Eur J Clin ­Pharmacol. 2018;74:201-208. doi: 10.1007/s00228-017-2360-x

28. Bielski RJ, Ventura D, Chang CC. A double-blind comparison of escitalopram and venlafaxine extended release in the treatment of major depressive disorder. J Clin Psychiatry. 2004;65:1190-1196. doi: 10.4088/jcp.v65n0906

29. Robinson M, Oakes TM, Raskin J, et al. Acute and long-term treatment of late-life major depressive disorder: duloxetine versus placebo. Am J Geriatr Psychiatry. 2014;22:34-45. doi: 10.1016/ j.jagp.2013.01.019

30. Holm KJ, Markham A. Mirtazapine: a review of its use in major depression. Drugs. 1999;57:607-631. doi: 10.2165/00003495-199957040-00010

31. Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev. 2001;7:249-264. doi: 10.1111/j.1527-3458.2001.tb00198.x

32. Lenze EJ, Mulsant BH, Blumberger DM, et al. Efficacy, safety and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised ­double-blind, placebo-controlled trial. Lancet. 2015;386:2404-2412. doi: 10.1016/S0140-6736(15)00308-6

33. Lenze EJ, Oughli HA. Antidepressant treatment for late-life depression: considering risks and benefits. J Am Geriatr Soc. 2019;67:1555-1556. doi: 10.1111/jgs.15964

34. Bondareff W, Alpert M, Friedhoff AJ, et al: Comparison of sertraline and nortriptyline in the treatment of major depressive disorder in late life. Am J Psychiatry. 2000;157:729-736. doi: 10.1176/appi.ajp.157.5.729

35. Lavretsky H, Reinlieb M, St Cyr N. Citalopram, methylphenidate, or their combination in geriatric depression: a randomized, ­double-blind, placebo controlled trial. Am J Psych. 2015;72:561-569. doi: 10.1176/appi.ajp.2014.14070889

36. Arthur A, Savva GM, Barnes LE, et al. Changing prevalence and treatment of depression among older people over two decades. Br J Psychiatry. 2020;21:49-54. doi: 10.1192/bjp.2019.193

37. Zuidersma M, Chua K-C, Hellier J, et al. Sertraline and mirtazapine versus placebo in subgroups of depression in dementia: findings from the HTA-SADD randomized controlled trial. Am J Geriatr Psychiatry. 2019;27:920-931. doi: 10.1016/­ j.jagp.2019.03.021

38. Ochs-Ross R, Wajs E, Daly EJ, et al. Comparison of long-term efficacy and safety of esketamine nasal spray plus oral antidepressant in younger versus older patients with treatment-resistant depression: post-hoc analysis of SUSTAIN-2, a long-term open-label phase 3 safety and efficacy study. Am J Geriatr Psychiatry. 2022;30:541-556. doi: 10.1016/j.jagp.2021.09.014

39. Devanand DP, Pelton GH, D’Antonio K, et al. Donepezil treatment in patients with depression and cognitive impairment on stable antidepressant treatment: a randomized controlled trial. Am J Geriatr Psychiatry. 2018;26:1050-1060. doi: 10.1016/ j­.jagp.2018.05.008

40. Obbels J, Vansteelandt K, Verwijk E, et al. MMSE changes during and after ECT in late life depression: a prospective study. Am J Geriatr Psychiatry. 2019;27:934-944. doi: 10.1016/ j.jagp.2019.04.006

41. Wagenmakers MJ, Vansteelandt K, van Exel E, et al. Transient cognitive impairment and white matter hyperintensities in severely depressed older patients treated with electroconvulsive therapy. Am J Geriatr Psychiatry. 2021:29:1117-1128. doi: 10.1016/j.jagp.2020.12.028

42. Trevizol AP, Goldberger KW, Mulsant BH, et al. Unilateral and bilateral repetitive transcranial magnetic stimulation for treatment-resistant late-life depression. Int J Ger Psychiatry. 2019;34:822-827. doi: 10.1002/gps.5091

43. Aben I, Verhey F, Stik J, et al. A comparative study into the one year cumulative incidence of depression after stroke and myocardial infarction.  J Neurol Neurosurg Psychiatry. 2003;74:581-585. doi: 10.1136/jnnp.74.5.581

44. Gallo JJ, Bogner HR, Morales KH, et al. The effect of a primary care practice-based depression intervention on mortality in older adults: a randomized trial. Ann Intern Med. 2007;146:689-698. doi: 10.7326/0003-4819-146-10-200705150-00002

45. Lee J, Jang SN, Cho SL. Gender differences in the trajectories and the risk factors of depressive symptoms in later life. Int ­Psychogeriatr. 2017;29:1495-1505. doi: 10.1017/S1041610217000709

46. Lee E, Cho HJ, Olmstead R, et al. Persistent sleep disturbance: a risk factor for recurrent depression in community-dwelling older adults. Sleep. 2013;36:1685-1691. doi: 10.5665/sleep.3128

47. Berk M, Woods RL, Nelson MR, et al. Effect of aspirin vs placebo on the prevention of depression in older people: a randomized clinical trial.  J Am Med A Psych. 2020;77:1012-1020. doi: 10.1001/jamapsychiatry.2020.1214

48. Okereke OI, Reynolds CF, Mischoulon D, et al. Effect of long-term vitamin D3 supplementation vs placebo on risk of depression or clinically relevant depressive symptoms and on change in mood scores: a randomized clinical trial. JAMA. 2020;324:471-480. doi: 10.1001/jama.2020.10224

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PRACTICE RECOMMENDATIONS

› Begin treatment with a selective serotonin reuptake inhibitor (SSRI) unless another antidepressant has worked well in the past. A

› Consider augmenting therapy with bupropion XL, mirtazapine, aripiprazole, or quetiapine for any patient who responds only partially to an SSRI. C

› Add psychotherapy to antidepressant pharmacotherapy, particularly for patients who have difficulties with executive functions such as planning and organization. B

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A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

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Depression and Bipolar Disorders in Patients With Alcohol Use Disorders (FULL)

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Depression and Bipolar Disorders in Patients With Alcohol Use Disorders
This review details methods for meeting the challenges of diagnosing and treating mood disorders that coexist with substance use disorders.

Co-occurrence of depression and substance abuse often poses diagnostic and therapeutic challenges. This article reviews the prevalence, clinical considerations, and treatment of depression coexisting with alcohol use disorders (AUDs).

Prevalence

Mood and substance use disorders (SUDs) are very common with an estimated lifetime prevalence in the U.S. of 17% for major depression, 4% for bipolar I and II disorders, 13% for alcohol abuse, and 5% for alcohol dependence.1 Almost all of the associations between disorders of mood or anxiety and drug use were positive and statistically significant in the National Epidemiologic Survey, on Alcohol and Related Conditions (NESARC), which included 43,093 noninstitutionalized patients.2

There is a reciprocal relationship between depression and alcoholism. Epidemiologic Catchment Area Survey results indicated that baseline symptoms of depression or alcohol abuse increased the risk of developing alcohol dependence or depression.3 The risk of developing depression were elevated among people with increasing levels of alcohol-induced debility. Conversely, the presence of depressive symptoms increased the chance of developing alcohol dependence. The association between alcohol dependence and depression may be attributable to the depressive effects of ethanol; depression often remits with sobriety. Psychosocial consequences of problem drinking also may contribute to affective illnesses.

Alcohol dependence poses a major depression risk that contributes to higher rates of alcohol use. In people with ethanol dependence, the prevalence of major depressive disorder (MDD) is 21%.4 People who are alcohol dependent are 4 times more likely than are nondependents to have MDD. Forty-one percent of people who seek treatment for current alcohol abuse have a mood disorder.

The NESARC survey revealed strong associations between depression, substance use, and other psychopathologies.5 Compared with MDD alone, SUD combined with MDD conferred high vulnerability to additional psychopathology, depressive episodes that were more severe and greater in number, and more suicide attempts.

Depression Clincal Considerations

Depression linked to recent alcohol abuse may not respond well to an antidepressant drug beyond what is achieved with ethanol abstinence. In one study, depressive symptoms were assessed over the course of alcohol-related hospitalizations.6 Depression was evident in 42% of patients 48 hours after admission, but only 6% remained clinically depressed by week 4 of hospitalization. Therefore, in the treatment of patients hospitalized for alcohol detoxification, it is common to observe them for 1 month before considering antidepressant medication. Mood likely will improve without pharmacotherapy.

However, delaying treatment for depression while a patient is hospitalized for alcohol detoxification presents some difficulties. Many patients do not remain sober during the first month after detoxification. One study found that 65% of patients imbibed alcohol within 2 weeks after discharge.7 Furthermore, 50% relapsed into heavy drinking during the same period. More than 25% of patients who used alcohol and were diagnosed with substance-induced depression at baseline were reclassified with MDD the next year.8

Careful clinical assessment is needed after alcohol detoxification. Depression that persists during ethanol abstinence predisposes a patient to relapse into heavy drinking. Therefore, failure to treat depression after alcohol detoxification poses considerable risk.9 A study of the effect of depression on the return to drinking among patients with alcohol dependence found that depression at entry into inpatient treatment for alcohol dependence predicted a shorter time to first drink.9 The prognosis for a drinking relapse was worse no matter whether the depression came first or was triggered by the alcohol. Depression does not predict drinking outcomes, but it is associated with a more rapid relapse to ethanol consumption.

Similarly, inpatients with premorbid or substanceinduced depression were more likely to meet the criteria for drug dependence during outpatient follow-up.10 In addition, patients who developed depression during the first 26 weeks after hospitalization were 3 times more likely than those without depression to relapse into drug dependence during follow-up.

Alcohol dependence may hasten the progression of depression. A study on the prognostic effect of alcoholism on the 10-year course of depression found a deleterious influence of current alcoholism after recovery from depression.11 Patients with MDD were more likely to transition from being ill to improving if either they were forgoing alcohol or had never abused it. Another investigation verified that alcohol and drug dependence increased perceptions of affective symptomatology.12

 

 

Substance-induced depression also increases the risk for suicide. In 602 patients with substance dependence, depression was classified as occurring before dependence, during abstinence, or during substance use.13 Depression increased the risk for suicide in 34% of patients
who had already attempted suicide at least once. Compared with depression absent substance abuse, depression preceding substance use was associated with high vulnerability to additional psychopathology, depressive episodes that were more severe and greater in number, and more suicide attempts. Substance dependence predicted severity of suicidal intent, and abstinence predicted number of attempts.

Psychiatric hospitalizations often involve patients with a history of suicidal thinking or behavior and substance-induced depression. Clinicians can make reliable assessments of the degree to which a presenting psychiatric syndrome is substance-induced.14 These patients require addiction treatment, including outpatient addiction services capable of caring for suicidal persons. These individuals also are more likely to be homeless, unemployed, and uncooperative.15

Taking a psychiatric history and making a detailed inquiry into potential suicidal behavior, recent substance abuse, and current mood symptoms are warranted in persons with depression and/or SUD. Close follow-up is especially important for depressed patients likely to relapse into alcoholism soon after hospital discharge. Failure to recognize MDD or a bipolar disorder in such a patient may result in more relapses, recurrence of mood episodes, and elevated risk of completing suicide.16

Bipolar Clinical Considerations

There is a lack of clarity regarding the effect of moderate-to-excessive alcohol use on the course of bipolar disorders. There is a negative effect on patients with alcohol-induced bipolar depression. In a study of group therapy patients with bipolar disorder co-occurring with substance dependence, data indicated that number of days of alcohol use predicted development of depression a month later.17 These findings were associated with heavy alcohol consumption. In these patients, substantial drinking increased the risk of a depressive episode. In another study, comorbid SUDs were correlated with suboptimal treatment compliance.18 The authors of a 1998 literature review concluded that comorbid SUD makes bipolar symptoms more severe.19

A number of studies have failed to confirm a negative effect of alcohol on bipolar depression.20 There were no differences in 1-year course and outcome between bipolar patients with different alcohol use levels (abstinence, incidental use, moderate abuse, excessive consumption). Other investigators concluded that SUDs were not associated with slower recovery from depression but could contribute to a higher risk of switching to a manic, mixed, or hypomanic state.21

Substance use disorders are associated with increased suicidal behavior in people with a bipolar disorder. The risk of attempted suicide is about double for these patients relative to bipolar patients who do not abuse alcohol.22 Of those who abuse drugs, 14% to 16% complete suicide.23

Psychotherapy

Reportedly, integrated cognitive behavioral therapy (CBT) provided better substance abuse outcomes compared with 12-step programs.24 There also was less substance abuse within the year after CBT. Integrated psychosocial treatment for patients with a mood disorder and substance abuse should involve simultaneous treatment of the 2 conditions. A sequential approach addresses the primary concern and subsequently treats the comorbid disorder, whereas a parallel approach manages both at the same time but in different surroundings. In both approaches, conflicting therapeutic ideologies are a potential difficulty. Given the multiple treatment locations and separate appointments, scheduling problems are an additional difficulty. Coexisting illnesses also are important to consider in the clinical treatment for bipolar patients. As with individual treatments, group therapies take either a sequential approach (more acute disorder treated first) or a parallel approach (disorders treated simultaneously but in separate settings).

Integrated group therapy (IGT) considers patients as having a single diagnosis, focuses on commonalities between relapse and recovery, and reviews the relationship between both conditions. One study compared IGT and treatment as usual in subjects with comorbid bipolar and AUD.25 The IGT group evidenced fewer days of alcohol use. Other research compared IGT with group drug treatment and found that IGT subjects were more likely to remain abstinent.26 This type of psychotherapy showed promise in a meta-analysis of integrated treatment in patients with depression and SUDs.26

Compared with placebo, sertraline/CBT combined treatment reduced alcohol consumption on drinking days.27 This combination was effective in reducing depression, especially in females.

Acceptance and commitment therapy (ACT) combines mindfulness and behavioral change to increase psychological flexibility. The goal in ACT is for patients to become more accepting of their unpleasant feelings. In a study of alcohol abusers with affective disorders, those treated with ACT, compared with controls, had higher abstinence rates and lower depression scores.28

Phamacotherapy and Bipolar Disorder

Even when bipolar symptoms were resolved with use of mood-stabilizing medications, usually some alcohol use continued, though no association was found between bipolar disorder and AUDs.29 With patients’ illness severity and ethanol consumption rated weekly over 7 years, no temporal correlation was found between drinking alcohol and bipolar symptoms.

Similarly, in a study, relief of depressive bipolar symptoms did not result in less frequent alcohol relapse.30 One hundred fifteen outpatients with bipolar disorder and AUD were randomly assigned to either 12 weeks of quetiapine therapy or placebo. Patients in the quetiapine group experienced significant improvement in mood, but sobriety was not enhanced.

Two studies indicated trends of reduced drinking with use of prescribed alcohol-deterrent drugs. An investigation that compared naltrexone with placebo did not reach statistical significance, but naltrexone was reasonably effective in reducing alcohol consumption and craving.31 A report on patients with bipolar disorder treated with acamprosate also did not identify any significant differences in alcohol drinking prognosis.32 Nevertheless, acamprosate was well tolerated and seemed to confer some clinical benefit.

There is a paucity of research focused on patients with bipolar disorder and substance dependence.33 In one trial, patients with bipolar disorder and a diagnosis of alcohol dependence were randomly assigned to receive either valproate or placebo.34 Valproate therapy decreased the number of heavy consumption days and drinks per drinking day in these patients. In a study of 362 patients with bipolar disorder and alcohol dependence treated with lithium or valproic acid, there was no change in drinking days despite adding quetiapine to the regimen.35

Pharmacotherapy and Depression

Lithium is not effective for patients with MDD and AUD. Lithium treatment for depressed patients with alcohol dependence did not improve abstinence, alcohol-related hospitalizations, or severity of either condition.36

Aripiprazole is an antipsychotic that partially agonizes dopamine receptors. Dopamine implicates reward circuitry and has a role in AUDs. Aripiprazole was used as an adjunctive intervention in a randomized trial of 35 patients with comorbid alcohol dependence and depression.37 There was less depression in both the aripiprazole plus escitalopram group and the escitalopram group. Imaging showed a change in activity in the left cingulate gyrus in the patients with comorbid alcohol dependence and MDD. The action of aripiprazole may be mediated through the anterior cingulate cortex.

Research on patients with alcohol dependence treated with fluoxetine found decreased Hamilton Depression Rating Scale (HDRS) scores but no change in alcohol consumption.38

Sertraline diminishes depressive symptoms in abstinent alcoholics. In one study, depressed, recently abstinent alcohol users were randomly assigned to receive sertraline 100 mg daily or placebo.39 Significant improvement was noted in HDRS and Beck Depression Inventory scores at 3- and 6-week intervals.

 

 

Citalopram was studied in patients randomly assigned to receive citalopram or placebo for alcohol abuse or dependence.40 Patients in the citalopram group had more days of drinking and showed little change in frequency of alcohol consumption. There was no improvement in depression severity in the citalopram group relative to the placebo group. Citalopram also has been studied in combination with naltrexone.41 Patients with depression and alcohol dependence were randomly assigned to receive either citalopram or placebo, as well as naltrexone. There were no significant differences in depression severity or drinking outcomes.

