Matthew MacAluso, DO

In July 2013, the FDA approved levomilnacipran for the treatment of major depressive disorder (MDD) in adults.¹ It is available in a once-daily, extended-release formulation (Table 1).¹ The drug is the fifth serotonin-norepinephrine reuptake inhibitor (SNRI) to be sold in the United States and the fourth to receive FDA approval for treating MDD.

Levomilnacipran is believed to be the more active enantiomer of milnacipran, which has been available in Europe for years and was approved by the FDA in 2009 for treating fibromyalgia. Efficacy of levomilnacipran for treating patients with MDD was established in three 8-week randomized controlled trials (RCTs).¹

Clinical implications

Levomilnacipran is indicated for treating MDD in adults and is unique compared with other SNRIs because it is relatively more selective for norepinephrine reuptake inhibition (NRI) compared with serotonin reuptake inhibition (SRI).¹ In vitro studies demonstrate that the drug has >10-fold greater selectivity for norepinephrine reuptake inhibition than it does for serotonin reuptake inhibition, compared with duloxetine or venlafaxine.²

This difference in selectivity could lend itself to treating symptoms of MDD that might be related to norepinephrine deficiency; these include decreased concentration, lassitude, mental and physical slowing, and decreased self-care.^3,4 Some authors claim that individual patients could experience improvement in their social and occupational functioning in addition to improvement in the core symptoms of depression.⁵

Levomilnacipran is the more active enantiomer of milnacipran, an SNRI that is approved for treating fibromyalgia in the United States and approved for treating depression in many other countries.⁶ In general, enantiomeric formulations are believed to have advantages over racemic formulations because they are less complex and have a more selective pharmacodynamic profile, better therapeutic index, lower liability for drug-drug interactions (DDIs), and a less complicated relationship between plasma concentration and pharmacodynamic effect.⁶ In addition, regulatory guidelines in the United States recommend development of enantiomers over racemates where appropriate.⁷

How it works

Levomilnacipran’s exact mechanism of action is unknown. Similar to other SNRIs, it binds with high affinity to the serotonin (5-HT) and norepinephrine (NE) transporters and potently inhibits 5-HT and NE reuptake. Levomilnacipran lacks significant affinity for any other receptors, ion channels, or transporters tested in vitro.² It differs from other SNRIs such as venlafaxine and duloxetine in having higher selectivity for norepinephrine vs serotonin reuptake inhibition. In vitro studies demonstrated a 2-fold preference for NE over 5-HT reuptake inhibition.²

Pharmacokinetics

Levomilnacipran reaches maximum plasma concentration within 6 to 8 hours of oral administration and has a half-life of approximately 12 hours, which makes it suitable for once-daily dosing. The concentration of levomilnacipran at steady state is proportional to the dosage of the drug when administered within the range of 25 to 300 mg once daily.¹

The drug’s mean apparent total clearance is 21 to 29 liters/hour and its bioavailability is not significantly affected when taken with food. The drug is widely distributed in the body and is converted primarily to 2 metabolites: desethy levomilnacipran and p-hydroxy-levomilnacipran. Both metabolites are inactive and undergo further conjugation with glucuronide. The drug is eliminated primarily via renal excretion.¹

The major enzyme that catalyzes metabolism of levomilnacipram is cytochrome P 450 (CYP) 3A4, which makes it susceptible to DDIs with drugs that inhibit or induce this enzyme. For example, a person taking levomilnacipran with a potent CYP3A4 inhibitor, such as ketoconazole, may require a dosage adjustment. No dosage adjustment is needed when given with a CYP3A4 inducer or substrate. Drinking alcohol with levomilnacipran may cause more rapid release of the drug into the blood stream.¹

Efficacy

Levomilnacipran decreased core symptoms of MDD and showed a statistically significant separation from placebo in 2 phase III RCTs (Table 2).^3,5 The first study was a 10-week flexible dose (75 or 100 mg) trial in 563 outpatients age 18 to 70 who met DSM-IV-TR criteria of MDD for >1 month and had a 17-item Hamilton Depression Rating Scale (HDRS-17) score >22 and a Sheehan Disability Scale (SDS) score >10.³ The primary efficacy measure was change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 10. Secondary efficacy measures included the HDRS-17, SDS, and Clinical Global Impressions-improvement scale. Efficacy analyses included 276 subjects treated with levomilnacipran and 277 treated with placebo.³

Levomilnacipran was significantly superior to placebo on the MADRS and HDRS-17 from baseline to week 10. Response and remission rates were
significantly greater for the levomilnacipran group compared with placebo. Response exceeded the 10% average advantage for drug vs placebo and 46% of levomilnacipran-treated patients achieved remission.³

The number needed to treat (NNT), based on the MADRS scores for the levomilnacipran group compared with the placebo group, was 6 for response and 5 for remission.³ By comparison, most studies of venlafaxine demonstrate a NNT of 8.³

Levomilnacipran generally was reported to be safe and well tolerated. The most common adverse events leading to discontinuation in the levomilnacipran group were nausea, vomiting, change in systolic and diastolic blood pressure, and increase in heart rate. The favorable tolerability profile of levomilnacipran may relate to the 2-fold greater potency for NE reuptake inhibition compared with 5-HT reuptake inhibition.³

The second study was an 11-week, fixed-dose trial of levomilnacipran using 40, 80, or 120 mg. A total of 724 outpatients age 18 to 65 who met DSM-IV-TR criteria for MDD and who had an ongoing episode of depression lasting >8 weeks were randomly assigned to receive placebo (n = 179) or levomilnacipran at 40 mg (n = 181), 80 mg (n = 181), or 120 mg (n = 183) once daily for 8 weeks of double-blind treatment followed by a 2-week, double-blind taper of the drug.⁵ The primary efficacy parameter was change from baseline on the MADRS and the secondary efficacy parameter was change from baseline in SDS total score. HDRS-17, CGI-I, and CGI-S were included as secondary outcome measures.⁵

Significant difference in MADRS total score were seen in the levomilnacipran group compared with the placebo group (least mean squared difference: 40 mg/d,  −3.23; 80 mg/d, −3.99; and 120 mg/d,  −4.86). Higher dosages produced a numerically greater change and significant separation from placebo occurred sooner in the 80-mg and 120-mg groups compared with the 40-mg group.⁵

Significant differences vs placebo were consistently observed across secondary outcome measures for the higher dosages of levomilnacipran, and improvement in SDS total score was noted in all levomilnacipran groups compared with the placebo group. When dosed at 120 mg/d, levomilnacipran produced significant improvement vs placebo on all SDS subscales and was as well tolerated as the 80 mg dosage.⁵

No new safety concerns were observed in the study. A dose-response relationship in tolerability was not demonstrated and the number of patients reporting adverse events and who discontinued participation because of adverse events was higher in the 80-mg group than in the 40-mg and 120-mg groups.⁵

Tolerability

Overall, levomilnacipran was well tolerated in clinical trials, during which 2,673 subjects were exposed to the drug—translating to 942 patient-years of exposure. These patients ranged in age from 18 to 78; 825 of these subjects were enrolled in long-term studies for 1 year. Dosing of levomilnacipran during these studies ranged from 40 to 120 mg once daily, without regard to food.¹

Nine percent of patients who received levomilnacipran in short-term studies discontinued because of adverse events, compared with 3% of patients who received placebo. The most common adverse event reported was nausea; other common adverse events reported included constipation, hyperhidrosis, elevated heart rate, erectile dysfunction, tachycardia, palpitations, and vomiting. Of these events, only erectile dysfunction and urinary hesitation were dose-related.¹ Among levo­milnacipran-treated female patients, <2% reported adverse events related to sexual dysfunction.

