Raymond Pary, MD

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. ˜

Click here to read the digital edition.

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. ˜

Click here to read the digital edition.

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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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.

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.