Treating depression with selective serotonin reuptake inhibitors (SSRIs) had variable results. Most SSRIs improve depression severity but largely have no effect on drinking outcomes.

Antidepressants

A meta-analysis on the efficacy of antidepressant medications in treating patients with depression and substance abuse revealed that the antidepressants had a somewhat advantageous effect.42 That finding was supported by the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.43 About 33% of patients with citalopramtreated major depression endorsed concurrent SUD symptoms, 19% reported diagnosable alcohol use, 6% had other drug abuses, and 5% exhibited both alcohol and drug use. The groups did not differ in time needed to attain a better mood or in rate of response to citalopram.

Patients with citalopram-treated MDD and alcohol or drug abuse responded about as well as those without an SUD. However, those with alcohol and/or drug abuse had reduced rates of remission, and their remission was delayed, as compared with those without alcohol or drug abuse. There were more suicide attempts and psychiatric hospitalizations among the cohort with drug abuse.

Selective serotonin reuptake inhibitors have a reported safety advantage in treating patients with a history of excessive alcohol intake.44 Another advantage is that SSRIs are seldom abused and seldom lower seizure thresholds significantly. Deleterious effects of alcohol on motor skills or cognition are not potentiated. Adverse effects are usually mild, and overdoses are rarely dangerous.

Antidepressant medication decreased depression and diminished the amount of drinking in patients with depression who use alcohol.45 In controlled research of patients with comorbid depression and alcohol dependence, fluoxetine reduced the severity of these conditions. Substantial reductions in depressive symptoms occurred during detoxification and washout in both groups. There was a strong relationship between depression and drinking among people with depression and AUD.

Desipramine can produce similar results, with positive antidepressant drug effects on depression and drinking. Therefore, pharmacotherapy is indicated for patients with depression who abuse ethanol. Research found that alcohol-dependent patients with depression responded to desipramine.46 Desipramine yielded prolonged abstinence in patients with depression who were using alcohol but not in alcohol users without depression.

A study of imipramine use in actively drinking outpatients found decreased alcohol consumption only for those whose depression responded to treatment.47 However, there was no influence on drinking outcome. Patients whose mood improved reported decreased alcohol consumption after imipramine therapy.

Conslusion

People with co-occurring depression and alcohol dependence are optimally treated with pharmacotherapies that address each condition. One investigation randomly assigned alcohol-dependent patients with depression to 14 weeks of treatment with sertraline 200 mg/d, naltrexone 100 mg/d, a combination of the drugs, or placebo.48 The combination treatment produced the best rate of abstinence before a heavy drinking relapse. Also, fewer patients tended to be depressed in the final weeks of treatment when prescribed the combined regimen. Pharmacotherapy is the best approach for both depression and AUDs. ˜

 

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14. Ries RK, Demirsoy A, Russo JE, Barrett J, Roy-Byrne PP. Reliability and clinical utility of DSM-IV substance-induced psychiatric disorders in acute psychiatric inpatients. Am J Addict. 2001;10(4):308-318.

15. Ries RK, Yuodelis-Flores C, Comtois KA, Roy-Byrne PP, Russo JE. Substanceinduced suicidal admissions to an acute psychiatric service: characteristics and outcomes. J Subst Abuse Treat. 2008;34(1):72-79.

16. Toliver BK, Anton RF. Assessment and treatment of mood disorders in the context of substance abuse. Dialogues Clin Neurosci. 2015;17(2):181-190.

17. Jaffee WB, Griffin ML, Gallop R, et al. Depression precipitated by alcohol use in patients with co-occurring bipolar and substance use disorders. J Clin Psychiatry. 2009;70(2):171-176.

18. Manwani SG, Szilagyi KA, Zablotsky B, Hennen J, Griffin ML, Weiss RD. Adherence to pharmacotherapy in bipolar disorder patients with and without co-occurring substance use disorders. J Clin Psychiatry. 2007;68(8):1172-1176.

19. Tohen M, Greenfield SF, Weiss RD, Zarate CA Jr, Vagge LM. The effect of comorbid substance disorders on the course of bipolar disorder: a review. Harv Rev Psychiatry. 1998;6(3):133-141.

20. van Zaane J, van den Brink W, Draisma S, Smit JH, Nolen WA. The effect of moderate and excessive alcohol use on the course and outcome of patients with bipolar disorders: a prospective cohort study. J Clin Psychiatry. 2010;71(7):885-893.

21. Ostacher MJ, Perlis RH, Nierenberg AA, et al; STEP-BD Investigators. Impact of substance use disorders on recovery from episodes of depression in bipolar disorder patients: prospective data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2010;167(3):289-297.

22. Oquendo MA, Currier D, Liu SM, Hasin DS, Grant BF, Blanco C. Increased risk for suicidal behavior in comorbid bipolar disorder and alcohol use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). J Clin Psychiatry. 2010;71(7):902-909.

23. Yoon YH, Chen CM, Yi HY, Moss HB. Effect of comorbid alcohol and drug use disorders on premature death of unipolar and bipolar decedents in the United States, 1999 to 2006. Compr Psychiatry. 2011;52(5):453-464.

24. Lydecker KP, Tate SR, Cummins KM, McQuaid J, Granholm E, Brown SA. Clinical outcomes of an integrated treatment for depression and substance use disorders. Psychol Addict Behav. 2010;24(3):453-465.

25. Weiss RD, Griffin ML, Kolodziej ME, et al. A randomized trial of integrated group therapy versus group drug counseling for patients with bipolar disorder and substance dependence. Am J Psychiatry. 2007;164(1):100-107.

26. Hesse M. Integrated psychological treatment for substance use and co-morbid anxiety or depression vs. treatment for substance use alone. A systematic review of the published literature. BMC Psychiatry. 2009;9:6.

27. Moak DH, Anton RF, Latham PK, Voronin KE, Waid RL, Durazo-Arvizu R. Sertraline and cognitive behavioral therapy for depressed alcoholics: results of a placebo-controlled trial. J Clin Psychopharmacol. 2003;23(6):553-562.

28. Thekiso TB, Murphy P, Milnes J, Lambe K, Curtin A, Farren CK. Acceptance and commitment therapy in the treatment of alcohol use disorder and comorbid affective disorder: a pilot matched control trial. Behav Ther. 2015;46(6):717-728.

29. Fleck DE, Amdt S, Delbello MP, Strakowski SM. Concurrent tracking of alcohol use and bipolar disorder symptoms. Bipolar Disord. 2006:8(4):338-344.

30. Brown ES, Gaza M, Carmody TJ. A randomized, double-blind, placebo-controlled add-on trial of quetiapine in outpatients with bipolar disorder and alcohol use disorders. J Clin Psychiatry. 2008;69(5):701-705.

31. Brown ES, Carmody TJ, Schmitz JM, et al. A randomized, double-blind, placebocontrolled pilot study of naltrexone in outpatients with bipolar disorder and alcohol dependence. Alcohol Clin Exp Res. 2009;33(11):1863-1869.

32. Tolliver BK, Desantis SM, Brown DG, Prisciandaro JJ, Brady KT. A randomized, double-blind, placebo-controlled clinical trial of acamprosate in alcoholdependent individuals with bipolar disorder: a preliminary report. Bipolar Disord. 2012;14(1):54-63.

33. Pettinati HM, O’Brien CP, Dundon WD. Current status of co-occurring mood and substance use disorders: a new therapeutic target. Am J Psychiatry. 2013;170(1):23-30.

34. Salloum IM, Cornelius JR, Daley DC, Kirisci L, Himmelhoch JM, Thase ME. Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo-controlled study. Arch Gen Psychiatry. 2005;62(1):37-45.

35. Farren CK, Hill KP, Weiss RD. Bipolar disorder and alcohol use disorder: a review. Curr Psychiatry Rep. 2012;14(6):659-666.

36. Dorus W, Ostrow DG, Anton R, et al. Lithium treatment of depressed and nondepressed alcoholics. JAMA. 1989;262(12):1646-1652.

37. Han DH, Kim SM, Choi JE, Min KJ, Renshaw PF. Adjunctive aripiprazole therapy with escitalopram in patients with co-morbid major depressive disorder and alcohol dependence: clinical and neuroimaging evidence. J Psychopharmacol. 2013;27(3):282-291.

38. Kranzler HR, Burleson JA, Korner P, et al. Placebo-controlled trial of fluoxetine as an adjunct to relapse prevention in alcoholics. Am J Psychiatry. 1995;152(3):391-397.

39. Roy A. Placebo-controlled study of sertraline in depressed recently abstinent alcoholics. Biol Psychiatry. 1998;44(7):633-637.

40. Charney DA, Heath LM, Zikos E, Palacios-Boix J, Gill KJ. Poorer drinking outcomes with citalopram treatment for alcohol dependence: a randomized, doubleblind, placebo-controlled trial. Alcohol Clin Exp Res. 2015;39(9):1756-1765.

41. Adamson SJ, Sellman JD, Foulds JA, et al. A randomized trial of combined citalopram and naltrexone for non-abstinent outpatients with co-occurring alcohol dependence and major depression. J Clin Psychopharmacol. 2015;35(2):143-149.

42. Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis. JAMA. 2004;291(15):1887-1896.

43. Davis LL, Wisniewski SR, Howland RH, et al. Does comorbid substance use disorder impair recovery from major depression with SSRI treatment? An analysis of the STAR*D level one treatment outcomes. Drug Alcohol Depend. 2010;107(2-3):161-170.

44. Pettinati HM. The use of selective reuptake inhibitors in treating alcoholic subtypes. J Clin Psychiatry. 2001;62(suppl 20):26-31.

45. Cornelius JR, Salloum IM, Ehler JG, et al. Fluoxetine in depressed alcoholics. A double-blind, placebo-controlled trial. Arch Gen Psychiatry. 1997;54(8):700-705.

46. Mason BJ, Kocsis JH, Ritvo EC, Cutler RB. A double-blind, placebo-controlled trial of desipramine for primary alcohol dependence stratified on the presence of absence of major depression. JAMA. 1996;275(10):761-767.

47. McGrath PJ, Nunes EV, Stewart JW, et al. Imipramine treatment of alcoholics with primary depression: a placebo-controlled clinical trial. Arch Gen Psychiatry. 1996;53(3):232-240.

48. Pettinati HM, Oslin DW, Kampman KM, et al. A double-blind, placebo-controlled trial combining sertraline and naltrexone for treating co-occurring depression and alcohol dependence. Am J Psychiatry. 2010;167(6):668-675.

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Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations— including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

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Dr. Pary is a psychiatrist at Louisville VAMC in Kentucky. Dr. Patel is a psychiatry resident, Dr. Lippmann is a professor, and Dr. Pary is an associate professor, all at the University of Louisville, Kentucky.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations— including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Author and Disclosure Information

Dr. Pary is a psychiatrist at Louisville VAMC in Kentucky. Dr. Patel is a psychiatry resident, Dr. Lippmann is a professor, and Dr. Pary is an associate professor, all at the University of Louisville, Kentucky.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations— including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

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This review details methods for meeting the challenges of diagnosing and treating mood disorders that coexist with substance use disorders.
This review details methods for meeting the challenges of diagnosing and treating mood disorders that coexist with substance use disorders.

Co-occurrence of depression and substance abuse often poses diagnostic and therapeutic challenges. This article reviews the prevalence, clinical considerations, and treatment of depression coexisting with alcohol use disorders (AUDs).

Prevalence

Mood and substance use disorders (SUDs) are very common with an estimated lifetime prevalence in the U.S. of 17% for major depression, 4% for bipolar I and II disorders, 13% for alcohol abuse, and 5% for alcohol dependence.1 Almost all of the associations between disorders of mood or anxiety and drug use were positive and statistically significant in the National Epidemiologic Survey, on Alcohol and Related Conditions (NESARC), which included 43,093 noninstitutionalized patients.2

There is a reciprocal relationship between depression and alcoholism. Epidemiologic Catchment Area Survey results indicated that baseline symptoms of depression or alcohol abuse increased the risk of developing alcohol dependence or depression.3 The risk of developing depression were elevated among people with increasing levels of alcohol-induced debility. Conversely, the presence of depressive symptoms increased the chance of developing alcohol dependence. The association between alcohol dependence and depression may be attributable to the depressive effects of ethanol; depression often remits with sobriety. Psychosocial consequences of problem drinking also may contribute to affective illnesses.

Alcohol dependence poses a major depression risk that contributes to higher rates of alcohol use. In people with ethanol dependence, the prevalence of major depressive disorder (MDD) is 21%.4 People who are alcohol dependent are 4 times more likely than are nondependents to have MDD. Forty-one percent of people who seek treatment for current alcohol abuse have a mood disorder.

The NESARC survey revealed strong associations between depression, substance use, and other psychopathologies.5 Compared with MDD alone, SUD combined with MDD conferred high vulnerability to additional psychopathology, depressive episodes that were more severe and greater in number, and more suicide attempts.

Depression Clincal Considerations

Depression linked to recent alcohol abuse may not respond well to an antidepressant drug beyond what is achieved with ethanol abstinence. In one study, depressive symptoms were assessed over the course of alcohol-related hospitalizations.6 Depression was evident in 42% of patients 48 hours after admission, but only 6% remained clinically depressed by week 4 of hospitalization. Therefore, in the treatment of patients hospitalized for alcohol detoxification, it is common to observe them for 1 month before considering antidepressant medication. Mood likely will improve without pharmacotherapy.

However, delaying treatment for depression while a patient is hospitalized for alcohol detoxification presents some difficulties. Many patients do not remain sober during the first month after detoxification. One study found that 65% of patients imbibed alcohol within 2 weeks after discharge.7 Furthermore, 50% relapsed into heavy drinking during the same period. More than 25% of patients who used alcohol and were diagnosed with substance-induced depression at baseline were reclassified with MDD the next year.8

Careful clinical assessment is needed after alcohol detoxification. Depression that persists during ethanol abstinence predisposes a patient to relapse into heavy drinking. Therefore, failure to treat depression after alcohol detoxification poses considerable risk.9 A study of the effect of depression on the return to drinking among patients with alcohol dependence found that depression at entry into inpatient treatment for alcohol dependence predicted a shorter time to first drink.9 The prognosis for a drinking relapse was worse no matter whether the depression came first or was triggered by the alcohol. Depression does not predict drinking outcomes, but it is associated with a more rapid relapse to ethanol consumption.

Similarly, inpatients with premorbid or substanceinduced depression were more likely to meet the criteria for drug dependence during outpatient follow-up.10 In addition, patients who developed depression during the first 26 weeks after hospitalization were 3 times more likely than those without depression to relapse into drug dependence during follow-up.

Alcohol dependence may hasten the progression of depression. A study on the prognostic effect of alcoholism on the 10-year course of depression found a deleterious influence of current alcoholism after recovery from depression.11 Patients with MDD were more likely to transition from being ill to improving if either they were forgoing alcohol or had never abused it. Another investigation verified that alcohol and drug dependence increased perceptions of affective symptomatology.12

 

 

Substance-induced depression also increases the risk for suicide. In 602 patients with substance dependence, depression was classified as occurring before dependence, during abstinence, or during substance use.13 Depression increased the risk for suicide in 34% of patients
who had already attempted suicide at least once. Compared with depression absent substance abuse, depression preceding substance use was associated with high vulnerability to additional psychopathology, depressive episodes that were more severe and greater in number, and more suicide attempts. Substance dependence predicted severity of suicidal intent, and abstinence predicted number of attempts.

Psychiatric hospitalizations often involve patients with a history of suicidal thinking or behavior and substance-induced depression. Clinicians can make reliable assessments of the degree to which a presenting psychiatric syndrome is substance-induced.14 These patients require addiction treatment, including outpatient addiction services capable of caring for suicidal persons. These individuals also are more likely to be homeless, unemployed, and uncooperative.15

Taking a psychiatric history and making a detailed inquiry into potential suicidal behavior, recent substance abuse, and current mood symptoms are warranted in persons with depression and/or SUD. Close follow-up is especially important for depressed patients likely to relapse into alcoholism soon after hospital discharge. Failure to recognize MDD or a bipolar disorder in such a patient may result in more relapses, recurrence of mood episodes, and elevated risk of completing suicide.16

Bipolar Clinical Considerations

There is a lack of clarity regarding the effect of moderate-to-excessive alcohol use on the course of bipolar disorders. There is a negative effect on patients with alcohol-induced bipolar depression. In a study of group therapy patients with bipolar disorder co-occurring with substance dependence, data indicated that number of days of alcohol use predicted development of depression a month later.17 These findings were associated with heavy alcohol consumption. In these patients, substantial drinking increased the risk of a depressive episode. In another study, comorbid SUDs were correlated with suboptimal treatment compliance.18 The authors of a 1998 literature review concluded that comorbid SUD makes bipolar symptoms more severe.19

A number of studies have failed to confirm a negative effect of alcohol on bipolar depression.20 There were no differences in 1-year course and outcome between bipolar patients with different alcohol use levels (abstinence, incidental use, moderate abuse, excessive consumption). Other investigators concluded that SUDs were not associated with slower recovery from depression but could contribute to a higher risk of switching to a manic, mixed, or hypomanic state.21

Substance use disorders are associated with increased suicidal behavior in people with a bipolar disorder. The risk of attempted suicide is about double for these patients relative to bipolar patients who do not abuse alcohol.22 Of those who abuse drugs, 14% to 16% complete suicide.23

Psychotherapy

Reportedly, integrated cognitive behavioral therapy (CBT) provided better substance abuse outcomes compared with 12-step programs.24 There also was less substance abuse within the year after CBT. Integrated psychosocial treatment for patients with a mood disorder and substance abuse should involve simultaneous treatment of the 2 conditions. A sequential approach addresses the primary concern and subsequently treats the comorbid disorder, whereas a parallel approach manages both at the same time but in different surroundings. In both approaches, conflicting therapeutic ideologies are a potential difficulty. Given the multiple treatment locations and separate appointments, scheduling problems are an additional difficulty. Coexisting illnesses also are important to consider in the clinical treatment for bipolar patients. As with individual treatments, group therapies take either a sequential approach (more acute disorder treated first) or a parallel approach (disorders treated simultaneously but in separate settings).