All SNRIs have well established associations with elevation in blood pressure and heart rate. Levomilnacipran resulted in a mean increase of 3 mm HG in systolic and 3.2 mm Hg in diastolic blood pressure in short-term, placebo-controlled trials.¹

Orthostatic hypotension was observed in 11.6% of patients in the levomilnacipran groups, compared with 9.7% in placebo groups in all short-term studies. Orthostatic reductions of blood pressure occurred in 5.8%, 6.1%, and 9.8% of levomilnacipran-treated patients with dosages of 40, 80, and 120 mg/d respectively, indicating a dose-dependent adverse event. A mean increase in heart rate of 7.2 beats per minute (bpm) also was seen in short-term studies in the levomilnacipran-treated group compared with 0.3 bpm in the placebo-treated group.¹ Clinicians should monitor blood pressure and heart rate routinely because of potential increases seen in some subjects in these studies, which excluded those who had significant cardiovascular disease.

Unique clinical issues

Both in-vitro and in-vivo studies found that levomilnacipran exhibited more potency for NE reuptake inhibition than for 5-HT reuptake inhibition at the lowest effective dosage (10 mg/kg). However as the dosage was increased (20 mg/kg and 40 mg/kg), it was equally potent at NE and 5-HT reuptake inhibition. This is in contrast to venlafaxine, which demonstrates a similar, but opposite, effect in terms of potentiation at the 5-HT and NE reuptake pumps.²

The greater noradrenergic effect of levomilnacipran could lend itself to treating certain subgroups of patients whose symptoms are believed to be related to deficiencies in NE (eg, lassitude).⁴ This concept is theoretical, and was not explicitly studied in clinical trials and the drug is not labeled in this way.

Contraindications

Contraindications to levomilnacipran are similar to those seen with SSRIs and SNRIs, including concomitant use of a monoamine oxidase inhibitor (MAOI) and the use of the levomilnacipran within 14 days of stopping an MAOI. Contraindications unique to levomilnacipran include hypersensitivity to levomilnacipran, milnacipran, or any component specific to the formulation; and uncontrolled narrow-angle glaucoma.¹

Dosing

The recommended dosage range of levomilnacipran is 40 to 120 mg once
daily with or without food. The capsules should be swallowed whole and should not be opened or crushed. As with most psychotropics, levomilnacipran should be taken at approximately the same time each day.¹

The manufacturer recommends an initial dose of levomilnacipran of 20 mg once daily for 2 days, increased to 40 mg once daily. Based on efficacy and tolerably, levomilnacipran can be increased in increments of 40 mg every 2 days.

Dosage adjustment is recommended for patients with moderate or severe renal impairment; and the maintenance dosage should not exceed 80 mg and 40 mg respectively in these populations. As with many antidepressants, gradual dosage reduction is recommended to avoid discontinuation symptoms.

Bottom Line

Levomilnacipran is FDA-approved for treating major depressive disorder in adults. In 2 randomized controlled trials, the drug showed a significant separation from placebo. Levomilnacipran generally was reported to be safe and well tolerated; common adverse events were nausea, vomiting, changes in blood pressure, and an increase in heart rate.

Related Resources

• Citrome L. Levomilnacipran for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? [published online September 8, 2013]. Int J Clin Pract. doi: 10.1111/ijcp.12298.
• Mago R, Forero G, Greenberg WM, et al. Safety and tolerability of levomilnacipran ER in major depressive disorder: results from an open-label, 48-week extension study. Clin Drug Investig. 2013;33(10):761-771.

Drug Brand Names
Duloxetine • Cymbalta        Milnacipran • Savella
Ketoconazole • Nizoral        Venlafaxine • Effexor    Levomilnacipran • Fetzima
 

Disclosures

Dr. Macaluso has been the principal investigator for clinical trials for AbbVie, Eisai, Envivo, Janssen, Naurex, and Pfizer. All clinical trial and study contracts and payments were made through the Kansas University Medical Center Research Institute. Drs. Kazanchi and Malhotra report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

In July 2013, the FDA approved levomilnacipran for the treatment of major depressive disorder (MDD) in adults.¹ It is available in a once-daily, extended-release formulation (Table 1).¹ The drug is the fifth serotonin-norepinephrine reuptake inhibitor (SNRI) to be sold in the United States and the fourth to receive FDA approval for treating MDD.

Levomilnacipran is believed to be the more active enantiomer of milnacipran, which has been available in Europe for years and was approved by the FDA in 2009 for treating fibromyalgia. Efficacy of levomilnacipran for treating patients with MDD was established in three 8-week randomized controlled trials (RCTs).¹

Clinical implications

Levomilnacipran is indicated for treating MDD in adults and is unique compared with other SNRIs because it is relatively more selective for norepinephrine reuptake inhibition (NRI) compared with serotonin reuptake inhibition (SRI).¹ In vitro studies demonstrate that the drug has >10-fold greater selectivity for norepinephrine reuptake inhibition than it does for serotonin reuptake inhibition, compared with duloxetine or venlafaxine.²

This difference in selectivity could lend itself to treating symptoms of MDD that might be related to norepinephrine deficiency; these include decreased concentration, lassitude, mental and physical slowing, and decreased self-care.^3,4 Some authors claim that individual patients could experience improvement in their social and occupational functioning in addition to improvement in the core symptoms of depression.⁵

Levomilnacipran is the more active enantiomer of milnacipran, an SNRI that is approved for treating fibromyalgia in the United States and approved for treating depression in many other countries.⁶ In general, enantiomeric formulations are believed to have advantages over racemic formulations because they are less complex and have a more selective pharmacodynamic profile, better therapeutic index, lower liability for drug-drug interactions (DDIs), and a less complicated relationship between plasma concentration and pharmacodynamic effect.⁶ In addition, regulatory guidelines in the United States recommend development of enantiomers over racemates where appropriate.⁷

How it works

Levomilnacipran’s exact mechanism of action is unknown. Similar to other SNRIs, it binds with high affinity to the serotonin (5-HT) and norepinephrine (NE) transporters and potently inhibits 5-HT and NE reuptake. Levomilnacipran lacks significant affinity for any other receptors, ion channels, or transporters tested in vitro.² It differs from other SNRIs such as venlafaxine and duloxetine in having higher selectivity for norepinephrine vs serotonin reuptake inhibition. In vitro studies demonstrated a 2-fold preference for NE over 5-HT reuptake inhibition.²

Pharmacokinetics

Levomilnacipran reaches maximum plasma concentration within 6 to 8 hours of oral administration and has a half-life of approximately 12 hours, which makes it suitable for once-daily dosing. The concentration of levomilnacipran at steady state is proportional to the dosage of the drug when administered within the range of 25 to 300 mg once daily.¹

The drug’s mean apparent total clearance is 21 to 29 liters/hour and its bioavailability is not significantly affected when taken with food. The drug is widely distributed in the body and is converted primarily to 2 metabolites: desethy levomilnacipran and p-hydroxy-levomilnacipran. Both metabolites are inactive and undergo further conjugation with glucuronide. The drug is eliminated primarily via renal excretion.¹

The major enzyme that catalyzes metabolism of levomilnacipram is cytochrome P 450 (CYP) 3A4, which makes it susceptible to DDIs with drugs that inhibit or induce this enzyme. For example, a person taking levomilnacipran with a potent CYP3A4 inhibitor, such as ketoconazole, may require a dosage adjustment. No dosage adjustment is needed when given with a CYP3A4 inducer or substrate. Drinking alcohol with levomilnacipran may cause more rapid release of the drug into the blood stream.¹