Integrated group therapy (IGT) considers patients as having a single diagnosis, focuses on commonalities between relapse and recovery, and reviews the relationship between both conditions. One study compared IGT and treatment as usual in subjects with comorbid bipolar and AUD.25 The IGT group evidenced fewer days of alcohol use. Other research compared IGT with group drug treatment and found that IGT subjects were more likely to remain abstinent.26 This type of psychotherapy showed promise in a meta-analysis of integrated treatment in patients with depression and SUDs.26

Compared with placebo, sertraline/CBT combined treatment reduced alcohol consumption on drinking days.27 This combination was effective in reducing depression, especially in females.

Acceptance and commitment therapy (ACT) combines mindfulness and behavioral change to increase psychological flexibility. The goal in ACT is for patients to become more accepting of their unpleasant feelings. In a study of alcohol abusers with affective disorders, those treated with ACT, compared with controls, had higher abstinence rates and lower depression scores.28

Phamacotherapy and Bipolar Disorder

Even when bipolar symptoms were resolved with use of mood-stabilizing medications, usually some alcohol use continued, though no association was found between bipolar disorder and AUDs.29 With patients’ illness severity and ethanol consumption rated weekly over 7 years, no temporal correlation was found between drinking alcohol and bipolar symptoms.

Similarly, in a study, relief of depressive bipolar symptoms did not result in less frequent alcohol relapse.30 One hundred fifteen outpatients with bipolar disorder and AUD were randomly assigned to either 12 weeks of quetiapine therapy or placebo. Patients in the quetiapine group experienced significant improvement in mood, but sobriety was not enhanced.

Two studies indicated trends of reduced drinking with use of prescribed alcohol-deterrent drugs. An investigation that compared naltrexone with placebo did not reach statistical significance, but naltrexone was reasonably effective in reducing alcohol consumption and craving.31 A report on patients with bipolar disorder treated with acamprosate also did not identify any significant differences in alcohol drinking prognosis.32 Nevertheless, acamprosate was well tolerated and seemed to confer some clinical benefit.

There is a paucity of research focused on patients with bipolar disorder and substance dependence.33 In one trial, patients with bipolar disorder and a diagnosis of alcohol dependence were randomly assigned to receive either valproate or placebo.34 Valproate therapy decreased the number of heavy consumption days and drinks per drinking day in these patients. In a study of 362 patients with bipolar disorder and alcohol dependence treated with lithium or valproic acid, there was no change in drinking days despite adding quetiapine to the regimen.35

Pharmacotherapy and Depression

Lithium is not effective for patients with MDD and AUD. Lithium treatment for depressed patients with alcohol dependence did not improve abstinence, alcohol-related hospitalizations, or severity of either condition.36

Aripiprazole is an antipsychotic that partially agonizes dopamine receptors. Dopamine implicates reward circuitry and has a role in AUDs. Aripiprazole was used as an adjunctive intervention in a randomized trial of 35 patients with comorbid alcohol dependence and depression.37 There was less depression in both the aripiprazole plus escitalopram group and the escitalopram group. Imaging showed a change in activity in the left cingulate gyrus in the patients with comorbid alcohol dependence and MDD. The action of aripiprazole may be mediated through the anterior cingulate cortex.

Research on patients with alcohol dependence treated with fluoxetine found decreased Hamilton Depression Rating Scale (HDRS) scores but no change in alcohol consumption.38

Sertraline diminishes depressive symptoms in abstinent alcoholics. In one study, depressed, recently abstinent alcohol users were randomly assigned to receive sertraline 100 mg daily or placebo.39 Significant improvement was noted in HDRS and Beck Depression Inventory scores at 3- and 6-week intervals.

 

 

Citalopram was studied in patients randomly assigned to receive citalopram or placebo for alcohol abuse or dependence.40 Patients in the citalopram group had more days of drinking and showed little change in frequency of alcohol consumption. There was no improvement in depression severity in the citalopram group relative to the placebo group. Citalopram also has been studied in combination with naltrexone.41 Patients with depression and alcohol dependence were randomly assigned to receive either citalopram or placebo, as well as naltrexone. There were no significant differences in depression severity or drinking outcomes.

Treating depression with selective serotonin reuptake inhibitors (SSRIs) had variable results. Most SSRIs improve depression severity but largely have no effect on drinking outcomes.

Antidepressants

A meta-analysis on the efficacy of antidepressant medications in treating patients with depression and substance abuse revealed that the antidepressants had a somewhat advantageous effect.42 That finding was supported by the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.43 About 33% of patients with citalopramtreated major depression endorsed concurrent SUD symptoms, 19% reported diagnosable alcohol use, 6% had other drug abuses, and 5% exhibited both alcohol and drug use. The groups did not differ in time needed to attain a better mood or in rate of response to citalopram.

Patients with citalopram-treated MDD and alcohol or drug abuse responded about as well as those without an SUD. However, those with alcohol and/or drug abuse had reduced rates of remission, and their remission was delayed, as compared with those without alcohol or drug abuse. There were more suicide attempts and psychiatric hospitalizations among the cohort with drug abuse.

Selective serotonin reuptake inhibitors have a reported safety advantage in treating patients with a history of excessive alcohol intake.44 Another advantage is that SSRIs are seldom abused and seldom lower seizure thresholds significantly. Deleterious effects of alcohol on motor skills or cognition are not potentiated. Adverse effects are usually mild, and overdoses are rarely dangerous.

Antidepressant medication decreased depression and diminished the amount of drinking in patients with depression who use alcohol.45 In controlled research of patients with comorbid depression and alcohol dependence, fluoxetine reduced the severity of these conditions. Substantial reductions in depressive symptoms occurred during detoxification and washout in both groups. There was a strong relationship between depression and drinking among people with depression and AUD.

Desipramine can produce similar results, with positive antidepressant drug effects on depression and drinking. Therefore, pharmacotherapy is indicated for patients with depression who abuse ethanol. Research found that alcohol-dependent patients with depression responded to desipramine.46 Desipramine yielded prolonged abstinence in patients with depression who were using alcohol but not in alcohol users without depression.

A study of imipramine use in actively drinking outpatients found decreased alcohol consumption only for those whose depression responded to treatment.47 However, there was no influence on drinking outcome. Patients whose mood improved reported decreased alcohol consumption after imipramine therapy.

Conslusion

People with co-occurring depression and alcohol dependence are optimally treated with pharmacotherapies that address each condition. One investigation randomly assigned alcohol-dependent patients with depression to 14 weeks of treatment with sertraline 200 mg/d, naltrexone 100 mg/d, a combination of the drugs, or placebo.48 The combination treatment produced the best rate of abstinence before a heavy drinking relapse. Also, fewer patients tended to be depressed in the final weeks of treatment when prescribed the combined regimen. Pharmacotherapy is the best approach for both depression and AUDs. ˜

 

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Co-occurrence of depression and substance abuse often poses diagnostic and therapeutic challenges. This article reviews the prevalence, clinical considerations, and treatment of depression coexisting with alcohol use disorders (AUDs).

Prevalence

Mood and substance use disorders (SUDs) are very common with an estimated lifetime prevalence in the U.S. of 17% for major depression, 4% for bipolar I and II disorders, 13% for alcohol abuse, and 5% for alcohol dependence.1 Almost all of the associations between disorders of mood or anxiety and drug use were positive and statistically significant in the National Epidemiologic Survey, on Alcohol and Related Conditions (NESARC), which included 43,093 noninstitutionalized patients.2

There is a reciprocal relationship between depression and alcoholism. Epidemiologic Catchment Area Survey results indicated that baseline symptoms of depression or alcohol abuse increased the risk of developing alcohol dependence or depression.3 The risk of developing depression were elevated among people with increasing levels of alcohol-induced debility. Conversely, the presence of depressive symptoms increased the chance of developing alcohol dependence. The association between alcohol dependence and depression may be attributable to the depressive effects of ethanol; depression often remits with sobriety. Psychosocial consequences of problem drinking also may contribute to affective illnesses.

Alcohol dependence poses a major depression risk that contributes to higher rates of alcohol use. In people with ethanol dependence, the prevalence of major depressive disorder (MDD) is 21%.4 People who are alcohol dependent are 4 times more likely than are nondependents to have MDD. Forty-one percent of people who seek treatment for current alcohol abuse have a mood disorder.

The NESARC survey revealed strong associations between depression, substance use, and other psychopathologies.5 Compared with MDD alone, SUD combined with MDD conferred high vulnerability to additional psychopathology, depressive episodes that were more severe and greater in number, and more suicide attempts.

Depression Clincal Considerations

Depression linked to recent alcohol abuse may not respond well to an antidepressant drug beyond what is achieved with ethanol abstinence. In one study, depressive symptoms were assessed over the course of alcohol-related hospitalizations.6 Depression was evident in 42% of patients 48 hours after admission, but only 6% remained clinically depressed by week 4 of hospitalization. Therefore, in the treatment of patients hospitalized for alcohol detoxification, it is common to observe them for 1 month before considering antidepressant medication. Mood likely will improve without pharmacotherapy.

However, delaying treatment for depression while a patient is hospitalized for alcohol detoxification presents some difficulties. Many patients do not remain sober during the first month after detoxification. One study found that 65% of patients imbibed alcohol within 2 weeks after discharge.7 Furthermore, 50% relapsed into heavy drinking during the same period. More than 25% of patients who used alcohol and were diagnosed with substance-induced depression at baseline were reclassified with MDD the next year.8

Careful clinical assessment is needed after alcohol detoxification. Depression that persists during ethanol abstinence predisposes a patient to relapse into heavy drinking. Therefore, failure to treat depression after alcohol detoxification poses considerable risk.9 A study of the effect of depression on the return to drinking among patients with alcohol dependence found that depression at entry into inpatient treatment for alcohol dependence predicted a shorter time to first drink.9 The prognosis for a drinking relapse was worse no matter whether the depression came first or was triggered by the alcohol. Depression does not predict drinking outcomes, but it is associated with a more rapid relapse to ethanol consumption.

Similarly, inpatients with premorbid or substanceinduced depression were more likely to meet the criteria for drug dependence during outpatient follow-up.10 In addition, patients who developed depression during the first 26 weeks after hospitalization were 3 times more likely than those without depression to relapse into drug dependence during follow-up.

Alcohol dependence may hasten the progression of depression. A study on the prognostic effect of alcoholism on the 10-year course of depression found a deleterious influence of current alcoholism after recovery from depression.11 Patients with MDD were more likely to transition from being ill to improving if either they were forgoing alcohol or had never abused it. Another investigation verified that alcohol and drug dependence increased perceptions of affective symptomatology.12

 

 

Substance-induced depression also increases the risk for suicide. In 602 patients with substance dependence, depression was classified as occurring before dependence, during abstinence, or during substance use.13 Depression increased the risk for suicide in 34% of patients
who had already attempted suicide at least once. Compared with depression absent substance abuse, depression preceding substance use was associated with high vulnerability to additional psychopathology, depressive episodes that were more severe and greater in number, and more suicide attempts. Substance dependence predicted severity of suicidal intent, and abstinence predicted number of attempts.

Psychiatric hospitalizations often involve patients with a history of suicidal thinking or behavior and substance-induced depression. Clinicians can make reliable assessments of the degree to which a presenting psychiatric syndrome is substance-induced.14 These patients require addiction treatment, including outpatient addiction services capable of caring for suicidal persons. These individuals also are more likely to be homeless, unemployed, and uncooperative.15

Taking a psychiatric history and making a detailed inquiry into potential suicidal behavior, recent substance abuse, and current mood symptoms are warranted in persons with depression and/or SUD. Close follow-up is especially important for depressed patients likely to relapse into alcoholism soon after hospital discharge. Failure to recognize MDD or a bipolar disorder in such a patient may result in more relapses, recurrence of mood episodes, and elevated risk of completing suicide.16

Bipolar Clinical Considerations

There is a lack of clarity regarding the effect of moderate-to-excessive alcohol use on the course of bipolar disorders. There is a negative effect on patients with alcohol-induced bipolar depression. In a study of group therapy patients with bipolar disorder co-occurring with substance dependence, data indicated that number of days of alcohol use predicted development of depression a month later.17 These findings were associated with heavy alcohol consumption. In these patients, substantial drinking increased the risk of a depressive episode. In another study, comorbid SUDs were correlated with suboptimal treatment compliance.18 The authors of a 1998 literature review concluded that comorbid SUD makes bipolar symptoms more severe.19

A number of studies have failed to confirm a negative effect of alcohol on bipolar depression.20 There were no differences in 1-year course and outcome between bipolar patients with different alcohol use levels (abstinence, incidental use, moderate abuse, excessive consumption). Other investigators concluded that SUDs were not associated with slower recovery from depression but could contribute to a higher risk of switching to a manic, mixed, or hypomanic state.21

Substance use disorders are associated with increased suicidal behavior in people with a bipolar disorder. The risk of attempted suicide is about double for these patients relative to bipolar patients who do not abuse alcohol.22 Of those who abuse drugs, 14% to 16% complete suicide.23

Psychotherapy

Reportedly, integrated cognitive behavioral therapy (CBT) provided better substance abuse outcomes compared with 12-step programs.24 There also was less substance abuse within the year after CBT. Integrated psychosocial treatment for patients with a mood disorder and substance abuse should involve simultaneous treatment of the 2 conditions. A sequential approach addresses the primary concern and subsequently treats the comorbid disorder, whereas a parallel approach manages both at the same time but in different surroundings. In both approaches, conflicting therapeutic ideologies are a potential difficulty. Given the multiple treatment locations and separate appointments, scheduling problems are an additional difficulty. Coexisting illnesses also are important to consider in the clinical treatment for bipolar patients. As with individual treatments, group therapies take either a sequential approach (more acute disorder treated first) or a parallel approach (disorders treated simultaneously but in separate settings).

Integrated group therapy (IGT) considers patients as having a single diagnosis, focuses on commonalities between relapse and recovery, and reviews the relationship between both conditions. One study compared IGT and treatment as usual in subjects with comorbid bipolar and AUD.25 The IGT group evidenced fewer days of alcohol use. Other research compared IGT with group drug treatment and found that IGT subjects were more likely to remain abstinent.26 This type of psychotherapy showed promise in a meta-analysis of integrated treatment in patients with depression and SUDs.26

Compared with placebo, sertraline/CBT combined treatment reduced alcohol consumption on drinking days.27 This combination was effective in reducing depression, especially in females.

Acceptance and commitment therapy (ACT) combines mindfulness and behavioral change to increase psychological flexibility. The goal in ACT is for patients to become more accepting of their unpleasant feelings. In a study of alcohol abusers with affective disorders, those treated with ACT, compared with controls, had higher abstinence rates and lower depression scores.28

Phamacotherapy and Bipolar Disorder

Even when bipolar symptoms were resolved with use of mood-stabilizing medications, usually some alcohol use continued, though no association was found between bipolar disorder and AUDs.29 With patients’ illness severity and ethanol consumption rated weekly over 7 years, no temporal correlation was found between drinking alcohol and bipolar symptoms.

Similarly, in a study, relief of depressive bipolar symptoms did not result in less frequent alcohol relapse.30 One hundred fifteen outpatients with bipolar disorder and AUD were randomly assigned to either 12 weeks of quetiapine therapy or placebo. Patients in the quetiapine group experienced significant improvement in mood, but sobriety was not enhanced.

Two studies indicated trends of reduced drinking with use of prescribed alcohol-deterrent drugs. An investigation that compared naltrexone with placebo did not reach statistical significance, but naltrexone was reasonably effective in reducing alcohol consumption and craving.31 A report on patients with bipolar disorder treated with acamprosate also did not identify any significant differences in alcohol drinking prognosis.32 Nevertheless, acamprosate was well tolerated and seemed to confer some clinical benefit.