Efficacy

Levomilnacipran decreased core symptoms of MDD and showed a statistically significant separation from placebo in 2 phase III RCTs (Table 2).^3,5 The first study was a 10-week flexible dose (75 or 100 mg) trial in 563 outpatients age 18 to 70 who met DSM-IV-TR criteria of MDD for >1 month and had a 17-item Hamilton Depression Rating Scale (HDRS-17) score >22 and a Sheehan Disability Scale (SDS) score >10.³ The primary efficacy measure was change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 10. Secondary efficacy measures included the HDRS-17, SDS, and Clinical Global Impressions-improvement scale. Efficacy analyses included 276 subjects treated with levomilnacipran and 277 treated with placebo.³

Levomilnacipran was significantly superior to placebo on the MADRS and HDRS-17 from baseline to week 10. Response and remission rates were
significantly greater for the levomilnacipran group compared with placebo. Response exceeded the 10% average advantage for drug vs placebo and 46% of levomilnacipran-treated patients achieved remission.³

The number needed to treat (NNT), based on the MADRS scores for the levomilnacipran group compared with the placebo group, was 6 for response and 5 for remission.³ By comparison, most studies of venlafaxine demonstrate a NNT of 8.³

Levomilnacipran generally was reported to be safe and well tolerated. The most common adverse events leading to discontinuation in the levomilnacipran group were nausea, vomiting, change in systolic and diastolic blood pressure, and increase in heart rate. The favorable tolerability profile of levomilnacipran may relate to the 2-fold greater potency for NE reuptake inhibition compared with 5-HT reuptake inhibition.³

The second study was an 11-week, fixed-dose trial of levomilnacipran using 40, 80, or 120 mg. A total of 724 outpatients age 18 to 65 who met DSM-IV-TR criteria for MDD and who had an ongoing episode of depression lasting >8 weeks were randomly assigned to receive placebo (n = 179) or levomilnacipran at 40 mg (n = 181), 80 mg (n = 181), or 120 mg (n = 183) once daily for 8 weeks of double-blind treatment followed by a 2-week, double-blind taper of the drug.⁵ The primary efficacy parameter was change from baseline on the MADRS and the secondary efficacy parameter was change from baseline in SDS total score. HDRS-17, CGI-I, and CGI-S were included as secondary outcome measures.⁵

Significant difference in MADRS total score were seen in the levomilnacipran group compared with the placebo group (least mean squared difference: 40 mg/d,  −3.23; 80 mg/d, −3.99; and 120 mg/d,  −4.86). Higher dosages produced a numerically greater change and significant separation from placebo occurred sooner in the 80-mg and 120-mg groups compared with the 40-mg group.⁵

Significant differences vs placebo were consistently observed across secondary outcome measures for the higher dosages of levomilnacipran, and improvement in SDS total score was noted in all levomilnacipran groups compared with the placebo group. When dosed at 120 mg/d, levomilnacipran produced significant improvement vs placebo on all SDS subscales and was as well tolerated as the 80 mg dosage.⁵

No new safety concerns were observed in the study. A dose-response relationship in tolerability was not demonstrated and the number of patients reporting adverse events and who discontinued participation because of adverse events was higher in the 80-mg group than in the 40-mg and 120-mg groups.⁵

Tolerability

Overall, levomilnacipran was well tolerated in clinical trials, during which 2,673 subjects were exposed to the drug—translating to 942 patient-years of exposure. These patients ranged in age from 18 to 78; 825 of these subjects were enrolled in long-term studies for 1 year. Dosing of levomilnacipran during these studies ranged from 40 to 120 mg once daily, without regard to food.¹

Nine percent of patients who received levomilnacipran in short-term studies discontinued because of adverse events, compared with 3% of patients who received placebo. The most common adverse event reported was nausea; other common adverse events reported included constipation, hyperhidrosis, elevated heart rate, erectile dysfunction, tachycardia, palpitations, and vomiting. Of these events, only erectile dysfunction and urinary hesitation were dose-related.¹ Among levo­milnacipran-treated female patients, <2% reported adverse events related to sexual dysfunction.

All SNRIs have well established associations with elevation in blood pressure and heart rate. Levomilnacipran resulted in a mean increase of 3 mm HG in systolic and 3.2 mm Hg in diastolic blood pressure in short-term, placebo-controlled trials.¹

Orthostatic hypotension was observed in 11.6% of patients in the levomilnacipran groups, compared with 9.7% in placebo groups in all short-term studies. Orthostatic reductions of blood pressure occurred in 5.8%, 6.1%, and 9.8% of levomilnacipran-treated patients with dosages of 40, 80, and 120 mg/d respectively, indicating a dose-dependent adverse event. A mean increase in heart rate of 7.2 beats per minute (bpm) also was seen in short-term studies in the levomilnacipran-treated group compared with 0.3 bpm in the placebo-treated group.¹ Clinicians should monitor blood pressure and heart rate routinely because of potential increases seen in some subjects in these studies, which excluded those who had significant cardiovascular disease.

Unique clinical issues

Both in-vitro and in-vivo studies found that levomilnacipran exhibited more potency for NE reuptake inhibition than for 5-HT reuptake inhibition at the lowest effective dosage (10 mg/kg). However as the dosage was increased (20 mg/kg and 40 mg/kg), it was equally potent at NE and 5-HT reuptake inhibition. This is in contrast to venlafaxine, which demonstrates a similar, but opposite, effect in terms of potentiation at the 5-HT and NE reuptake pumps.²

The greater noradrenergic effect of levomilnacipran could lend itself to treating certain subgroups of patients whose symptoms are believed to be related to deficiencies in NE (eg, lassitude).⁴ This concept is theoretical, and was not explicitly studied in clinical trials and the drug is not labeled in this way.

Contraindications

Contraindications to levomilnacipran are similar to those seen with SSRIs and SNRIs, including concomitant use of a monoamine oxidase inhibitor (MAOI) and the use of the levomilnacipran within 14 days of stopping an MAOI. Contraindications unique to levomilnacipran include hypersensitivity to levomilnacipran, milnacipran, or any component specific to the formulation; and uncontrolled narrow-angle glaucoma.¹

Dosing

The recommended dosage range of levomilnacipran is 40 to 120 mg once
daily with or without food. The capsules should be swallowed whole and should not be opened or crushed. As with most psychotropics, levomilnacipran should be taken at approximately the same time each day.¹

The manufacturer recommends an initial dose of levomilnacipran of 20 mg once daily for 2 days, increased to 40 mg once daily. Based on efficacy and tolerably, levomilnacipran can be increased in increments of 40 mg every 2 days.

Dosage adjustment is recommended for patients with moderate or severe renal impairment; and the maintenance dosage should not exceed 80 mg and 40 mg respectively in these populations. As with many antidepressants, gradual dosage reduction is recommended to avoid discontinuation symptoms.

Bottom Line

Levomilnacipran is FDA-approved for treating major depressive disorder in adults. In 2 randomized controlled trials, the drug showed a significant separation from placebo. Levomilnacipran generally was reported to be safe and well tolerated; common adverse events were nausea, vomiting, changes in blood pressure, and an increase in heart rate.