There is a paucity of research focused on patients with bipolar disorder and substance dependence.33 In one trial, patients with bipolar disorder and a diagnosis of alcohol dependence were randomly assigned to receive either valproate or placebo.34 Valproate therapy decreased the number of heavy consumption days and drinks per drinking day in these patients. In a study of 362 patients with bipolar disorder and alcohol dependence treated with lithium or valproic acid, there was no change in drinking days despite adding quetiapine to the regimen.35

Pharmacotherapy and Depression

Lithium is not effective for patients with MDD and AUD. Lithium treatment for depressed patients with alcohol dependence did not improve abstinence, alcohol-related hospitalizations, or severity of either condition.36

Aripiprazole is an antipsychotic that partially agonizes dopamine receptors. Dopamine implicates reward circuitry and has a role in AUDs. Aripiprazole was used as an adjunctive intervention in a randomized trial of 35 patients with comorbid alcohol dependence and depression.37 There was less depression in both the aripiprazole plus escitalopram group and the escitalopram group. Imaging showed a change in activity in the left cingulate gyrus in the patients with comorbid alcohol dependence and MDD. The action of aripiprazole may be mediated through the anterior cingulate cortex.

Research on patients with alcohol dependence treated with fluoxetine found decreased Hamilton Depression Rating Scale (HDRS) scores but no change in alcohol consumption.38

Sertraline diminishes depressive symptoms in abstinent alcoholics. In one study, depressed, recently abstinent alcohol users were randomly assigned to receive sertraline 100 mg daily or placebo.39 Significant improvement was noted in HDRS and Beck Depression Inventory scores at 3- and 6-week intervals.

 

 

Citalopram was studied in patients randomly assigned to receive citalopram or placebo for alcohol abuse or dependence.40 Patients in the citalopram group had more days of drinking and showed little change in frequency of alcohol consumption. There was no improvement in depression severity in the citalopram group relative to the placebo group. Citalopram also has been studied in combination with naltrexone.41 Patients with depression and alcohol dependence were randomly assigned to receive either citalopram or placebo, as well as naltrexone. There were no significant differences in depression severity or drinking outcomes.

Treating depression with selective serotonin reuptake inhibitors (SSRIs) had variable results. Most SSRIs improve depression severity but largely have no effect on drinking outcomes.

Antidepressants

A meta-analysis on the efficacy of antidepressant medications in treating patients with depression and substance abuse revealed that the antidepressants had a somewhat advantageous effect.42 That finding was supported by the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.43 About 33% of patients with citalopramtreated major depression endorsed concurrent SUD symptoms, 19% reported diagnosable alcohol use, 6% had other drug abuses, and 5% exhibited both alcohol and drug use. The groups did not differ in time needed to attain a better mood or in rate of response to citalopram.

Patients with citalopram-treated MDD and alcohol or drug abuse responded about as well as those without an SUD. However, those with alcohol and/or drug abuse had reduced rates of remission, and their remission was delayed, as compared with those without alcohol or drug abuse. There were more suicide attempts and psychiatric hospitalizations among the cohort with drug abuse.

Selective serotonin reuptake inhibitors have a reported safety advantage in treating patients with a history of excessive alcohol intake.44 Another advantage is that SSRIs are seldom abused and seldom lower seizure thresholds significantly. Deleterious effects of alcohol on motor skills or cognition are not potentiated. Adverse effects are usually mild, and overdoses are rarely dangerous.

Antidepressant medication decreased depression and diminished the amount of drinking in patients with depression who use alcohol.45 In controlled research of patients with comorbid depression and alcohol dependence, fluoxetine reduced the severity of these conditions. Substantial reductions in depressive symptoms occurred during detoxification and washout in both groups. There was a strong relationship between depression and drinking among people with depression and AUD.

Desipramine can produce similar results, with positive antidepressant drug effects on depression and drinking. Therefore, pharmacotherapy is indicated for patients with depression who abuse ethanol. Research found that alcohol-dependent patients with depression responded to desipramine.46 Desipramine yielded prolonged abstinence in patients with depression who were using alcohol but not in alcohol users without depression.

A study of imipramine use in actively drinking outpatients found decreased alcohol consumption only for those whose depression responded to treatment.47 However, there was no influence on drinking outcome. Patients whose mood improved reported decreased alcohol consumption after imipramine therapy.

Conslusion

People with co-occurring depression and alcohol dependence are optimally treated with pharmacotherapies that address each condition. One investigation randomly assigned alcohol-dependent patients with depression to 14 weeks of treatment with sertraline 200 mg/d, naltrexone 100 mg/d, a combination of the drugs, or placebo.48 The combination treatment produced the best rate of abstinence before a heavy drinking relapse. Also, fewer patients tended to be depressed in the final weeks of treatment when prescribed the combined regimen. Pharmacotherapy is the best approach for both depression and AUDs. ˜

 

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References

1. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):593-602.

2. Conway KP, Compton W, Stinson FS, Grant BF. Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2006;67(2):247-257.

3. Gilman SE, Abraham HD. A longitudinal study of the order of onset of alcohol dependence and major depression. Drug Alcohol Depend. 2001;63(3):277-286.

4. Kessler RC, Crum RM, Warner LA, Nelson CB, Schulenberg J, Anthony JC. Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey. Arch Gen Psychiatry. 1997;54(4):313-321.

5. Blanco C, Alegría AA, Liu SM, et al. Differences among major depressive disorder with and without co-occurring substance use disorders and substance-induced depressive disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2012;73(6):865-873.

6. Brown SA, Schuckit MA. Changes in depression among abstinent alcoholics. J Stud Alcohol. 1988;49(5):412-417.

7. Kiefer F, Jahn H, Tarnaske T, et al. Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 2003;60(1):92-99.

8. Ramsey SE, Kahler CW, Read JP, Stuart GL, Brown RA. Discriminating between substance-induced and independent depressive episodes in alcohol-dependent patients. J Stud Alcohol. 2004;65(5):672-676.

9. Greenfield SF, Weiss RD, Muenz LR, et al. The effect of depression on return to drinking: a prospective study. Arch Gen Psychiatry. 1998;55(3):259-265.

10. Hasin D, Liu X, Nunes E, McCloud S, Samet S, Endicott J. Effects of major depression on remission and relapse of substance dependence. Arch Gen Psychiatry. 2002;59(4):375-380.

11. Mueller TI, Lavori PW, Martin B, et al. Prognostic effect of the variable course of alcoholism on the 10-year course of depression. Am J Psychiatry. 1994;151(5):701-706.

12. Agosti V, Levin FR. The effects of alcohol and drug dependence on the course of depression. Am J Addict. 2006;15(1):71-75.

13. Aharonovich E, Liu X, Nunes E, Hasin DS. Suicide attempts in substance abusers: effects of major depression in relation to substance use disorders. Am J Psychiatry. 2002;159(9):1600-1602.

14. Ries RK, Demirsoy A, Russo JE, Barrett J, Roy-Byrne PP. Reliability and clinical utility of DSM-IV substance-induced psychiatric disorders in acute psychiatric inpatients. Am J Addict. 2001;10(4):308-318.

15. Ries RK, Yuodelis-Flores C, Comtois KA, Roy-Byrne PP, Russo JE. Substanceinduced suicidal admissions to an acute psychiatric service: characteristics and outcomes. J Subst Abuse Treat. 2008;34(1):72-79.

16. Toliver BK, Anton RF. Assessment and treatment of mood disorders in the context of substance abuse. Dialogues Clin Neurosci. 2015;17(2):181-190.

17. Jaffee WB, Griffin ML, Gallop R, et al. Depression precipitated by alcohol use in patients with co-occurring bipolar and substance use disorders. J Clin Psychiatry. 2009;70(2):171-176.

18. Manwani SG, Szilagyi KA, Zablotsky B, Hennen J, Griffin ML, Weiss RD. Adherence to pharmacotherapy in bipolar disorder patients with and without co-occurring substance use disorders. J Clin Psychiatry. 2007;68(8):1172-1176.

19. Tohen M, Greenfield SF, Weiss RD, Zarate CA Jr, Vagge LM. The effect of comorbid substance disorders on the course of bipolar disorder: a review. Harv Rev Psychiatry. 1998;6(3):133-141.

20. van Zaane J, van den Brink W, Draisma S, Smit JH, Nolen WA. The effect of moderate and excessive alcohol use on the course and outcome of patients with bipolar disorders: a prospective cohort study. J Clin Psychiatry. 2010;71(7):885-893.

21. Ostacher MJ, Perlis RH, Nierenberg AA, et al; STEP-BD Investigators. Impact of substance use disorders on recovery from episodes of depression in bipolar disorder patients: prospective data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2010;167(3):289-297.

22. Oquendo MA, Currier D, Liu SM, Hasin DS, Grant BF, Blanco C. Increased risk for suicidal behavior in comorbid bipolar disorder and alcohol use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). J Clin Psychiatry. 2010;71(7):902-909.

23. Yoon YH, Chen CM, Yi HY, Moss HB. Effect of comorbid alcohol and drug use disorders on premature death of unipolar and bipolar decedents in the United States, 1999 to 2006. Compr Psychiatry. 2011;52(5):453-464.

24. Lydecker KP, Tate SR, Cummins KM, McQuaid J, Granholm E, Brown SA. Clinical outcomes of an integrated treatment for depression and substance use disorders. Psychol Addict Behav. 2010;24(3):453-465.

25. Weiss RD, Griffin ML, Kolodziej ME, et al. A randomized trial of integrated group therapy versus group drug counseling for patients with bipolar disorder and substance dependence. Am J Psychiatry. 2007;164(1):100-107.

26. Hesse M. Integrated psychological treatment for substance use and co-morbid anxiety or depression vs. treatment for substance use alone. A systematic review of the published literature. BMC Psychiatry. 2009;9:6.

27. Moak DH, Anton RF, Latham PK, Voronin KE, Waid RL, Durazo-Arvizu R. Sertraline and cognitive behavioral therapy for depressed alcoholics: results of a placebo-controlled trial. J Clin Psychopharmacol. 2003;23(6):553-562.

28. Thekiso TB, Murphy P, Milnes J, Lambe K, Curtin A, Farren CK. Acceptance and commitment therapy in the treatment of alcohol use disorder and comorbid affective disorder: a pilot matched control trial. Behav Ther. 2015;46(6):717-728.

29. Fleck DE, Amdt S, Delbello MP, Strakowski SM. Concurrent tracking of alcohol use and bipolar disorder symptoms. Bipolar Disord. 2006:8(4):338-344.

30. Brown ES, Gaza M, Carmody TJ. A randomized, double-blind, placebo-controlled add-on trial of quetiapine in outpatients with bipolar disorder and alcohol use disorders. J Clin Psychiatry. 2008;69(5):701-705.

31. Brown ES, Carmody TJ, Schmitz JM, et al. A randomized, double-blind, placebocontrolled pilot study of naltrexone in outpatients with bipolar disorder and alcohol dependence. Alcohol Clin Exp Res. 2009;33(11):1863-1869.

32. Tolliver BK, Desantis SM, Brown DG, Prisciandaro JJ, Brady KT. A randomized, double-blind, placebo-controlled clinical trial of acamprosate in alcoholdependent individuals with bipolar disorder: a preliminary report. Bipolar Disord. 2012;14(1):54-63.

33. Pettinati HM, O’Brien CP, Dundon WD. Current status of co-occurring mood and substance use disorders: a new therapeutic target. Am J Psychiatry. 2013;170(1):23-30.

34. Salloum IM, Cornelius JR, Daley DC, Kirisci L, Himmelhoch JM, Thase ME. Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo-controlled study. Arch Gen Psychiatry. 2005;62(1):37-45.

35. Farren CK, Hill KP, Weiss RD. Bipolar disorder and alcohol use disorder: a review. Curr Psychiatry Rep. 2012;14(6):659-666.

36. Dorus W, Ostrow DG, Anton R, et al. Lithium treatment of depressed and nondepressed alcoholics. JAMA. 1989;262(12):1646-1652.

37. Han DH, Kim SM, Choi JE, Min KJ, Renshaw PF. Adjunctive aripiprazole therapy with escitalopram in patients with co-morbid major depressive disorder and alcohol dependence: clinical and neuroimaging evidence. J Psychopharmacol. 2013;27(3):282-291.

38. Kranzler HR, Burleson JA, Korner P, et al. Placebo-controlled trial of fluoxetine as an adjunct to relapse prevention in alcoholics. Am J Psychiatry. 1995;152(3):391-397.

39. Roy A. Placebo-controlled study of sertraline in depressed recently abstinent alcoholics. Biol Psychiatry. 1998;44(7):633-637.

40. Charney DA, Heath LM, Zikos E, Palacios-Boix J, Gill KJ. Poorer drinking outcomes with citalopram treatment for alcohol dependence: a randomized, doubleblind, placebo-controlled trial. Alcohol Clin Exp Res. 2015;39(9):1756-1765.

41. Adamson SJ, Sellman JD, Foulds JA, et al. A randomized trial of combined citalopram and naltrexone for non-abstinent outpatients with co-occurring alcohol dependence and major depression. J Clin Psychopharmacol. 2015;35(2):143-149.

42. Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis. JAMA. 2004;291(15):1887-1896.

43. Davis LL, Wisniewski SR, Howland RH, et al. Does comorbid substance use disorder impair recovery from major depression with SSRI treatment? An analysis of the STAR*D level one treatment outcomes. Drug Alcohol Depend. 2010;107(2-3):161-170.

44. Pettinati HM. The use of selective reuptake inhibitors in treating alcoholic subtypes. J Clin Psychiatry. 2001;62(suppl 20):26-31.

45. Cornelius JR, Salloum IM, Ehler JG, et al. Fluoxetine in depressed alcoholics. A double-blind, placebo-controlled trial. Arch Gen Psychiatry. 1997;54(8):700-705.

46. Mason BJ, Kocsis JH, Ritvo EC, Cutler RB. A double-blind, placebo-controlled trial of desipramine for primary alcohol dependence stratified on the presence of absence of major depression. JAMA. 1996;275(10):761-767.

47. McGrath PJ, Nunes EV, Stewart JW, et al. Imipramine treatment of alcoholics with primary depression: a placebo-controlled clinical trial. Arch Gen Psychiatry. 1996;53(3):232-240.

48. Pettinati HM, Oslin DW, Kampman KM, et al. A double-blind, placebo-controlled trial combining sertraline and naltrexone for treating co-occurring depression and alcohol dependence. Am J Psychiatry. 2010;167(6):668-675.

References

1. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):593-602.

2. Conway KP, Compton W, Stinson FS, Grant BF. Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2006;67(2):247-257.

3. Gilman SE, Abraham HD. A longitudinal study of the order of onset of alcohol dependence and major depression. Drug Alcohol Depend. 2001;63(3):277-286.

4. Kessler RC, Crum RM, Warner LA, Nelson CB, Schulenberg J, Anthony JC. Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey. Arch Gen Psychiatry. 1997;54(4):313-321.

5. Blanco C, Alegría AA, Liu SM, et al. Differences among major depressive disorder with and without co-occurring substance use disorders and substance-induced depressive disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2012;73(6):865-873.

6. Brown SA, Schuckit MA. Changes in depression among abstinent alcoholics. J Stud Alcohol. 1988;49(5):412-417.

7. Kiefer F, Jahn H, Tarnaske T, et al. Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 2003;60(1):92-99.

8. Ramsey SE, Kahler CW, Read JP, Stuart GL, Brown RA. Discriminating between substance-induced and independent depressive episodes in alcohol-dependent patients. J Stud Alcohol. 2004;65(5):672-676.

9. Greenfield SF, Weiss RD, Muenz LR, et al. The effect of depression on return to drinking: a prospective study. Arch Gen Psychiatry. 1998;55(3):259-265.

10. Hasin D, Liu X, Nunes E, McCloud S, Samet S, Endicott J. Effects of major depression on remission and relapse of substance dependence. Arch Gen Psychiatry. 2002;59(4):375-380.

11. Mueller TI, Lavori PW, Martin B, et al. Prognostic effect of the variable course of alcoholism on the 10-year course of depression. Am J Psychiatry. 1994;151(5):701-706.

12. Agosti V, Levin FR. The effects of alcohol and drug dependence on the course of depression. Am J Addict. 2006;15(1):71-75.

13. Aharonovich E, Liu X, Nunes E, Hasin DS. Suicide attempts in substance abusers: effects of major depression in relation to substance use disorders. Am J Psychiatry. 2002;159(9):1600-1602.

14. Ries RK, Demirsoy A, Russo JE, Barrett J, Roy-Byrne PP. Reliability and clinical utility of DSM-IV substance-induced psychiatric disorders in acute psychiatric inpatients. Am J Addict. 2001;10(4):308-318.

15. Ries RK, Yuodelis-Flores C, Comtois KA, Roy-Byrne PP, Russo JE. Substanceinduced suicidal admissions to an acute psychiatric service: characteristics and outcomes. J Subst Abuse Treat. 2008;34(1):72-79.

16. Toliver BK, Anton RF. Assessment and treatment of mood disorders in the context of substance abuse. Dialogues Clin Neurosci. 2015;17(2):181-190.

17. Jaffee WB, Griffin ML, Gallop R, et al. Depression precipitated by alcohol use in patients with co-occurring bipolar and substance use disorders. J Clin Psychiatry. 2009;70(2):171-176.

18. Manwani SG, Szilagyi KA, Zablotsky B, Hennen J, Griffin ML, Weiss RD. Adherence to pharmacotherapy in bipolar disorder patients with and without co-occurring substance use disorders. J Clin Psychiatry. 2007;68(8):1172-1176.

19. Tohen M, Greenfield SF, Weiss RD, Zarate CA Jr, Vagge LM. The effect of comorbid substance disorders on the course of bipolar disorder: a review. Harv Rev Psychiatry. 1998;6(3):133-141.

20. van Zaane J, van den Brink W, Draisma S, Smit JH, Nolen WA. The effect of moderate and excessive alcohol use on the course and outcome of patients with bipolar disorders: a prospective cohort study. J Clin Psychiatry. 2010;71(7):885-893.

21. Ostacher MJ, Perlis RH, Nierenberg AA, et al; STEP-BD Investigators. Impact of substance use disorders on recovery from episodes of depression in bipolar disorder patients: prospective data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2010;167(3):289-297.

22. Oquendo MA, Currier D, Liu SM, Hasin DS, Grant BF, Blanco C. Increased risk for suicidal behavior in comorbid bipolar disorder and alcohol use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). J Clin Psychiatry. 2010;71(7):902-909.

23. Yoon YH, Chen CM, Yi HY, Moss HB. Effect of comorbid alcohol and drug use disorders on premature death of unipolar and bipolar decedents in the United States, 1999 to 2006. Compr Psychiatry. 2011;52(5):453-464.

24. Lydecker KP, Tate SR, Cummins KM, McQuaid J, Granholm E, Brown SA. Clinical outcomes of an integrated treatment for depression and substance use disorders. Psychol Addict Behav. 2010;24(3):453-465.

25. Weiss RD, Griffin ML, Kolodziej ME, et al. A randomized trial of integrated group therapy versus group drug counseling for patients with bipolar disorder and substance dependence. Am J Psychiatry. 2007;164(1):100-107.

26. Hesse M. Integrated psychological treatment for substance use and co-morbid anxiety or depression vs. treatment for substance use alone. A systematic review of the published literature. BMC Psychiatry. 2009;9:6.

27. Moak DH, Anton RF, Latham PK, Voronin KE, Waid RL, Durazo-Arvizu R. Sertraline and cognitive behavioral therapy for depressed alcoholics: results of a placebo-controlled trial. J Clin Psychopharmacol. 2003;23(6):553-562.

28. Thekiso TB, Murphy P, Milnes J, Lambe K, Curtin A, Farren CK. Acceptance and commitment therapy in the treatment of alcohol use disorder and comorbid affective disorder: a pilot matched control trial. Behav Ther. 2015;46(6):717-728.

29. Fleck DE, Amdt S, Delbello MP, Strakowski SM. Concurrent tracking of alcohol use and bipolar disorder symptoms. Bipolar Disord. 2006:8(4):338-344.

30. Brown ES, Gaza M, Carmody TJ. A randomized, double-blind, placebo-controlled add-on trial of quetiapine in outpatients with bipolar disorder and alcohol use disorders. J Clin Psychiatry. 2008;69(5):701-705.

31. Brown ES, Carmody TJ, Schmitz JM, et al. A randomized, double-blind, placebocontrolled pilot study of naltrexone in outpatients with bipolar disorder and alcohol dependence. Alcohol Clin Exp Res. 2009;33(11):1863-1869.

32. Tolliver BK, Desantis SM, Brown DG, Prisciandaro JJ, Brady KT. A randomized, double-blind, placebo-controlled clinical trial of acamprosate in alcoholdependent individuals with bipolar disorder: a preliminary report. Bipolar Disord. 2012;14(1):54-63.

33. Pettinati HM, O’Brien CP, Dundon WD. Current status of co-occurring mood and substance use disorders: a new therapeutic target. Am J Psychiatry. 2013;170(1):23-30.

34. Salloum IM, Cornelius JR, Daley DC, Kirisci L, Himmelhoch JM, Thase ME. Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo-controlled study. Arch Gen Psychiatry. 2005;62(1):37-45.

35. Farren CK, Hill KP, Weiss RD. Bipolar disorder and alcohol use disorder: a review. Curr Psychiatry Rep. 2012;14(6):659-666.

36. Dorus W, Ostrow DG, Anton R, et al. Lithium treatment of depressed and nondepressed alcoholics. JAMA. 1989;262(12):1646-1652.

37. Han DH, Kim SM, Choi JE, Min KJ, Renshaw PF. Adjunctive aripiprazole therapy with escitalopram in patients with co-morbid major depressive disorder and alcohol dependence: clinical and neuroimaging evidence. J Psychopharmacol. 2013;27(3):282-291.

38. Kranzler HR, Burleson JA, Korner P, et al. Placebo-controlled trial of fluoxetine as an adjunct to relapse prevention in alcoholics. Am J Psychiatry. 1995;152(3):391-397.

39. Roy A. Placebo-controlled study of sertraline in depressed recently abstinent alcoholics. Biol Psychiatry. 1998;44(7):633-637.

40. Charney DA, Heath LM, Zikos E, Palacios-Boix J, Gill KJ. Poorer drinking outcomes with citalopram treatment for alcohol dependence: a randomized, doubleblind, placebo-controlled trial. Alcohol Clin Exp Res. 2015;39(9):1756-1765.

41. Adamson SJ, Sellman JD, Foulds JA, et al. A randomized trial of combined citalopram and naltrexone for non-abstinent outpatients with co-occurring alcohol dependence and major depression. J Clin Psychopharmacol. 2015;35(2):143-149.

42. Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis. JAMA. 2004;291(15):1887-1896.

43. Davis LL, Wisniewski SR, Howland RH, et al. Does comorbid substance use disorder impair recovery from major depression with SSRI treatment? An analysis of the STAR*D level one treatment outcomes. Drug Alcohol Depend. 2010;107(2-3):161-170.

44. Pettinati HM. The use of selective reuptake inhibitors in treating alcoholic subtypes. J Clin Psychiatry. 2001;62(suppl 20):26-31.

45. Cornelius JR, Salloum IM, Ehler JG, et al. Fluoxetine in depressed alcoholics. A double-blind, placebo-controlled trial. Arch Gen Psychiatry. 1997;54(8):700-705.

46. Mason BJ, Kocsis JH, Ritvo EC, Cutler RB. A double-blind, placebo-controlled trial of desipramine for primary alcohol dependence stratified on the presence of absence of major depression. JAMA. 1996;275(10):761-767.

47. McGrath PJ, Nunes EV, Stewart JW, et al. Imipramine treatment of alcoholics with primary depression: a placebo-controlled clinical trial. Arch Gen Psychiatry. 1996;53(3):232-240.

48. Pettinati HM, Oslin DW, Kampman KM, et al. A double-blind, placebo-controlled trial combining sertraline and naltrexone for treating co-occurring depression and alcohol dependence. Am J Psychiatry. 2010;167(6):668-675.

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A Review of Psychostimulants for Adults With Depression

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A survey of medical literature suggests that for patients with depression who have not responded to other augmentation strategies, psychostimulants may offer improvements in mood, energy, and concentration.

Depression is a common condition that significantly impairs social and occupational functioning. Many patients do not respond to first-line pharmacotherapies and are considered to have treatment-resistant depression (TRD). These patients may benefit from augmentation of their antidepressant to reduce depression. Multiple medications have demonstrated various degrees of efficacy for augmentation, including psychostimulants. This article reviews studies of psychostimulants as augmentation agents for TRD and discusses risks, offers advice, and makes recommendations for clinicians who prescribe stimulants.

Background

Major depressive disorder (MDD) is a common psychiatric condition that significantly impairs quality of life.1 It is a recurrent illness, averaging 2 relapses per decade. The probability of recurrence increases with the number of depressive episodes.2,3 A patient who experiences major depressive episodes alternating with euthymia has unipolar depression; whereas one who experiences major depressive episodes alternating with episodes of mania or hypomania has bipolar depression.4

Despite adequate dose and duration of pharmacotherapy, many individuals with unipolar or bipolar depression do not achieve and sustain remission.5 Remission rates decrease and relapse rates increase with subsequent failed antidepressant trials.6 It is difficult to identify factors that predict treatment resistance, but one review of antidepressant studies found that patients who did not demonstrate a response within 3 weeks of medication initiation were less likely to respond after a longer duration.7

Treatment-resistant depression is commonly, but not universally, defined as lack of response after trials of 2 or more antidepressants with different mechanisms of action for sufficient duration.5 This definition will be used here as well. Other definitions have proposed stages of TRD, but these require further study to evaluate their reliability and predictive utility.8 Due to lack of consensus regarding the definition of TRD, it is not possible to determine the exact prevalence of TRD.

Patients with TRD may benefit from augmentation of their medication regimen. Augmentation with lithium has yielded conflicting results, and its efficacy with newer antidepressants is not well studied.9-12 Triiodothyronine, buspirone, and pindolol have demonstrated some efficacy when added to serotonin reuptake inhibitors (SRIs).10,12,13 Second-generation antipsychotic drugs, antidepressant drug combinations, omega-3 fatty acids, S-adenosyl methionine (SAMe), and L-methylfolate have demonstrated some efficacy in some studies as well.12,14-23 In patients with depression who have not responded to these strategies, psychostimulant augmentation may be appropriate.

Methods

A literature search was conducted following an algorithmic approach in the MEDLINE/PubMed database for studies in English from January 1985 to August 2014 of stimulants as augmenting agents for depression, using the Medical Subject Headings stimulant, depression, and augmentation, combined with an AND operator. The search was limited to adult humans and excluded case reports and letters, to identify studies with stronger evidence. Also excluded were studies using caffeine (to augment electroconvulsive therapy for depression) and pemoline as the sole augmenting stimulant as well as studies of patients with comorbid mental health diagnoses and studies that initiated stimulants and antidepressants simultaneously to assess antidepressant response.

This review organized results by stimulant rather than by depression type, even though some studies used > 1 stimulant or recruited patients with different types of depression. Although prevalence, prognosis, and monotherapy differ for unipolar and bipolar depression, psychostimulants target similar symptoms, despite augmenting different monotherapies in unipolar and bipolar depression. Therefore, no distinction is made between assessing studies of stimulants for unipolar and bipolar depression.

Results

A total of 70 articles were identified, and 31 studies met inclusion criteria (Figure). Of the studies included, 12 were double-blind, placebo-controlled (DBPC) trials and 19 were retrospective chart reviews or open studies. Most studies evaluated depression, using validated scales, such as the Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale, Clinical Global Impressions of Severity, Inventory of Depressive Symptoms, Carroll Depression Rating Scale, Global Assessment of Functioning, Quick Inventory of Depressive Symptomatology, or the Psychiatric Symptom Assessment Scale. Study details are provided in Tables 1 to 4.

Dextroamphetamine and Methylphenidate

Dextroamphetamine and methylphenidate are indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) and exert their effects by inhibiting uptake of norepinephrine and dopamine.24 In one chart review, patients received dextroamphetamine or methylphenidate augmentation of monoamine oxidase inhibitors (MAOIs) alone or with concurrent tricyclic antidepressants; the majority reported decreased depression.25 In an openlabel trial, dextroamphetamine was titrated to efficacy in patients who were receiving an MAOI with or without pemoline.26 Nearly 80% of patients reported long-lasting improvement in depression. In an open-label trial, all patients reported decreased depression when methylphenidate was added to SRIs; however, no scales were used.27

In a case series, patients with both major depression and persistent depressive disorder (dysthymia) experienced a substantial, quick, and sustained response to dextroamphetamine or methylphenidate augmentation.28 Addition of lisdexamfetamine significantly reduced depressive symptoms in individuals with inadequate response to escitalopram.29 Patients with full or partial remission of depression noted improved executive function and residual depressive symptoms after lisdexamfetamine was added to SRI monotherapy.30 In a trial in which patients received dexamphetamine or methylphenidate as monotherapy or augmentation, 30% to 34% of patients reported mood improvement, but 36% reported no improvement.31 In an extension study, low-dose psychostimulants quickly diminished melancholia.32

Methylphenidate was safe and effective in patients with bipolar depression receiving treatment for 1 to 5 years; 44% evidenced significant improvement.33 When offered to patients with bipolar depression, patients receiving methylphenidate or dextroamphetamine reported less depression or sedation and did not develop tolerance, mania, or misuse.34 A case series concluded that methylphenidate addition to mood stabilizers was generally effective and safe.35

However, not all preparations of methylphenidate have demonstrated efficacy. In one study, osmotic controlledrelease oral system (OROS) methylphenidate improved apathy and fatigue but not overall depression.36 Although OROS methylphenidate similarly failed to demonstrate statistically significant efficacy in another study, more responders were documented in the treatment group.37

Although this review focuses on stimulants as augmenting agents in patients with depression, it is worth noting the limited number of studies evaluating stimulants’ effect on depression in patients with traumatic brain injury. This observation is of concern, as these conditions are frequently comorbid in returning veterans. One study noted that methylphenidate was an effective monotherapy for depression; whereas another study found that methylphenidate monotherapy reduced depression as well as sertraline, was better tolerated, and improved fatigue and cognition.38,39

Modafinil and Armodafinil

Modafinil and armodafinil (the R-enantiomer of modafinil) are indicated for improving wakefulness in individuals with narcolepsy, obstructive sleep apnea, and shift work sleep disorder by modulating glutamate, gamma amino-butyric acid, and histamine.40,41 Although they increase extracellular dopamine concentrations, they do not cause an increase in dopamine release and may have less misuse potential than that of dextroamphetamine and methylphenidate.40,41 In a study of 7 patients with unipolar or bipolar depression, all patients achieved full or partial remission with minimal adverse effects (AEs).42 In a prospective study, 41% of patients reported only mild depression or full remission with modafinil augmentation.43

Multiple trials and a pooled analysis noted decreased depression and fatigue and improved cognition in patients receiving modafinil augmentation compared with mood stabilizers or antidepressants.44-49 Modafinil is a useful adjunct for partial responders to SRIs, resulting in rapid mood improvement and decreased fatigue.50-54 However, in one study, modafinil did not demonstrate efficacy compared with placebo. This result was attributed to premature study termination after 2 modafinil-treated patients developed suicidal ideation.55 A post hoc analysis found no difference in frequency of suicidal ideation between groups.

Two DBPC studies evaluated armodafinil in patients with bipolar depression. In both studies it was added to a mood-stabilizing agent (lithium, valproate, aripiprazole, olanzapine, lamotrigine, risperidone, or ziprasidone), and patients receiving armodafinil reported significant reductions
in depression.56,57

Atomoxetine

Atomoxetine is a norepinephrine reuptake inhibitor indicated for the treatment of ADHD and is considered to have no misuse potential due to lack of dopamine modulation.58 In one study, 15 patients received atomoxetine added to their antidepressant, and 60% experienced significant symptom reduction.59 A chart review noted decreases in fatigue and depression when atomoxetine was added to an SRI, mirtazapine, or amitriptyline.60 However, in a DBPC trial, atomoxetine did not lead to significant changes in depression.61

Discussion

There is a limited amount of high-quality evidence to support psychostimulant augmentation, as noted by the relatively few DBPC trials, most of short duration. The evidence supports their efficacy primarily for unipolar depression, as 14 studies evaluated patients with unipolar depression, whereas only 7 studies evaluated patients with bipolar depression. The remaining studies recruited patients with both depression types. Collectively, modafinil and armodafinil have the most evidence in DBPC trials.

There are relatively few DBPC trials with high power and sufficient duration for dextroamphetamine and methylphenidate preparations. This discovery is surprising, considering the duration that these medications have been available. However, several chart reviews and open-label trials provided some evidence to support their use in patients without a history of substance misuse or cardiac conditions.62 Osmotic controlled- release oral system methylphenidate seems to be ineffective, and the efficacy of atomoxetine for augmentation
is uncertain.