Related Resources

• Citrome L. Levomilnacipran for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? [published online September 8, 2013]. Int J Clin Pract. doi: 10.1111/ijcp.12298.
• Mago R, Forero G, Greenberg WM, et al. Safety and tolerability of levomilnacipran ER in major depressive disorder: results from an open-label, 48-week extension study. Clin Drug Investig. 2013;33(10):761-771.

Drug Brand Names
Duloxetine • Cymbalta        Milnacipran • Savella
Ketoconazole • Nizoral        Venlafaxine • Effexor    Levomilnacipran • Fetzima
 

Disclosures

Dr. Macaluso has been the principal investigator for clinical trials for AbbVie, Eisai, Envivo, Janssen, Naurex, and Pfizer. All clinical trial and study contracts and payments were made through the Kansas University Medical Center Research Institute. Drs. Kazanchi and Malhotra report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

In July 2013, the FDA approved levomilnacipran for the treatment of major depressive disorder (MDD) in adults.¹ It is available in a once-daily, extended-release formulation (Table 1).¹ The drug is the fifth serotonin-norepinephrine reuptake inhibitor (SNRI) to be sold in the United States and the fourth to receive FDA approval for treating MDD.

Levomilnacipran is believed to be the more active enantiomer of milnacipran, which has been available in Europe for years and was approved by the FDA in 2009 for treating fibromyalgia. Efficacy of levomilnacipran for treating patients with MDD was established in three 8-week randomized controlled trials (RCTs).¹

Clinical implications

Levomilnacipran is indicated for treating MDD in adults and is unique compared with other SNRIs because it is relatively more selective for norepinephrine reuptake inhibition (NRI) compared with serotonin reuptake inhibition (SRI).¹ In vitro studies demonstrate that the drug has >10-fold greater selectivity for norepinephrine reuptake inhibition than it does for serotonin reuptake inhibition, compared with duloxetine or venlafaxine.²

This difference in selectivity could lend itself to treating symptoms of MDD that might be related to norepinephrine deficiency; these include decreased concentration, lassitude, mental and physical slowing, and decreased self-care.^3,4 Some authors claim that individual patients could experience improvement in their social and occupational functioning in addition to improvement in the core symptoms of depression.⁵

Levomilnacipran is the more active enantiomer of milnacipran, an SNRI that is approved for treating fibromyalgia in the United States and approved for treating depression in many other countries.⁶ In general, enantiomeric formulations are believed to have advantages over racemic formulations because they are less complex and have a more selective pharmacodynamic profile, better therapeutic index, lower liability for drug-drug interactions (DDIs), and a less complicated relationship between plasma concentration and pharmacodynamic effect.⁶ In addition, regulatory guidelines in the United States recommend development of enantiomers over racemates where appropriate.⁷

How it works

Levomilnacipran’s exact mechanism of action is unknown. Similar to other SNRIs, it binds with high affinity to the serotonin (5-HT) and norepinephrine (NE) transporters and potently inhibits 5-HT and NE reuptake. Levomilnacipran lacks significant affinity for any other receptors, ion channels, or transporters tested in vitro.² It differs from other SNRIs such as venlafaxine and duloxetine in having higher selectivity for norepinephrine vs serotonin reuptake inhibition. In vitro studies demonstrated a 2-fold preference for NE over 5-HT reuptake inhibition.²

Pharmacokinetics

Levomilnacipran reaches maximum plasma concentration within 6 to 8 hours of oral administration and has a half-life of approximately 12 hours, which makes it suitable for once-daily dosing. The concentration of levomilnacipran at steady state is proportional to the dosage of the drug when administered within the range of 25 to 300 mg once daily.¹

The drug’s mean apparent total clearance is 21 to 29 liters/hour and its bioavailability is not significantly affected when taken with food. The drug is widely distributed in the body and is converted primarily to 2 metabolites: desethy levomilnacipran and p-hydroxy-levomilnacipran. Both metabolites are inactive and undergo further conjugation with glucuronide. The drug is eliminated primarily via renal excretion.¹

The major enzyme that catalyzes metabolism of levomilnacipram is cytochrome P 450 (CYP) 3A4, which makes it susceptible to DDIs with drugs that inhibit or induce this enzyme. For example, a person taking levomilnacipran with a potent CYP3A4 inhibitor, such as ketoconazole, may require a dosage adjustment. No dosage adjustment is needed when given with a CYP3A4 inducer or substrate. Drinking alcohol with levomilnacipran may cause more rapid release of the drug into the blood stream.¹

Efficacy

Levomilnacipran decreased core symptoms of MDD and showed a statistically significant separation from placebo in 2 phase III RCTs (Table 2).^3,5 The first study was a 10-week flexible dose (75 or 100 mg) trial in 563 outpatients age 18 to 70 who met DSM-IV-TR criteria of MDD for >1 month and had a 17-item Hamilton Depression Rating Scale (HDRS-17) score >22 and a Sheehan Disability Scale (SDS) score >10.³ The primary efficacy measure was change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 10. Secondary efficacy measures included the HDRS-17, SDS, and Clinical Global Impressions-improvement scale. Efficacy analyses included 276 subjects treated with levomilnacipran and 277 treated with placebo.³

Levomilnacipran was significantly superior to placebo on the MADRS and HDRS-17 from baseline to week 10. Response and remission rates were
significantly greater for the levomilnacipran group compared with placebo. Response exceeded the 10% average advantage for drug vs placebo and 46% of levomilnacipran-treated patients achieved remission.³

The number needed to treat (NNT), based on the MADRS scores for the levomilnacipran group compared with the placebo group, was 6 for response and 5 for remission.³ By comparison, most studies of venlafaxine demonstrate a NNT of 8.³

Levomilnacipran generally was reported to be safe and well tolerated. The most common adverse events leading to discontinuation in the levomilnacipran group were nausea, vomiting, change in systolic and diastolic blood pressure, and increase in heart rate. The favorable tolerability profile of levomilnacipran may relate to the 2-fold greater potency for NE reuptake inhibition compared with 5-HT reuptake inhibition.³

The second study was an 11-week, fixed-dose trial of levomilnacipran using 40, 80, or 120 mg. A total of 724 outpatients age 18 to 65 who met DSM-IV-TR criteria for MDD and who had an ongoing episode of depression lasting >8 weeks were randomly assigned to receive placebo (n = 179) or levomilnacipran at 40 mg (n = 181), 80 mg (n = 181), or 120 mg (n = 183) once daily for 8 weeks of double-blind treatment followed by a 2-week, double-blind taper of the drug.⁵ The primary efficacy parameter was change from baseline on the MADRS and the secondary efficacy parameter was change from baseline in SDS total score. HDRS-17, CGI-I, and CGI-S were included as secondary outcome measures.⁵

Significant difference in MADRS total score were seen in the levomilnacipran group compared with the placebo group (least mean squared difference: 40 mg/d,  −3.23; 80 mg/d, −3.99; and 120 mg/d,  −4.86). Higher dosages produced a numerically greater change and significant separation from placebo occurred sooner in the 80-mg and 120-mg groups compared with the 40-mg group.⁵

Significant differences vs placebo were consistently observed across secondary outcome measures for the higher dosages of levomilnacipran, and improvement in SDS total score was noted in all levomilnacipran groups compared with the placebo group. When dosed at 120 mg/d, levomilnacipran produced significant improvement vs placebo on all SDS subscales and was as well tolerated as the 80 mg dosage.⁵

No new safety concerns were observed in the study. A dose-response relationship in tolerability was not demonstrated and the number of patients reporting adverse events and who discontinued participation because of adverse events was higher in the 80-mg group than in the 40-mg and 120-mg groups.⁵

Tolerability

Overall, levomilnacipran was well tolerated in clinical trials, during which 2,673 subjects were exposed to the drug—translating to 942 patient-years of exposure. These patients ranged in age from 18 to 78; 825 of these subjects were enrolled in long-term studies for 1 year. Dosing of levomilnacipran during these studies ranged from 40 to 120 mg once daily, without regard to food.¹

Nine percent of patients who received levomilnacipran in short-term studies discontinued because of adverse events, compared with 3% of patients who received placebo. The most common adverse event reported was nausea; other common adverse events reported included constipation, hyperhidrosis, elevated heart rate, erectile dysfunction, tachycardia, palpitations, and vomiting. Of these events, only erectile dysfunction and urinary hesitation were dose-related.¹ Among levo­milnacipran-treated female patients, <2% reported adverse events related to sexual dysfunction.