Precautions

Prescribing physicians who offer stimulants should consider potential AEs, such as psychosis, anorexia, anxiety, insomnia, mood changes (eg, anger),  misuse, addiction, mania, and cardiovascular problems. Psychostimulants have been implicated in precipitating psychosis.63,64 However, in a 12-month study of 250 adults with ADHD, 73 reported AEs, and only 31 discontinued the stimulant. Adverse effects leading to discontinuation included mood instability (n = 7), agitation (n = 6), irritability (n = 4), or decreased appetite (n = 4).65

Although associated with the risks of anorexia and insomnia in patients with ADHD, methylphenidate rapidly improved daytime sleepiness and mood, and—paradoxically—appetite and nighttime sleep in medically ill elderly patients with depression.66 Misuse or abuse of methylphenidate and dextroamphetamine were noted in 23% of patients referred for substance misuse.67 Nonetheless, little evidence exists that these drugs possess significant misuse potential in patients taking them as prescribed. As a prodrug, lisdexamfetamine is hypothesized to have less abuse potential compared with dextroamphetamine and methylphenidate, but it carries the same prescribing and monitoring precautions.68 Risks related to stimulant usage extend to manic symptoms.69 Patients with bipolar disorder should not receive stimulants if they have a history of stimulant-induced mania, rapid cycling, or psychosis.70

Long-term cardiovascular safety data exist for dextroamphetamine and methylphenidate but are limited or unavailable for modafinil, armodafinil, and atomoxetine. A retrospective cohort study found no significant increase in the number of cardiac events in patients receiving dextroamphetamine,
methylphenidate, or atomoxetine for an average of 1 year compared with controls.71 Another cohort study of > 44,000 patients found that initiation of
methylphenidate was associated with increased risk of sudden death or arrhythmia, but the risk was attributed to an unmeasured confounding factor, as the authors found a negative correlation between methylphenidate dose and all cardiovascular events.72

Recent practice guidelines recommend that before prescribing stimulants, clinicians should perform a physical examination (including heart and lung auscultation), obtain vital signs and height and weight, and request an electrocardiogram in case of abnormal findings on a cardiovascular examination or in case of a personal or family history of heart disease. Before offering atomoxetine, clinicians should evaluate the patient for a history of liver disease (and check liver function studies in case of a positive history). Clinicians should also assess risk of self-harm prior to initiating psychostimulant therapy.73 Throughout treatment, clinicians should evaluate the patient for changes in blood pressure, pulse, weight or mood, as well as the development of dependence or misuse. Urine toxicology testing is recommended for dextroamphetamine and methylphenidate to screen for adherence and diversion.

Limitations

Using only PubMed and MEDLINE databases limited the search to articles published in English after 1985, excluding letters and case reports to identify studies with higher evidence (the studies were not weighted based on study design). In addition, the studies had certain limitations. These include a limited number of DBPC trials, most were of short duration. It is also difficult to compare studies due to various rating scales used and concurrent
medication regimens of study subjects. These limitations raise questions surrounding the long-term efficacy of stimulants, and there is no consensus for how long a stimulant should be continued if beneficial. Longer, higherpowered, DBPC trials are warranted to determine longterm efficacy and safety of stimulant augmentation.62

Conclusion

For patients with depression who have not responded to other augmentation strategies, psychostimulants may be offered to improve mood, energy, and concentration. For clinicians considering stimulant augmentation, modafinil and armodafinil are reasonable choices given their efficacy in double-blind, placebo-controlled trials and lower risk of misuse. Dextroamphetamine (particularly lisdexamphetamine) and methylphenidate may be appropriate for patients who have not benefited from or tolerated modafinil or armodafinil, provided these patients do not have a medical history of cardiac disease or current substance use.

Osmotic controlled-release oral system methylphenidate seems to be ineffective as an augmenting agent. The efficacy of atomoxetine for augmentation is questionable, but atomoxetine could be offered if other stimulants were contraindicated, ineffective, or poorly tolerated. Both OROS methylphenidate and atomoxetine should be evaluated in additional trials before they can be recommended as augmentation therapies. Certain psychostimulants may be appropriate and reasonable adjunctive pharmacotherapies for patients with unipolar or bipolar depression who have failed other augmentation strategies, for patients who have significant fatigue or cognitive complaints, or for elderly patients with melancholic or somatic features of depression.

Acknowledgements
The authors thank Maureen Humphrey-Shelton and Kathy Thomas for their help in obtaining references.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

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Drs. Pary, Jijakli, and Tobias are psychiatrists at the Robley Rex VAMC in Louisville, Kentucky. Dr. Scarff is a psychiatrist at the William Jennings Bryan Dorn Veterans Affairs Community Based Outpatient Clinic in Spartanburg, South Carolina. Dr. Lippmann is professor emeritus in the Department of Psychiatry and Behavioral Sciences at the University of Louisville School of Medicine in Kentucky.

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Drs. Pary, Jijakli, and Tobias are psychiatrists at the Robley Rex VAMC in Louisville, Kentucky. Dr. Scarff is a psychiatrist at the William Jennings Bryan Dorn Veterans Affairs Community Based Outpatient Clinic in Spartanburg, South Carolina. Dr. Lippmann is professor emeritus in the Department of Psychiatry and Behavioral Sciences at the University of Louisville School of Medicine in Kentucky.

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Drs. Pary, Jijakli, and Tobias are psychiatrists at the Robley Rex VAMC in Louisville, Kentucky. Dr. Scarff is a psychiatrist at the William Jennings Bryan Dorn Veterans Affairs Community Based Outpatient Clinic in Spartanburg, South Carolina. Dr. Lippmann is professor emeritus in the Department of Psychiatry and Behavioral Sciences at the University of Louisville School of Medicine in Kentucky.

A survey of medical literature suggests that for patients with depression who have not responded to other augmentation strategies, psychostimulants may offer improvements in mood, energy, and concentration.
A survey of medical literature suggests that for patients with depression who have not responded to other augmentation strategies, psychostimulants may offer improvements in mood, energy, and concentration.

Depression is a common condition that significantly impairs social and occupational functioning. Many patients do not respond to first-line pharmacotherapies and are considered to have treatment-resistant depression (TRD). These patients may benefit from augmentation of their antidepressant to reduce depression. Multiple medications have demonstrated various degrees of efficacy for augmentation, including psychostimulants. This article reviews studies of psychostimulants as augmentation agents for TRD and discusses risks, offers advice, and makes recommendations for clinicians who prescribe stimulants.

Background

Major depressive disorder (MDD) is a common psychiatric condition that significantly impairs quality of life.1 It is a recurrent illness, averaging 2 relapses per decade. The probability of recurrence increases with the number of depressive episodes.2,3 A patient who experiences major depressive episodes alternating with euthymia has unipolar depression; whereas one who experiences major depressive episodes alternating with episodes of mania or hypomania has bipolar depression.4

Despite adequate dose and duration of pharmacotherapy, many individuals with unipolar or bipolar depression do not achieve and sustain remission.5 Remission rates decrease and relapse rates increase with subsequent failed antidepressant trials.6 It is difficult to identify factors that predict treatment resistance, but one review of antidepressant studies found that patients who did not demonstrate a response within 3 weeks of medication initiation were less likely to respond after a longer duration.7

Treatment-resistant depression is commonly, but not universally, defined as lack of response after trials of 2 or more antidepressants with different mechanisms of action for sufficient duration.5 This definition will be used here as well. Other definitions have proposed stages of TRD, but these require further study to evaluate their reliability and predictive utility.8 Due to lack of consensus regarding the definition of TRD, it is not possible to determine the exact prevalence of TRD.

Patients with TRD may benefit from augmentation of their medication regimen. Augmentation with lithium has yielded conflicting results, and its efficacy with newer antidepressants is not well studied.9-12 Triiodothyronine, buspirone, and pindolol have demonstrated some efficacy when added to serotonin reuptake inhibitors (SRIs).10,12,13 Second-generation antipsychotic drugs, antidepressant drug combinations, omega-3 fatty acids, S-adenosyl methionine (SAMe), and L-methylfolate have demonstrated some efficacy in some studies as well.12,14-23 In patients with depression who have not responded to these strategies, psychostimulant augmentation may be appropriate.

Methods

A literature search was conducted following an algorithmic approach in the MEDLINE/PubMed database for studies in English from January 1985 to August 2014 of stimulants as augmenting agents for depression, using the Medical Subject Headings stimulant, depression, and augmentation, combined with an AND operator. The search was limited to adult humans and excluded case reports and letters, to identify studies with stronger evidence. Also excluded were studies using caffeine (to augment electroconvulsive therapy for depression) and pemoline as the sole augmenting stimulant as well as studies of patients with comorbid mental health diagnoses and studies that initiated stimulants and antidepressants simultaneously to assess antidepressant response.

This review organized results by stimulant rather than by depression type, even though some studies used > 1 stimulant or recruited patients with different types of depression. Although prevalence, prognosis, and monotherapy differ for unipolar and bipolar depression, psychostimulants target similar symptoms, despite augmenting different monotherapies in unipolar and bipolar depression. Therefore, no distinction is made between assessing studies of stimulants for unipolar and bipolar depression.

Results

A total of 70 articles were identified, and 31 studies met inclusion criteria (Figure). Of the studies included, 12 were double-blind, placebo-controlled (DBPC) trials and 19 were retrospective chart reviews or open studies. Most studies evaluated depression, using validated scales, such as the Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale, Clinical Global Impressions of Severity, Inventory of Depressive Symptoms, Carroll Depression Rating Scale, Global Assessment of Functioning, Quick Inventory of Depressive Symptomatology, or the Psychiatric Symptom Assessment Scale. Study details are provided in Tables 1 to 4.

Dextroamphetamine and Methylphenidate

Dextroamphetamine and methylphenidate are indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) and exert their effects by inhibiting uptake of norepinephrine and dopamine.24 In one chart review, patients received dextroamphetamine or methylphenidate augmentation of monoamine oxidase inhibitors (MAOIs) alone or with concurrent tricyclic antidepressants; the majority reported decreased depression.25 In an openlabel trial, dextroamphetamine was titrated to efficacy in patients who were receiving an MAOI with or without pemoline.26 Nearly 80% of patients reported long-lasting improvement in depression. In an open-label trial, all patients reported decreased depression when methylphenidate was added to SRIs; however, no scales were used.27

In a case series, patients with both major depression and persistent depressive disorder (dysthymia) experienced a substantial, quick, and sustained response to dextroamphetamine or methylphenidate augmentation.28 Addition of lisdexamfetamine significantly reduced depressive symptoms in individuals with inadequate response to escitalopram.29 Patients with full or partial remission of depression noted improved executive function and residual depressive symptoms after lisdexamfetamine was added to SRI monotherapy.30 In a trial in which patients received dexamphetamine or methylphenidate as monotherapy or augmentation, 30% to 34% of patients reported mood improvement, but 36% reported no improvement.31 In an extension study, low-dose psychostimulants quickly diminished melancholia.32

Methylphenidate was safe and effective in patients with bipolar depression receiving treatment for 1 to 5 years; 44% evidenced significant improvement.33 When offered to patients with bipolar depression, patients receiving methylphenidate or dextroamphetamine reported less depression or sedation and did not develop tolerance, mania, or misuse.34 A case series concluded that methylphenidate addition to mood stabilizers was generally effective and safe.35

However, not all preparations of methylphenidate have demonstrated efficacy. In one study, osmotic controlledrelease oral system (OROS) methylphenidate improved apathy and fatigue but not overall depression.36 Although OROS methylphenidate similarly failed to demonstrate statistically significant efficacy in another study, more responders were documented in the treatment group.37

Although this review focuses on stimulants as augmenting agents in patients with depression, it is worth noting the limited number of studies evaluating stimulants’ effect on depression in patients with traumatic brain injury. This observation is of concern, as these conditions are frequently comorbid in returning veterans. One study noted that methylphenidate was an effective monotherapy for depression; whereas another study found that methylphenidate monotherapy reduced depression as well as sertraline, was better tolerated, and improved fatigue and cognition.38,39

Modafinil and Armodafinil

Modafinil and armodafinil (the R-enantiomer of modafinil) are indicated for improving wakefulness in individuals with narcolepsy, obstructive sleep apnea, and shift work sleep disorder by modulating glutamate, gamma amino-butyric acid, and histamine.40,41 Although they increase extracellular dopamine concentrations, they do not cause an increase in dopamine release and may have less misuse potential than that of dextroamphetamine and methylphenidate.40,41 In a study of 7 patients with unipolar or bipolar depression, all patients achieved full or partial remission with minimal adverse effects (AEs).42 In a prospective study, 41% of patients reported only mild depression or full remission with modafinil augmentation.43

Multiple trials and a pooled analysis noted decreased depression and fatigue and improved cognition in patients receiving modafinil augmentation compared with mood stabilizers or antidepressants.44-49 Modafinil is a useful adjunct for partial responders to SRIs, resulting in rapid mood improvement and decreased fatigue.50-54 However, in one study, modafinil did not demonstrate efficacy compared with placebo. This result was attributed to premature study termination after 2 modafinil-treated patients developed suicidal ideation.55 A post hoc analysis found no difference in frequency of suicidal ideation between groups.

Two DBPC studies evaluated armodafinil in patients with bipolar depression. In both studies it was added to a mood-stabilizing agent (lithium, valproate, aripiprazole, olanzapine, lamotrigine, risperidone, or ziprasidone), and patients receiving armodafinil reported significant reductions
in depression.56,57

Atomoxetine

Atomoxetine is a norepinephrine reuptake inhibitor indicated for the treatment of ADHD and is considered to have no misuse potential due to lack of dopamine modulation.58 In one study, 15 patients received atomoxetine added to their antidepressant, and 60% experienced significant symptom reduction.59 A chart review noted decreases in fatigue and depression when atomoxetine was added to an SRI, mirtazapine, or amitriptyline.60 However, in a DBPC trial, atomoxetine did not lead to significant changes in depression.61

Discussion

There is a limited amount of high-quality evidence to support psychostimulant augmentation, as noted by the relatively few DBPC trials, most of short duration. The evidence supports their efficacy primarily for unipolar depression, as 14 studies evaluated patients with unipolar depression, whereas only 7 studies evaluated patients with bipolar depression. The remaining studies recruited patients with both depression types. Collectively, modafinil and armodafinil have the most evidence in DBPC trials.

There are relatively few DBPC trials with high power and sufficient duration for dextroamphetamine and methylphenidate preparations. This discovery is surprising, considering the duration that these medications have been available. However, several chart reviews and open-label trials provided some evidence to support their use in patients without a history of substance misuse or cardiac conditions.62 Osmotic controlled- release oral system methylphenidate seems to be ineffective, and the efficacy of atomoxetine for augmentation
is uncertain.

Precautions

Prescribing physicians who offer stimulants should consider potential AEs, such as psychosis, anorexia, anxiety, insomnia, mood changes (eg, anger),  misuse, addiction, mania, and cardiovascular problems. Psychostimulants have been implicated in precipitating psychosis.63,64 However, in a 12-month study of 250 adults with ADHD, 73 reported AEs, and only 31 discontinued the stimulant. Adverse effects leading to discontinuation included mood instability (n = 7), agitation (n = 6), irritability (n = 4), or decreased appetite (n = 4).65

Although associated with the risks of anorexia and insomnia in patients with ADHD, methylphenidate rapidly improved daytime sleepiness and mood, and—paradoxically—appetite and nighttime sleep in medically ill elderly patients with depression.66 Misuse or abuse of methylphenidate and dextroamphetamine were noted in 23% of patients referred for substance misuse.67 Nonetheless, little evidence exists that these drugs possess significant misuse potential in patients taking them as prescribed. As a prodrug, lisdexamfetamine is hypothesized to have less abuse potential compared with dextroamphetamine and methylphenidate, but it carries the same prescribing and monitoring precautions.68 Risks related to stimulant usage extend to manic symptoms.69 Patients with bipolar disorder should not receive stimulants if they have a history of stimulant-induced mania, rapid cycling, or psychosis.70

Long-term cardiovascular safety data exist for dextroamphetamine and methylphenidate but are limited or unavailable for modafinil, armodafinil, and atomoxetine. A retrospective cohort study found no significant increase in the number of cardiac events in patients receiving dextroamphetamine,
methylphenidate, or atomoxetine for an average of 1 year compared with controls.71 Another cohort study of > 44,000 patients found that initiation of
methylphenidate was associated with increased risk of sudden death or arrhythmia, but the risk was attributed to an unmeasured confounding factor, as the authors found a negative correlation between methylphenidate dose and all cardiovascular events.72

Recent practice guidelines recommend that before prescribing stimulants, clinicians should perform a physical examination (including heart and lung auscultation), obtain vital signs and height and weight, and request an electrocardiogram in case of abnormal findings on a cardiovascular examination or in case of a personal or family history of heart disease. Before offering atomoxetine, clinicians should evaluate the patient for a history of liver disease (and check liver function studies in case of a positive history). Clinicians should also assess risk of self-harm prior to initiating psychostimulant therapy.73 Throughout treatment, clinicians should evaluate the patient for changes in blood pressure, pulse, weight or mood, as well as the development of dependence or misuse. Urine toxicology testing is recommended for dextroamphetamine and methylphenidate to screen for adherence and diversion.

Limitations

Using only PubMed and MEDLINE databases limited the search to articles published in English after 1985, excluding letters and case reports to identify studies with higher evidence (the studies were not weighted based on study design). In addition, the studies had certain limitations. These include a limited number of DBPC trials, most were of short duration. It is also difficult to compare studies due to various rating scales used and concurrent
medication regimens of study subjects. These limitations raise questions surrounding the long-term efficacy of stimulants, and there is no consensus for how long a stimulant should be continued if beneficial. Longer, higherpowered, DBPC trials are warranted to determine longterm efficacy and safety of stimulant augmentation.62

Conclusion

For patients with depression who have not responded to other augmentation strategies, psychostimulants may be offered to improve mood, energy, and concentration. For clinicians considering stimulant augmentation, modafinil and armodafinil are reasonable choices given their efficacy in double-blind, placebo-controlled trials and lower risk of misuse. Dextroamphetamine (particularly lisdexamphetamine) and methylphenidate may be appropriate for patients who have not benefited from or tolerated modafinil or armodafinil, provided these patients do not have a medical history of cardiac disease or current substance use.