All SNRIs have well established associations with elevation in blood pressure and heart rate. Levomilnacipran resulted in a mean increase of 3 mm HG in systolic and 3.2 mm Hg in diastolic blood pressure in short-term, placebo-controlled trials.¹

Orthostatic hypotension was observed in 11.6% of patients in the levomilnacipran groups, compared with 9.7% in placebo groups in all short-term studies. Orthostatic reductions of blood pressure occurred in 5.8%, 6.1%, and 9.8% of levomilnacipran-treated patients with dosages of 40, 80, and 120 mg/d respectively, indicating a dose-dependent adverse event. A mean increase in heart rate of 7.2 beats per minute (bpm) also was seen in short-term studies in the levomilnacipran-treated group compared with 0.3 bpm in the placebo-treated group.¹ Clinicians should monitor blood pressure and heart rate routinely because of potential increases seen in some subjects in these studies, which excluded those who had significant cardiovascular disease.

Unique clinical issues

Both in-vitro and in-vivo studies found that levomilnacipran exhibited more potency for NE reuptake inhibition than for 5-HT reuptake inhibition at the lowest effective dosage (10 mg/kg). However as the dosage was increased (20 mg/kg and 40 mg/kg), it was equally potent at NE and 5-HT reuptake inhibition. This is in contrast to venlafaxine, which demonstrates a similar, but opposite, effect in terms of potentiation at the 5-HT and NE reuptake pumps.²

The greater noradrenergic effect of levomilnacipran could lend itself to treating certain subgroups of patients whose symptoms are believed to be related to deficiencies in NE (eg, lassitude).⁴ This concept is theoretical, and was not explicitly studied in clinical trials and the drug is not labeled in this way.

Contraindications

Contraindications to levomilnacipran are similar to those seen with SSRIs and SNRIs, including concomitant use of a monoamine oxidase inhibitor (MAOI) and the use of the levomilnacipran within 14 days of stopping an MAOI. Contraindications unique to levomilnacipran include hypersensitivity to levomilnacipran, milnacipran, or any component specific to the formulation; and uncontrolled narrow-angle glaucoma.¹

Dosing

The recommended dosage range of levomilnacipran is 40 to 120 mg once
daily with or without food. The capsules should be swallowed whole and should not be opened or crushed. As with most psychotropics, levomilnacipran should be taken at approximately the same time each day.¹

The manufacturer recommends an initial dose of levomilnacipran of 20 mg once daily for 2 days, increased to 40 mg once daily. Based on efficacy and tolerably, levomilnacipran can be increased in increments of 40 mg every 2 days.

Dosage adjustment is recommended for patients with moderate or severe renal impairment; and the maintenance dosage should not exceed 80 mg and 40 mg respectively in these populations. As with many antidepressants, gradual dosage reduction is recommended to avoid discontinuation symptoms.

Bottom Line

Levomilnacipran is FDA-approved for treating major depressive disorder in adults. In 2 randomized controlled trials, the drug showed a significant separation from placebo. Levomilnacipran generally was reported to be safe and well tolerated; common adverse events were nausea, vomiting, changes in blood pressure, and an increase in heart rate.

Related Resources

• Citrome L. Levomilnacipran for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? [published online September 8, 2013]. Int J Clin Pract. doi: 10.1111/ijcp.12298.
• Mago R, Forero G, Greenberg WM, et al. Safety and tolerability of levomilnacipran ER in major depressive disorder: results from an open-label, 48-week extension study. Clin Drug Investig. 2013;33(10):761-771.

Drug Brand Names
Duloxetine • Cymbalta        Milnacipran • Savella
Ketoconazole • Nizoral        Venlafaxine • Effexor    Levomilnacipran • Fetzima
 

Disclosures

Dr. Macaluso has been the principal investigator for clinical trials for AbbVie, Eisai, Envivo, Janssen, Naurex, and Pfizer. All clinical trial and study contracts and payments were made through the Kansas University Medical Center Research Institute. Drs. Kazanchi and Malhotra report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Medication nonadherence is a common problem when treating patients with schizophrenia that can worsen prognosis and lead to sub-optimal treatment outcomes. In this article, we discuss common reasons for nonadherence and describe evidence-based treatments intended to increase adherence and improve outcomes (Box).^1-6

Common reasons for nonadherence

The primary predictor of future nonadherence is a history of nonadherence. It is important to understand patients’ reasons for nonadherence so that practical and evidence-based solutions can be implemented into the treatment plans of individual patients.

The 2009 Expert Consensus Guidelines on Adherence Problems in Patients with Serious and Persistent Mental Illness divided variables related to nonadherence into 3 categories:

• those that lie within the patient (intrinsic)
• those that are related to the patient’s relationship with healthcare providers, family, or caregivers (extrinsic)
• those that are related to the healthcare delivery system (extrinsic).⁷

Among intrinsic variables, studies have shown a correlation between nonadherence and education level, lower socioeconomic status, homelessness, and male sex.⁷ (The Expert Consensus Guidelines considered homelessness to be an intrinsic factor because it was used as a demographic variable in the studies.)

Cognitive and negative symptoms associated with schizophrenia are an intrinsic risk factor for nonadherence because patients might not remember when or how to take medication.⁷ In a study by Freudenreich and co-workers⁸ of 81 outpatients who had a diagnosis of schizophrenia, the presence of negative symptoms predicted a negative attitude toward psychotropic medications. Poor insight might be the result of cognitive dysfunction associated with schizophrenia, and often is due to a lack of awareness of the importance of taking medications.

Limited insight into the need for treatment can be problematic early in the course of the illness when it may be directly related to positive symptoms. Perkins and colleagues⁹ demonstrated that patients recovering from a first psychotic episode who had limited insight into their illness and lacked desire to seek treatment were less adherent with medication. In another study, 5% of psychiatrists surveyed thought that many of their patients with schizophrenia were nonadherent because those patients did not believe that medications were effective or useful.¹⁰

Comorbid substance abuse disorders can contribute to medication nonadherence. In an analysis of 6,731 patients with schizophrenia, Novick and co-workers reported that alcohol dependence and substance abuse in the previous month predicted medication nonadherence.¹¹ Hunt and colleagues demonstrated that, among 99 nonadherent patients with schizophrenia, time to first readmission was shorter for patients with comorbid substance abuse disorders compared with patients who had a diagnosis of schizophrenia only. Over the 4-year study period, the 28 patients who had a dual diagnosis (schizophrenia and substance abuse) accounted for 57% of all hospital readmissions.¹²

Several variables that affect medication adherence are related to the patient’s relationship with healthcare providers, family, caregivers, and the service delivery system.⁷ These include:

• the perceived stigma of being given a diagnosis of a serious mental illness
• adverse effects related to medications
• poor social and family support
• difficulty gaining access to mental health services.^7,10

Societal stigma associated with seeking treatment from a mental health professional may contribute to nonadherence in some patients. In 1 study,¹³ 36% of people surveyed would not want to work closely with a person who has a serious mental illness.