Osmotic controlled-release oral system methylphenidate seems to be ineffective as an augmenting agent. The efficacy of atomoxetine for augmentation is questionable, but atomoxetine could be offered if other stimulants were contraindicated, ineffective, or poorly tolerated. Both OROS methylphenidate and atomoxetine should be evaluated in additional trials before they can be recommended as augmentation therapies. Certain psychostimulants may be appropriate and reasonable adjunctive pharmacotherapies for patients with unipolar or bipolar depression who have failed other augmentation strategies, for patients who have significant fatigue or cognitive complaints, or for elderly patients with melancholic or somatic features of depression.

Acknowledgements
The authors thank Maureen Humphrey-Shelton and Kathy Thomas for their help in obtaining references.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

Depression is a common condition that significantly impairs social and occupational functioning. Many patients do not respond to first-line pharmacotherapies and are considered to have treatment-resistant depression (TRD). These patients may benefit from augmentation of their antidepressant to reduce depression. Multiple medications have demonstrated various degrees of efficacy for augmentation, including psychostimulants. This article reviews studies of psychostimulants as augmentation agents for TRD and discusses risks, offers advice, and makes recommendations for clinicians who prescribe stimulants.

Background

Major depressive disorder (MDD) is a common psychiatric condition that significantly impairs quality of life.1 It is a recurrent illness, averaging 2 relapses per decade. The probability of recurrence increases with the number of depressive episodes.2,3 A patient who experiences major depressive episodes alternating with euthymia has unipolar depression; whereas one who experiences major depressive episodes alternating with episodes of mania or hypomania has bipolar depression.4

Despite adequate dose and duration of pharmacotherapy, many individuals with unipolar or bipolar depression do not achieve and sustain remission.5 Remission rates decrease and relapse rates increase with subsequent failed antidepressant trials.6 It is difficult to identify factors that predict treatment resistance, but one review of antidepressant studies found that patients who did not demonstrate a response within 3 weeks of medication initiation were less likely to respond after a longer duration.7

Treatment-resistant depression is commonly, but not universally, defined as lack of response after trials of 2 or more antidepressants with different mechanisms of action for sufficient duration.5 This definition will be used here as well. Other definitions have proposed stages of TRD, but these require further study to evaluate their reliability and predictive utility.8 Due to lack of consensus regarding the definition of TRD, it is not possible to determine the exact prevalence of TRD.

Patients with TRD may benefit from augmentation of their medication regimen. Augmentation with lithium has yielded conflicting results, and its efficacy with newer antidepressants is not well studied.9-12 Triiodothyronine, buspirone, and pindolol have demonstrated some efficacy when added to serotonin reuptake inhibitors (SRIs).10,12,13 Second-generation antipsychotic drugs, antidepressant drug combinations, omega-3 fatty acids, S-adenosyl methionine (SAMe), and L-methylfolate have demonstrated some efficacy in some studies as well.12,14-23 In patients with depression who have not responded to these strategies, psychostimulant augmentation may be appropriate.

Methods

A literature search was conducted following an algorithmic approach in the MEDLINE/PubMed database for studies in English from January 1985 to August 2014 of stimulants as augmenting agents for depression, using the Medical Subject Headings stimulant, depression, and augmentation, combined with an AND operator. The search was limited to adult humans and excluded case reports and letters, to identify studies with stronger evidence. Also excluded were studies using caffeine (to augment electroconvulsive therapy for depression) and pemoline as the sole augmenting stimulant as well as studies of patients with comorbid mental health diagnoses and studies that initiated stimulants and antidepressants simultaneously to assess antidepressant response.

This review organized results by stimulant rather than by depression type, even though some studies used > 1 stimulant or recruited patients with different types of depression. Although prevalence, prognosis, and monotherapy differ for unipolar and bipolar depression, psychostimulants target similar symptoms, despite augmenting different monotherapies in unipolar and bipolar depression. Therefore, no distinction is made between assessing studies of stimulants for unipolar and bipolar depression.

Results

A total of 70 articles were identified, and 31 studies met inclusion criteria (Figure). Of the studies included, 12 were double-blind, placebo-controlled (DBPC) trials and 19 were retrospective chart reviews or open studies. Most studies evaluated depression, using validated scales, such as the Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale, Clinical Global Impressions of Severity, Inventory of Depressive Symptoms, Carroll Depression Rating Scale, Global Assessment of Functioning, Quick Inventory of Depressive Symptomatology, or the Psychiatric Symptom Assessment Scale. Study details are provided in Tables 1 to 4.

Dextroamphetamine and Methylphenidate

Dextroamphetamine and methylphenidate are indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) and exert their effects by inhibiting uptake of norepinephrine and dopamine.24 In one chart review, patients received dextroamphetamine or methylphenidate augmentation of monoamine oxidase inhibitors (MAOIs) alone or with concurrent tricyclic antidepressants; the majority reported decreased depression.25 In an openlabel trial, dextroamphetamine was titrated to efficacy in patients who were receiving an MAOI with or without pemoline.26 Nearly 80% of patients reported long-lasting improvement in depression. In an open-label trial, all patients reported decreased depression when methylphenidate was added to SRIs; however, no scales were used.27

In a case series, patients with both major depression and persistent depressive disorder (dysthymia) experienced a substantial, quick, and sustained response to dextroamphetamine or methylphenidate augmentation.28 Addition of lisdexamfetamine significantly reduced depressive symptoms in individuals with inadequate response to escitalopram.29 Patients with full or partial remission of depression noted improved executive function and residual depressive symptoms after lisdexamfetamine was added to SRI monotherapy.30 In a trial in which patients received dexamphetamine or methylphenidate as monotherapy or augmentation, 30% to 34% of patients reported mood improvement, but 36% reported no improvement.31 In an extension study, low-dose psychostimulants quickly diminished melancholia.32

Methylphenidate was safe and effective in patients with bipolar depression receiving treatment for 1 to 5 years; 44% evidenced significant improvement.33 When offered to patients with bipolar depression, patients receiving methylphenidate or dextroamphetamine reported less depression or sedation and did not develop tolerance, mania, or misuse.34 A case series concluded that methylphenidate addition to mood stabilizers was generally effective and safe.35

However, not all preparations of methylphenidate have demonstrated efficacy. In one study, osmotic controlledrelease oral system (OROS) methylphenidate improved apathy and fatigue but not overall depression.36 Although OROS methylphenidate similarly failed to demonstrate statistically significant efficacy in another study, more responders were documented in the treatment group.37

Although this review focuses on stimulants as augmenting agents in patients with depression, it is worth noting the limited number of studies evaluating stimulants’ effect on depression in patients with traumatic brain injury. This observation is of concern, as these conditions are frequently comorbid in returning veterans. One study noted that methylphenidate was an effective monotherapy for depression; whereas another study found that methylphenidate monotherapy reduced depression as well as sertraline, was better tolerated, and improved fatigue and cognition.38,39

Modafinil and Armodafinil

Modafinil and armodafinil (the R-enantiomer of modafinil) are indicated for improving wakefulness in individuals with narcolepsy, obstructive sleep apnea, and shift work sleep disorder by modulating glutamate, gamma amino-butyric acid, and histamine.40,41 Although they increase extracellular dopamine concentrations, they do not cause an increase in dopamine release and may have less misuse potential than that of dextroamphetamine and methylphenidate.40,41 In a study of 7 patients with unipolar or bipolar depression, all patients achieved full or partial remission with minimal adverse effects (AEs).42 In a prospective study, 41% of patients reported only mild depression or full remission with modafinil augmentation.43

Multiple trials and a pooled analysis noted decreased depression and fatigue and improved cognition in patients receiving modafinil augmentation compared with mood stabilizers or antidepressants.44-49 Modafinil is a useful adjunct for partial responders to SRIs, resulting in rapid mood improvement and decreased fatigue.50-54 However, in one study, modafinil did not demonstrate efficacy compared with placebo. This result was attributed to premature study termination after 2 modafinil-treated patients developed suicidal ideation.55 A post hoc analysis found no difference in frequency of suicidal ideation between groups.

Two DBPC studies evaluated armodafinil in patients with bipolar depression. In both studies it was added to a mood-stabilizing agent (lithium, valproate, aripiprazole, olanzapine, lamotrigine, risperidone, or ziprasidone), and patients receiving armodafinil reported significant reductions
in depression.56,57

Atomoxetine

Atomoxetine is a norepinephrine reuptake inhibitor indicated for the treatment of ADHD and is considered to have no misuse potential due to lack of dopamine modulation.58 In one study, 15 patients received atomoxetine added to their antidepressant, and 60% experienced significant symptom reduction.59 A chart review noted decreases in fatigue and depression when atomoxetine was added to an SRI, mirtazapine, or amitriptyline.60 However, in a DBPC trial, atomoxetine did not lead to significant changes in depression.61

Discussion

There is a limited amount of high-quality evidence to support psychostimulant augmentation, as noted by the relatively few DBPC trials, most of short duration. The evidence supports their efficacy primarily for unipolar depression, as 14 studies evaluated patients with unipolar depression, whereas only 7 studies evaluated patients with bipolar depression. The remaining studies recruited patients with both depression types. Collectively, modafinil and armodafinil have the most evidence in DBPC trials.

There are relatively few DBPC trials with high power and sufficient duration for dextroamphetamine and methylphenidate preparations. This discovery is surprising, considering the duration that these medications have been available. However, several chart reviews and open-label trials provided some evidence to support their use in patients without a history of substance misuse or cardiac conditions.62 Osmotic controlled- release oral system methylphenidate seems to be ineffective, and the efficacy of atomoxetine for augmentation
is uncertain.

Precautions

Prescribing physicians who offer stimulants should consider potential AEs, such as psychosis, anorexia, anxiety, insomnia, mood changes (eg, anger),  misuse, addiction, mania, and cardiovascular problems. Psychostimulants have been implicated in precipitating psychosis.63,64 However, in a 12-month study of 250 adults with ADHD, 73 reported AEs, and only 31 discontinued the stimulant. Adverse effects leading to discontinuation included mood instability (n = 7), agitation (n = 6), irritability (n = 4), or decreased appetite (n = 4).65

Although associated with the risks of anorexia and insomnia in patients with ADHD, methylphenidate rapidly improved daytime sleepiness and mood, and—paradoxically—appetite and nighttime sleep in medically ill elderly patients with depression.66 Misuse or abuse of methylphenidate and dextroamphetamine were noted in 23% of patients referred for substance misuse.67 Nonetheless, little evidence exists that these drugs possess significant misuse potential in patients taking them as prescribed. As a prodrug, lisdexamfetamine is hypothesized to have less abuse potential compared with dextroamphetamine and methylphenidate, but it carries the same prescribing and monitoring precautions.68 Risks related to stimulant usage extend to manic symptoms.69 Patients with bipolar disorder should not receive stimulants if they have a history of stimulant-induced mania, rapid cycling, or psychosis.70

Long-term cardiovascular safety data exist for dextroamphetamine and methylphenidate but are limited or unavailable for modafinil, armodafinil, and atomoxetine. A retrospective cohort study found no significant increase in the number of cardiac events in patients receiving dextroamphetamine,
methylphenidate, or atomoxetine for an average of 1 year compared with controls.71 Another cohort study of > 44,000 patients found that initiation of
methylphenidate was associated with increased risk of sudden death or arrhythmia, but the risk was attributed to an unmeasured confounding factor, as the authors found a negative correlation between methylphenidate dose and all cardiovascular events.72

Recent practice guidelines recommend that before prescribing stimulants, clinicians should perform a physical examination (including heart and lung auscultation), obtain vital signs and height and weight, and request an electrocardiogram in case of abnormal findings on a cardiovascular examination or in case of a personal or family history of heart disease. Before offering atomoxetine, clinicians should evaluate the patient for a history of liver disease (and check liver function studies in case of a positive history). Clinicians should also assess risk of self-harm prior to initiating psychostimulant therapy.73 Throughout treatment, clinicians should evaluate the patient for changes in blood pressure, pulse, weight or mood, as well as the development of dependence or misuse. Urine toxicology testing is recommended for dextroamphetamine and methylphenidate to screen for adherence and diversion.

Limitations

Using only PubMed and MEDLINE databases limited the search to articles published in English after 1985, excluding letters and case reports to identify studies with higher evidence (the studies were not weighted based on study design). In addition, the studies had certain limitations. These include a limited number of DBPC trials, most were of short duration. It is also difficult to compare studies due to various rating scales used and concurrent
medication regimens of study subjects. These limitations raise questions surrounding the long-term efficacy of stimulants, and there is no consensus for how long a stimulant should be continued if beneficial. Longer, higherpowered, DBPC trials are warranted to determine longterm efficacy and safety of stimulant augmentation.62

Conclusion

For patients with depression who have not responded to other augmentation strategies, psychostimulants may be offered to improve mood, energy, and concentration. For clinicians considering stimulant augmentation, modafinil and armodafinil are reasonable choices given their efficacy in double-blind, placebo-controlled trials and lower risk of misuse. Dextroamphetamine (particularly lisdexamphetamine) and methylphenidate may be appropriate for patients who have not benefited from or tolerated modafinil or armodafinil, provided these patients do not have a medical history of cardiac disease or current substance use.

Osmotic controlled-release oral system methylphenidate seems to be ineffective as an augmenting agent. The efficacy of atomoxetine for augmentation is questionable, but atomoxetine could be offered if other stimulants were contraindicated, ineffective, or poorly tolerated. Both OROS methylphenidate and atomoxetine should be evaluated in additional trials before they can be recommended as augmentation therapies. Certain psychostimulants may be appropriate and reasonable adjunctive pharmacotherapies for patients with unipolar or bipolar depression who have failed other augmentation strategies, for patients who have significant fatigue or cognitive complaints, or for elderly patients with melancholic or somatic features of depression.

Acknowledgements
The authors thank Maureen Humphrey-Shelton and Kathy Thomas for their help in obtaining references.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

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22. Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: A double blind randomized clinical trial. Am J Psychiatry. 2010;167(8):942-948.

23. Papakostas GI, Shelton RC, Zajecka JM, et al. L-methylfolate as adjunctive therapy
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30. Madhoo M, Keefe RS, Roth RM, et al. Lisdexamfetamine dimesylate augmentation in adults with persistent executive dysfunction after partial or full remission of major depressive disorder. Neuropsychopharmacology. 2014;39(6):1388-1398.

31. Parker G, Brotchie H. Do the old psychostimulant drugs have a role in managing treatment-resistant depression. Acta Psychiatr Scand. 2010;121(4):308-314.

32. Parker G, Brotchie H, McClure G, Fletcher K. Psychostimulants for managing unipolar and bipolar treatment-resistant melancholic depression: A medium term evaluation of cost benefits. J Affect Disord. 2013;151(1):360-364.

33. Lydon E, El-Mallakh RS. Naturalistic long-term use of methylphenidate in bipolar disorder. J Clin Psychopharmacol. 2006;26(5):516-518.

34. Carlson PJ, Merlock MC, Suppes T. Adjunctive stimulant use in patients with bipolar disorder: Treatment of residual depression and sedation. Bipolar Disord. 2004;6(5):416-420.

35. El-Mallakh RS. An open study of methylphenidate in bipolar depression. Bipolar Disord. 2000;2(1):56-59.

36. Ravindran AV, Kennedy SH, O’Donovan MC, Fallu A, Camacho F, Binder CE. Osmotic-release oral system methylphenidate augmentation of antidepressant monotherapy in major depressive disorder: Results of a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2008;69(1):87-94.

37. Patkar AA, Masand PS, Pae CU, et al. A randomized, double-blind, placebocontrolled
trial of augmentation with an extended release formulation of methylphenidate in outpatients with treatment-resistant depression. J Clin Psychopharmacol. 2006;26(6):653-656.

38. Lee H, Kim SW, Kim JM, Shin IS, Yang SJ, Yoon JS Comparing effects of methylphenidate, sertraline, and placebo on neuropsychiatric sequelae in patients with
traumatic brain injury. Hum Psychopharmacol. 2005;20(2):97-104.

39. Gualtieri CT, Evans RW. Stimulant treatment for the neurobehavioural sequelae of traumatic brain injury. Brain Inj. 1988;2(4):273-290.

40. Provigil [package insert]. North Wales, PA: Cephalon Inc; 2015.

41. Nuvigil [package insert]. Frazer, PA: Cephalon, Inc; 2013.

42. Menza MA, Kaufman KR, Castellanos A. Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry. 2000;61(5):378-381.

43. Markovitz PJ, Wagner S. An open-label trial of modafinil augmentation in patients with partial response to antidepressant therapy. J Clin Psychopharmacol. 2003;23(2):207-209.

44. Fernandes PP, Petty F. Modafinil for remitted bipolar depression with hypersomnia. Ann Pharmacother. 2003;37(12):1807-1809.

45. Nasr S. Modafinil as adjunctive therapy in depressed outpatients. Ann Clin Psychiatry. 2004;16(3):133-138.

46. DeBattista C, Lembke A, Solvason HB, Ghebremichael R, Poirier J. A prospective trial of modafinil as an adjunctive treatment of major depression. J Clin Psychopharmacol. 2004;24(1):87-90.