Adverse effects contribute significantly to nonadherence

Limited treatment options (which may be expensive) can make it difficult to manage the adverse effects of antipsychotics. In a cross-sectional survey of 876 patients, investigators reported that: 1) <50% of patients were adherent with medication, and 2) 80% experienced ≥1 side effect that was reported to be “somewhat bothersome” in self-ratings (Table 1).¹⁴ Extrapyramidal symptoms (EPS) and agitation were most strongly associated with nonadherence; weight gain, akathisia, and sexual dysfunction also were associated with nonadherence.¹⁴ This study did not distinguish adverse effects associated with first-generation antipsychotics (FGAs) from those associated with second-generation antipsychotics (SGAs), even though 71.7% of patients studied were taking an SGA.

A meta-analysis by Leucht and co-workers¹⁵ compared 15 antipsychotics (the FGAs haloperidol and chlorpromazine and 13 SGAs) for efficacy and tolerability in schizophrenia. Haloperidol had the highest rate of discontinuation for any

Antipsychotic binding affinities to dopamine 2 (D2), serotonin 2A (5-HT2A), histamine (H1), and other receptors have an impact on a medication’s side-effect profile. Because of individual patient characteristics, you might be faced with choosing a medication that has a lower risk of EPS but a higher risk of weight gain and metabolic complications—or the inverse. Understanding binding affinities, side-effect profiles, and how to minimize or utilize adverse effects (ie, giving a drug that is approved to treat schizophrenia and is associated with weight gain to a patient with schizophrenia who has lost weight) may lead to greater adherence (Table 2¹⁶ and Table 3¹⁷).

Adequate support is essential

The therapeutic alliance plays a key role in patients’ attitudes toward taking medication. Magura and colleagues¹⁸ found that one-third of psychiatric patients (13% of whom had a diagnosis of schizophrenia) reported that their psychiatrist did not spend enough time with them explaining side effects, and felt “rushed.”

Patients with schizophrenia often require access to social support systems provided by family members, friends, and community agencies that provide case management and attendant care services. Patients who are adherent to medication tend to have greater perceived family involvement in medication treatment, and tend to have been raised in a family that had more of a positive attitude toward medication.¹⁹

In our practice, we have observed that recent state and federal budget cuts have resulted in patients having greater difficulty gaining access to case management and attendant care services, which then leads to increased rates of medication nonadherence. Be aware that variables such as limited office hours, financial hardship, and cultural and language barriers can compromise a patient’s ability to seek and continue care.

In the following section, we lay out techniques for improving adherence in patients with schizophrenia.

Employ general and specific strategies to boost adherence

How can you raise medication adherence concerns with patients, keeping in mind that they often overestimate their adherence?

Ask. Some clinicians ask questions such as “Are you taking your medication?”, although a more effective approach might be to ask how the patient is taking his (her) medication. Asking questions such as “When do you take your medication?” and “In the past week, how many doses do you think you missed?” might be more effective ways to inquire about adherence.⁷

The Expert Consensus Guidelines recommend asking patients about medication adherence monthly for those who are stable, doing well, and believed to be adherent. For those who are new to a practice or who are not doing well, inquire about medication adherence at least weekly.⁷

In our practice, patients who are unstable but do not require inpatient hospitalization typically are seen more often in the clinic, or are referred to intensive outpatient or partial hospitalization programs. If an unstable patient is unable to come in for more frequent appointments, we arrange phone conferences between her and her provider. If a patient is not doing well and has a case manager, we often ask that case manager to visit the patient, in person, more often than he (she) would otherwise.

Take a nonjudgmental approach when raising these issues with patients. Questions such as “We all forget to take our medication sometimes; do you?” help to normalize nonadherence, and improve the therapeutic alliance, and might result in the patient being more honest with the clinician.⁷ Because patients may be apprehensive about discussing adverse events, clinicians must be proactive about improving the therapeutic alliance and making patients feel comfortable when discussing sensitive topics. Clinicians should try to convey the idea that, although adherence is a concern, so is quality of life. A clinicians’ willingness to take a flexible approach that is nonpunitive nor authoritarian can aid the therapeutic alliance and improve overall adherence.

Be sensitive to financial, cultural, and language variables that can affect access to care. The Expert Consensus Guidelines recommend asking patients if they can afford their medication. In our practice, we have seen patients with schizophrenia discharged from the hospital only to be readmitted 1 month later because they could not afford to fill their prescriptions.

It is important to have translation services available, in person or by phone, for patients who do not speak English. Furthermore, it is important to understand the limitations that your practice might place on access to care. Ask patients if they have ever had trouble making an appointment when they needed to be seen, or if they called the office with a question and did not receive an answer in a timely fashion; doing so allows you to assess the practice’s ability to meet patients’ needs and helps you build a therapeutic alliance.

Make objective assessments. It is important for practitioners to not base their assessment of medication adherence solely on subjective findings. Asking patients to bring in their medication bottles for pill counts and checking with the patients’ pharmacies for information about refill frequency can provide some objective data. Electronic monitoring systems use microprocessors inserted into bottle caps to record the occurrence and timing of each bottle opening. Studies show that these electronic monitoring systems are the gold standard for determining medication adherence and could be used in cases where it is unclear if the patient is taking his (her) medication.^7,20 Such systems have successfully monitored medication adherence in clinical trials, but their use in clinical practice is complicated by ethical and legal considerations and cost issues.

Simplify the regimen. Using medications with once-daily dosing, for example, can help improve adherence. Pfeiffer and co-workers²¹ found that patients whose medication regimens were changed from once daily to more than once daily experienced a decrease in medication adherence. Conversely, a decrease in dosing frequency was significantly associated with improved adherence. More than once-daily dosing was only weakly associated with poorer adherence among patients already on a stable regimen.

Discussing positive and negative aspects of past medication trials with a patient and inquiring if she prefers a specific medication can be an effective way to build the therapeutic relationship and help with adherence.

Direct patients to psychosocial interventions. These can be broadly classified as:

• educational approaches
• group therapy approaches
• family interventions
• cognitive treatments
• combination approaches.

Psychoeducational approaches have limited effect on improving adherence when delivered to individual patients. However, 1 study showed that psychoeducation was effective at improving adherence when extended to include the patient’s family.²²

Motivational interviewing techniques, behavioral approaches, and family interventions are effective at increasing medication adherence. One study looked at the value of training a patient-identified informant to supervise and administer medication. This person, usually a family member or close support, was responsible for obtaining medication from the pharmacy, administering the medication, and recording adherence. After 1 year, 67% of patients who used an informant were adherent, compared with only 45% in the group that did not have informant support.²² Case managers, attendant care workers, home health nurses, and assertive community treatment (ACT) teams also can participate in this manner; it is important, therefore, for you to be aware of the resources available in your community and to understand your role as patient advocate.