47. Nasr S, Wendt B, Steiner K. Absence of mood switch with and tolerance to modafinil: A replication study from a large private practice. J Affect Disord. 2006;95(1-3):111-114.

48. DeBattista C, Doghramji K, Menza MA, Rosenthal MH, Fieve RR; Modafinil in Depression Study Group. Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: A preliminary doubleblind, placebo-controlled study. J Clin Psychiatry. 2003;64(9):1057-1064.

49. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry. 2007;164(8):1242-1249.

50. Fava M, Thase ME, DeBattista C, Doghramji K, Arora S, Hughes RJ. Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness. Ann Clin Psychiatry. 2007;19(3):153-159.

51. Thase ME, Fava M, DeBattista C, Arora S, Hughes RJ. Modafinil augmentation of SSRI therapy in patients with major depressive disorder and excessive sleepiness and fatigue: A 12-week, open-label, extension study. CNS Spectr. 2006;11(2):93-102.

52. Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry. 2005;66(1):85-93.

53. Abolfazli R, Hosseini M, Ghanizadeh A, et al. Double-blind randomized parallelgroup clinical trial of efficacy of the combination fluoxetine plus modafinil versus fluoxetine plus placebo in the treatment of major depression. Depress Anxiety. 2011;28(4):297-302.

54. Rasmussen NA, Schrøder P, Olsen LR, Brødsgaard M, Undén M, Bech P. Modafinil augmentation in depressed patients with partial response to antidepressants: A pilot study on self-reported symptoms covered by the Major Depression Inventory (MDI) and the Symptom Checklist (SCL-92). Nord J Psychiatry. 2005;59(3):173-178.

55. Dunlop BW, Crits-Christoph P, Evans DL, et al. Coadministration of modafinil and a selective serotonin reuptake inhibitor from the initiation of treatment of major depressive disorder with fatigue and sleepiness: A double-blind, placebocontrolled study. J Clin Psychopharmacol. 2007;27(6):614-619.

56. Calabrese JR, Ketter TA, Youakim JM, Tiller JM, Yang R, Frye MA. Adjunctive armodafinil
for major depressive episodes associated with bipolar I disorder: A randomized multicenter, double-blind, placebo-controlled, proof-of-concept study. J Clin Psychiatry. 2010;71(10):1363-1370.

57. Calabrese JR, Frye MA, Yang R, Ketter TA; Armodafinil Treatment Trial Study Network. Efficacy and safety of adjunctive armodafinil in adults with major depressive episodes associated with bipolar I disorder: A randomized, double-blind, placebo-controlled, multicenter trial. J Clin Psychiatry. 2014;75(10):1054-1061.

58. Strattera [package insert]. Indianapolis, IN. Lilly; 2015.

59. Carpenter LL, Milosavljevic N, Schecter JM, Tyrka AR, Price LH. Augmentation with open-label atomoxetine for partial or nonresponse to antidepressants. J Clin Psychiatry. 2005;66(10):1234-1238.

60. Papakostas GI, Petersen TJ, Burns AM, Fava M. Adjunctive atomoxetine for residual
fatigue in major depressive disorder. J Psychiatr Res. 2006;40(4):370-373.

61. Michelson D, Adler LA, Amsterdam JD, et al. Addition of atomoxetine for depression
incompletely responsive to sertraline: A randomized, double-blind, placebocontrolled study. J Clin Psychiatry. 2007;68(4):582-587.

62. Corp SA, Gitlin MJ, Altshuler LL. A review of the use of stimulants and stimulant alternatives in treating bipolar depression and major depressive disorder. J Clin Psychiatry. 2014;75(9):1010-1018.

63. Kraemer M, Uekermann J, Wiltfang J, Kis B. Methylphenidate-induced psychosis in adult attention-deficit/hyperactivity disorder: Report of 3 new cases and review of the literature. Clin Neuropharmacol. 2010;33(4):204-206.

64. Berman SM, Kuczenski R, McCracken JT, London ED. Potential adverse effects of amphetamine treatment on brain and behavior: A review. Mol Psychiatry. 2009;14(2):123-142.

65. Fredriksen M, Dahl AA, Martinsen EW, Klungsøyr O, Haavik J, Peleikis DE. Effectiveness of one-year pharmacological treatment of adult attention-deficit/hyperactivity disorder (ADHD): An open-label prospective study of time in treatment, dose, side-effects and comorbidity. Eur Neuropsychopharmacol. 2014;24(12):1873-1874.

66. Hardy SE. Methylphenidate for the treatment of depressive symptoms, including fatigue and apathy, in medically ill older adults and terminally ill adults. Am J Geriatr Pharmacother. 2009;7(1):34-59.

67. Williams RJ, Goodale LA, Shay-Fiddler MA, Gloster SP, Chang SY. Methylphenidate and dextroamphetamine abuse in substance-abusing adolescents. Am J Addict. 2004;13(4):381-389.

68. Madaan V, Kolli V, Bestha DP, Shah MJ. Update on optimal use of lisdexamfetamine in the treatment of ADHD. Neuropsychiatr Dis Treat. 2013;9:977-983.

69. Ross RG. Psychotic and manic-like symptoms during stimulant treatment of attention deficit hyperactivity disorder. Am J Psychiatry. 2006;163(7):1149-1152.

70. Dell’Osso B, Ketter TA. Use of adjunctive stimulants in adult bipolar depression. Int J Neuropsychopharmacol. 2013;16(1):55-68.

71. Habel LA, Cooper WO, Sox CM, et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA. 2011;306(24):2673-2683.

72. Schelleman H, Bilker WB, Kimmel SE, et al. Methylphenidate and risk of serious cardiovascular events in adults. Am J Psychiatry. 2012;169(2):178-185.

73. Bolea-Alamañac B, Nutt DJ, Adamou M, et al; British Association for Psychopharmacology. Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: Update on recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2014;28(3):179-203.

74. Moher D, Liberati A, Tetzlaff J, Altman DG; The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6(6):e1000097.

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18. Carpenter LL, Yasman S, Price LH. A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. Biol Psychiatry. 2002;51(2):183-188.

19. Hannan N, Hamzah Z, Akinpeloye HO, Meagher D. Venlafaxine-mirtazapine combination therapy in the treatment of persistent depressive illness. J Psychopharmacol. 2007;21(2):161-164.

20. McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: A STAR*D report. Am J Psychiatry. 2006;163(9):1531-1541.

21. Blier P, Ward HE, Tremblay P, Laberge L, Hébert C, Bergeron R. Combination of antidepressant medications from treatment initiation for major depressive disorder: A double-blind randomized study. Am J Psychiatry. 2010;167(3):281-288.

22. Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: A double blind randomized clinical trial. Am J Psychiatry. 2010;167(8):942-948.

23. Papakostas GI, Shelton RC, Zajecka JM, et al. L-methylfolate as adjunctive therapy
for SSRI-resistant major depression: Results of two randomized, double-blind,
parallel-sequential trials. Am J Psychiatry. 2012;169(12):1267-1274.

24. Korston TR. Drugs of abuse. In: Katzung BG, ed. Basic and Clinical Pharmacology. 9th ed. New York, NY: McGraw-Hill; 2004:521-523.

25. Feighner JP, Herbstein J, Damlouji N. Combined MAOI, TCA, and direct stimulant therapy of treatment-resistant depression. J Clin Psychiatry. 1985;46(6):206-209.

26. Fawcett J, Kravitz HM, Zajecka JM, Schaff MR. CNS stimulant potentiation of monoamine oxidase inhibitors in treatment-refractory depression. J Clin Psychopharmacol. 1991;11(2):127-132.

27. Stoll AL, Pillay SS, Diamond L, Workum SB, Cole JO. Methylphenidate augmentation of serotonin selective reuptake inhibitors: A case series. J Clin Psychiatry. 1996;57(2):72-76.

28. Masand PS, Anand VS, Tanquary JF. Psychostimulant augmentation of second generation antidepressants: A case series. Depress Anxiety. 1998;7(2):89-91.

29. Trivedi MH, Cutler AJ, Richards C, et al. A randomized control trial of the efficacy and safety of lisdesxamfetamine dimesylate as augmentation therapy in adults with residual symptoms of major depressive disorder after treatment with escitalopram. J Clin Psychiatry. 2013;74(8):802-809.

30. Madhoo M, Keefe RS, Roth RM, et al. Lisdexamfetamine dimesylate augmentation in adults with persistent executive dysfunction after partial or full remission of major depressive disorder. Neuropsychopharmacology. 2014;39(6):1388-1398.

31. Parker G, Brotchie H. Do the old psychostimulant drugs have a role in managing treatment-resistant depression. Acta Psychiatr Scand. 2010;121(4):308-314.

32. Parker G, Brotchie H, McClure G, Fletcher K. Psychostimulants for managing unipolar and bipolar treatment-resistant melancholic depression: A medium term evaluation of cost benefits. J Affect Disord. 2013;151(1):360-364.

33. Lydon E, El-Mallakh RS. Naturalistic long-term use of methylphenidate in bipolar disorder. J Clin Psychopharmacol. 2006;26(5):516-518.

34. Carlson PJ, Merlock MC, Suppes T. Adjunctive stimulant use in patients with bipolar disorder: Treatment of residual depression and sedation. Bipolar Disord. 2004;6(5):416-420.

35. El-Mallakh RS. An open study of methylphenidate in bipolar depression. Bipolar Disord. 2000;2(1):56-59.

36. Ravindran AV, Kennedy SH, O’Donovan MC, Fallu A, Camacho F, Binder CE. Osmotic-release oral system methylphenidate augmentation of antidepressant monotherapy in major depressive disorder: Results of a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2008;69(1):87-94.

37. Patkar AA, Masand PS, Pae CU, et al. A randomized, double-blind, placebocontrolled
trial of augmentation with an extended release formulation of methylphenidate in outpatients with treatment-resistant depression. J Clin Psychopharmacol. 2006;26(6):653-656.

38. Lee H, Kim SW, Kim JM, Shin IS, Yang SJ, Yoon JS Comparing effects of methylphenidate, sertraline, and placebo on neuropsychiatric sequelae in patients with
traumatic brain injury. Hum Psychopharmacol. 2005;20(2):97-104.

39. Gualtieri CT, Evans RW. Stimulant treatment for the neurobehavioural sequelae of traumatic brain injury. Brain Inj. 1988;2(4):273-290.

40. Provigil [package insert]. North Wales, PA: Cephalon Inc; 2015.

41. Nuvigil [package insert]. Frazer, PA: Cephalon, Inc; 2013.

42. Menza MA, Kaufman KR, Castellanos A. Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry. 2000;61(5):378-381.

43. Markovitz PJ, Wagner S. An open-label trial of modafinil augmentation in patients with partial response to antidepressant therapy. J Clin Psychopharmacol. 2003;23(2):207-209.

44. Fernandes PP, Petty F. Modafinil for remitted bipolar depression with hypersomnia. Ann Pharmacother. 2003;37(12):1807-1809.

45. Nasr S. Modafinil as adjunctive therapy in depressed outpatients. Ann Clin Psychiatry. 2004;16(3):133-138.

46. DeBattista C, Lembke A, Solvason HB, Ghebremichael R, Poirier J. A prospective trial of modafinil as an adjunctive treatment of major depression. J Clin Psychopharmacol. 2004;24(1):87-90.

47. Nasr S, Wendt B, Steiner K. Absence of mood switch with and tolerance to modafinil: A replication study from a large private practice. J Affect Disord. 2006;95(1-3):111-114.

48. DeBattista C, Doghramji K, Menza MA, Rosenthal MH, Fieve RR; Modafinil in Depression Study Group. Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: A preliminary doubleblind, placebo-controlled study. J Clin Psychiatry. 2003;64(9):1057-1064.

49. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry. 2007;164(8):1242-1249.

50. Fava M, Thase ME, DeBattista C, Doghramji K, Arora S, Hughes RJ. Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness. Ann Clin Psychiatry. 2007;19(3):153-159.

51. Thase ME, Fava M, DeBattista C, Arora S, Hughes RJ. Modafinil augmentation of SSRI therapy in patients with major depressive disorder and excessive sleepiness and fatigue: A 12-week, open-label, extension study. CNS Spectr. 2006;11(2):93-102.

52. Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry. 2005;66(1):85-93.

53. Abolfazli R, Hosseini M, Ghanizadeh A, et al. Double-blind randomized parallelgroup clinical trial of efficacy of the combination fluoxetine plus modafinil versus fluoxetine plus placebo in the treatment of major depression. Depress Anxiety. 2011;28(4):297-302.

54. Rasmussen NA, Schrøder P, Olsen LR, Brødsgaard M, Undén M, Bech P. Modafinil augmentation in depressed patients with partial response to antidepressants: A pilot study on self-reported symptoms covered by the Major Depression Inventory (MDI) and the Symptom Checklist (SCL-92). Nord J Psychiatry. 2005;59(3):173-178.

55. Dunlop BW, Crits-Christoph P, Evans DL, et al. Coadministration of modafinil and a selective serotonin reuptake inhibitor from the initiation of treatment of major depressive disorder with fatigue and sleepiness: A double-blind, placebocontrolled study. J Clin Psychopharmacol. 2007;27(6):614-619.

56. Calabrese JR, Ketter TA, Youakim JM, Tiller JM, Yang R, Frye MA. Adjunctive armodafinil
for major depressive episodes associated with bipolar I disorder: A randomized multicenter, double-blind, placebo-controlled, proof-of-concept study. J Clin Psychiatry. 2010;71(10):1363-1370.

57. Calabrese JR, Frye MA, Yang R, Ketter TA; Armodafinil Treatment Trial Study Network. Efficacy and safety of adjunctive armodafinil in adults with major depressive episodes associated with bipolar I disorder: A randomized, double-blind, placebo-controlled, multicenter trial. J Clin Psychiatry. 2014;75(10):1054-1061.

58. Strattera [package insert]. Indianapolis, IN. Lilly; 2015.

59. Carpenter LL, Milosavljevic N, Schecter JM, Tyrka AR, Price LH. Augmentation with open-label atomoxetine for partial or nonresponse to antidepressants. J Clin Psychiatry. 2005;66(10):1234-1238.

60. Papakostas GI, Petersen TJ, Burns AM, Fava M. Adjunctive atomoxetine for residual
fatigue in major depressive disorder. J Psychiatr Res. 2006;40(4):370-373.

61. Michelson D, Adler LA, Amsterdam JD, et al. Addition of atomoxetine for depression
incompletely responsive to sertraline: A randomized, double-blind, placebocontrolled study. J Clin Psychiatry. 2007;68(4):582-587.

62. Corp SA, Gitlin MJ, Altshuler LL. A review of the use of stimulants and stimulant alternatives in treating bipolar depression and major depressive disorder. J Clin Psychiatry. 2014;75(9):1010-1018.

63. Kraemer M, Uekermann J, Wiltfang J, Kis B. Methylphenidate-induced psychosis in adult attention-deficit/hyperactivity disorder: Report of 3 new cases and review of the literature. Clin Neuropharmacol. 2010;33(4):204-206.

64. Berman SM, Kuczenski R, McCracken JT, London ED. Potential adverse effects of amphetamine treatment on brain and behavior: A review. Mol Psychiatry. 2009;14(2):123-142.

65. Fredriksen M, Dahl AA, Martinsen EW, Klungsøyr O, Haavik J, Peleikis DE. Effectiveness of one-year pharmacological treatment of adult attention-deficit/hyperactivity disorder (ADHD): An open-label prospective study of time in treatment, dose, side-effects and comorbidity. Eur Neuropsychopharmacol. 2014;24(12):1873-1874.

66. Hardy SE. Methylphenidate for the treatment of depressive symptoms, including fatigue and apathy, in medically ill older adults and terminally ill adults. Am J Geriatr Pharmacother. 2009;7(1):34-59.

67. Williams RJ, Goodale LA, Shay-Fiddler MA, Gloster SP, Chang SY. Methylphenidate and dextroamphetamine abuse in substance-abusing adolescents. Am J Addict. 2004;13(4):381-389.

68. Madaan V, Kolli V, Bestha DP, Shah MJ. Update on optimal use of lisdexamfetamine in the treatment of ADHD. Neuropsychiatr Dis Treat. 2013;9:977-983.

69. Ross RG. Psychotic and manic-like symptoms during stimulant treatment of attention deficit hyperactivity disorder. Am J Psychiatry. 2006;163(7):1149-1152.

70. Dell’Osso B, Ketter TA. Use of adjunctive stimulants in adult bipolar depression. Int J Neuropsychopharmacol. 2013;16(1):55-68.

71. Habel LA, Cooper WO, Sox CM, et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA. 2011;306(24):2673-2683.

72. Schelleman H, Bilker WB, Kimmel SE, et al. Methylphenidate and risk of serious cardiovascular events in adults. Am J Psychiatry. 2012;169(2):178-185.

73. Bolea-Alamañac B, Nutt DJ, Adamou M, et al; British Association for Psychopharmacology. Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: Update on recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2014;28(3):179-203.

74. Moher D, Liberati A, Tetzlaff J, Altman DG; The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6(6):e1000097.

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