Substance abuse is a strong risk factor for nonadherence among patients with schizophrenia,¹⁸ which makes it important to assess patients for substance use and encourage those who do abuse to seek treatment. Although 1 study showed no correlation between Alcoholics Anonymous (AA) attendance and medication adherence,¹² many AA and Narcotics Anonymous groups do not discuss psychiatric medications during group meetings. Magura and colleagues encouraged the use of “dual focus” groups that involve mental health professionals and addiction treatment specialists discussing mental health and substance abuse issues at the same setting.¹⁸

Prescribe long-acting injectable antipsychotics. Typically, long-acting injectable antipsychotics (LAIs) are reserved for patients who have a history of nonadherence. In a small study (N = 97) comparing LAI risperidone and oral risperidone or oral haloperidol, patients treated with an LAI had significantly fewer all-cause discontinuations (26.0%, compared with 70.2%) at 24 months.²³ The Adherence to Treatment and Therapeutic Strategies in Schizophrenic Patients study examined 1,848 patients with schizophrenia and reached similar findings regarding LAI antipsychotics.²⁴ (Note: Aripiprazole, fluphenazine, haloperidol, olanzapine, and paliperidone also are available in an LAI formulation.)

Bottom Line

Antipsychotic nonadherence in schizophrenia is a major problem for patients, families, and society. Being able to identify patients at risk for nonadherence, understanding the reasons for their nonadherence, and seeking practical solutions to the problem are all the responsibility of the treating physician. Psychoeducation, addressing substance abuse, modifying dosing, and using long-acting injectable antipsychotics may help improve adherence.

Related Resources

• Velligan DI, Weiden PJ, Sajatovic M, et al; Expert Consensus Panel on Adherence Problems in Serious and Persistent Mental Illness. Assessment of adherence problems in patients with serious and persistent mental illness: recommendations from the Expert Consensus Guidelines. J Clin Psychiatry. 2009;70(suppl 4):1-46.
• National Alliance on Mental Illness. www.nami.org.
• Assertive Community Treatment (ACT) Organization. www.actassociation.org.

Drug Brand Names

Aripiprazole • Abilify        Chlorpromazine • Thorazine      Clozapine • Clozaril       Fluphenazine • Permitil    Haloperidol • Haldol                  Iloperidone • Fanapt       Olanzapine • Zyprexa      Paliperidone • Invega               Perphenazine • Trilafon    Quetiapine • Seroquel      Risperidone • Risperdal            Ziprasidone • Geodon

Disclosures

Dr. Macaluso has been the principal investigator for clinical trials for AbbVie, Eisai, Envivo, Janssen, Naurex, and Pfizer. All clinical trial and study contracts and payments were made through the Kansas University Medical Center Research Institute. Dr. McKnight reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Medication nonadherence is a common problem when treating patients with schizophrenia that can worsen prognosis and lead to sub-optimal treatment outcomes. In this article, we discuss common reasons for nonadherence and describe evidence-based treatments intended to increase adherence and improve outcomes (Box).^1-6

Common reasons for nonadherence

The primary predictor of future nonadherence is a history of nonadherence. It is important to understand patients’ reasons for nonadherence so that practical and evidence-based solutions can be implemented into the treatment plans of individual patients.

The 2009 Expert Consensus Guidelines on Adherence Problems in Patients with Serious and Persistent Mental Illness divided variables related to nonadherence into 3 categories:

• those that lie within the patient (intrinsic)
• those that are related to the patient’s relationship with healthcare providers, family, or caregivers (extrinsic)
• those that are related to the healthcare delivery system (extrinsic).⁷

Among intrinsic variables, studies have shown a correlation between nonadherence and education level, lower socioeconomic status, homelessness, and male sex.⁷ (The Expert Consensus Guidelines considered homelessness to be an intrinsic factor because it was used as a demographic variable in the studies.)

Cognitive and negative symptoms associated with schizophrenia are an intrinsic risk factor for nonadherence because patients might not remember when or how to take medication.⁷ In a study by Freudenreich and co-workers⁸ of 81 outpatients who had a diagnosis of schizophrenia, the presence of negative symptoms predicted a negative attitude toward psychotropic medications. Poor insight might be the result of cognitive dysfunction associated with schizophrenia, and often is due to a lack of awareness of the importance of taking medications.

Limited insight into the need for treatment can be problematic early in the course of the illness when it may be directly related to positive symptoms. Perkins and colleagues⁹ demonstrated that patients recovering from a first psychotic episode who had limited insight into their illness and lacked desire to seek treatment were less adherent with medication. In another study, 5% of psychiatrists surveyed thought that many of their patients with schizophrenia were nonadherent because those patients did not believe that medications were effective or useful.¹⁰

Comorbid substance abuse disorders can contribute to medication nonadherence. In an analysis of 6,731 patients with schizophrenia, Novick and co-workers reported that alcohol dependence and substance abuse in the previous month predicted medication nonadherence.¹¹ Hunt and colleagues demonstrated that, among 99 nonadherent patients with schizophrenia, time to first readmission was shorter for patients with comorbid substance abuse disorders compared with patients who had a diagnosis of schizophrenia only. Over the 4-year study period, the 28 patients who had a dual diagnosis (schizophrenia and substance abuse) accounted for 57% of all hospital readmissions.¹²

Several variables that affect medication adherence are related to the patient’s relationship with healthcare providers, family, caregivers, and the service delivery system.⁷ These include:

• the perceived stigma of being given a diagnosis of a serious mental illness
• adverse effects related to medications
• poor social and family support
• difficulty gaining access to mental health services.^7,10

Societal stigma associated with seeking treatment from a mental health professional may contribute to nonadherence in some patients. In 1 study,¹³ 36% of people surveyed would not want to work closely with a person who has a serious mental illness.

Adverse effects contribute significantly to nonadherence

Limited treatment options (which may be expensive) can make it difficult to manage the adverse effects of antipsychotics. In a cross-sectional survey of 876 patients, investigators reported that: 1) <50% of patients were adherent with medication, and 2) 80% experienced ≥1 side effect that was reported to be “somewhat bothersome” in self-ratings (Table 1).¹⁴ Extrapyramidal symptoms (EPS) and agitation were most strongly associated with nonadherence; weight gain, akathisia, and sexual dysfunction also were associated with nonadherence.¹⁴ This study did not distinguish adverse effects associated with first-generation antipsychotics (FGAs) from those associated with second-generation antipsychotics (SGAs), even though 71.7% of patients studied were taking an SGA.

A meta-analysis by Leucht and co-workers¹⁵ compared 15 antipsychotics (the FGAs haloperidol and chlorpromazine and 13 SGAs) for efficacy and tolerability in schizophrenia. Haloperidol had the highest rate of discontinuation for any

Antipsychotic binding affinities to dopamine 2 (D2), serotonin 2A (5-HT2A), histamine (H1), and other receptors have an impact on a medication’s side-effect profile. Because of individual patient characteristics, you might be faced with choosing a medication that has a lower risk of EPS but a higher risk of weight gain and metabolic complications—or the inverse. Understanding binding affinities, side-effect profiles, and how to minimize or utilize adverse effects (ie, giving a drug that is approved to treat schizophrenia and is associated with weight gain to a patient with schizophrenia who has lost weight) may lead to greater adherence (Table 2¹⁶ and Table 3¹⁷).

Adequate support is essential

The therapeutic alliance plays a key role in patients’ attitudes toward taking medication. Magura and colleagues¹⁸ found that one-third of psychiatric patients (13% of whom had a diagnosis of schizophrenia) reported that their psychiatrist did not spend enough time with them explaining side effects, and felt “rushed.”

Patients with schizophrenia often require access to social support systems provided by family members, friends, and community agencies that provide case management and attendant care services. Patients who are adherent to medication tend to have greater perceived family involvement in medication treatment, and tend to have been raised in a family that had more of a positive attitude toward medication.¹⁹

In our practice, we have observed that recent state and federal budget cuts have resulted in patients having greater difficulty gaining access to case management and attendant care services, which then leads to increased rates of medication nonadherence. Be aware that variables such as limited office hours, financial hardship, and cultural and language barriers can compromise a patient’s ability to seek and continue care.

In the following section, we lay out techniques for improving adherence in patients with schizophrenia.

Employ general and specific strategies to boost adherence

How can you raise medication adherence concerns with patients, keeping in mind that they often overestimate their adherence?

Ask. Some clinicians ask questions such as “Are you taking your medication?”, although a more effective approach might be to ask how the patient is taking his (her) medication. Asking questions such as “When do you take your medication?” and “In the past week, how many doses do you think you missed?” might be more effective ways to inquire about adherence.⁷

The Expert Consensus Guidelines recommend asking patients about medication adherence monthly for those who are stable, doing well, and believed to be adherent. For those who are new to a practice or who are not doing well, inquire about medication adherence at least weekly.⁷

In our practice, patients who are unstable but do not require inpatient hospitalization typically are seen more often in the clinic, or are referred to intensive outpatient or partial hospitalization programs. If an unstable patient is unable to come in for more frequent appointments, we arrange phone conferences between her and her provider. If a patient is not doing well and has a case manager, we often ask that case manager to visit the patient, in person, more often than he (she) would otherwise.

Take a nonjudgmental approach when raising these issues with patients. Questions such as “We all forget to take our medication sometimes; do you?” help to normalize nonadherence, and improve the therapeutic alliance, and might result in the patient being more honest with the clinician.⁷ Because patients may be apprehensive about discussing adverse events, clinicians must be proactive about improving the therapeutic alliance and making patients feel comfortable when discussing sensitive topics. Clinicians should try to convey the idea that, although adherence is a concern, so is quality of life. A clinicians’ willingness to take a flexible approach that is nonpunitive nor authoritarian can aid the therapeutic alliance and improve overall adherence.

Be sensitive to financial, cultural, and language variables that can affect access to care. The Expert Consensus Guidelines recommend asking patients if they can afford their medication. In our practice, we have seen patients with schizophrenia discharged from the hospital only to be readmitted 1 month later because they could not afford to fill their prescriptions.

It is important to have translation services available, in person or by phone, for patients who do not speak English. Furthermore, it is important to understand the limitations that your practice might place on access to care. Ask patients if they have ever had trouble making an appointment when they needed to be seen, or if they called the office with a question and did not receive an answer in a timely fashion; doing so allows you to assess the practice’s ability to meet patients’ needs and helps you build a therapeutic alliance.

Make objective assessments. It is important for practitioners to not base their assessment of medication adherence solely on subjective findings. Asking patients to bring in their medication bottles for pill counts and checking with the patients’ pharmacies for information about refill frequency can provide some objective data. Electronic monitoring systems use microprocessors inserted into bottle caps to record the occurrence and timing of each bottle opening. Studies show that these electronic monitoring systems are the gold standard for determining medication adherence and could be used in cases where it is unclear if the patient is taking his (her) medication.^7,20 Such systems have successfully monitored medication adherence in clinical trials, but their use in clinical practice is complicated by ethical and legal considerations and cost issues.

Simplify the regimen. Using medications with once-daily dosing, for example, can help improve adherence. Pfeiffer and co-workers²¹ found that patients whose medication regimens were changed from once daily to more than once daily experienced a decrease in medication adherence. Conversely, a decrease in dosing frequency was significantly associated with improved adherence. More than once-daily dosing was only weakly associated with poorer adherence among patients already on a stable regimen.

Discussing positive and negative aspects of past medication trials with a patient and inquiring if she prefers a specific medication can be an effective way to build the therapeutic relationship and help with adherence.

Direct patients to psychosocial interventions. These can be broadly classified as:

• educational approaches
• group therapy approaches
• family interventions
• cognitive treatments
• combination approaches.

Psychoeducational approaches have limited effect on improving adherence when delivered to individual patients. However, 1 study showed that psychoeducation was effective at improving adherence when extended to include the patient’s family.²²

Motivational interviewing techniques, behavioral approaches, and family interventions are effective at increasing medication adherence. One study looked at the value of training a patient-identified informant to supervise and administer medication. This person, usually a family member or close support, was responsible for obtaining medication from the pharmacy, administering the medication, and recording adherence. After 1 year, 67% of patients who used an informant were adherent, compared with only 45% in the group that did not have informant support.²² Case managers, attendant care workers, home health nurses, and assertive community treatment (ACT) teams also can participate in this manner; it is important, therefore, for you to be aware of the resources available in your community and to understand your role as patient advocate.

Substance abuse is a strong risk factor for nonadherence among patients with schizophrenia,¹⁸ which makes it important to assess patients for substance use and encourage those who do abuse to seek treatment. Although 1 study showed no correlation between Alcoholics Anonymous (AA) attendance and medication adherence,¹² many AA and Narcotics Anonymous groups do not discuss psychiatric medications during group meetings. Magura and colleagues encouraged the use of “dual focus” groups that involve mental health professionals and addiction treatment specialists discussing mental health and substance abuse issues at the same setting.¹⁸

Prescribe long-acting injectable antipsychotics. Typically, long-acting injectable antipsychotics (LAIs) are reserved for patients who have a history of nonadherence. In a small study (N = 97) comparing LAI risperidone and oral risperidone or oral haloperidol, patients treated with an LAI had significantly fewer all-cause discontinuations (26.0%, compared with 70.2%) at 24 months.²³ The Adherence to Treatment and Therapeutic Strategies in Schizophrenic Patients study examined 1,848 patients with schizophrenia and reached similar findings regarding LAI antipsychotics.²⁴ (Note: Aripiprazole, fluphenazine, haloperidol, olanzapine, and paliperidone also are available in an LAI formulation.)

Bottom Line

Antipsychotic nonadherence in schizophrenia is a major problem for patients, families, and society. Being able to identify patients at risk for nonadherence, understanding the reasons for their nonadherence, and seeking practical solutions to the problem are all the responsibility of the treating physician. Psychoeducation, addressing substance abuse, modifying dosing, and using long-acting injectable antipsychotics may help improve adherence.

Related Resources

• Velligan DI, Weiden PJ, Sajatovic M, et al; Expert Consensus Panel on Adherence Problems in Serious and Persistent Mental Illness. Assessment of adherence problems in patients with serious and persistent mental illness: recommendations from the Expert Consensus Guidelines. J Clin Psychiatry. 2009;70(suppl 4):1-46.
• National Alliance on Mental Illness. www.nami.org.
• Assertive Community Treatment (ACT) Organization. www.actassociation.org.

Drug Brand Names

Aripiprazole • Abilify        Chlorpromazine • Thorazine      Clozapine • Clozaril       Fluphenazine • Permitil    Haloperidol • Haldol                  Iloperidone • Fanapt       Olanzapine • Zyprexa      Paliperidone • Invega               Perphenazine • Trilafon    Quetiapine • Seroquel      Risperidone • Risperdal            Ziprasidone • Geodon

Disclosures

Dr. Macaluso has been the principal investigator for clinical trials for AbbVie, Eisai, Envivo, Janssen, Naurex, and Pfizer. All clinical trial and study contracts and payments were made through the Kansas University Medical Center Research Institute. Dr. McKnight reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Medication nonadherence is a common problem when treating patients with schizophrenia that can worsen prognosis and lead to sub-optimal treatment outcomes. In this article, we discuss common reasons for nonadherence and describe evidence-based treatments intended to increase adherence and improve outcomes (Box).^1-6

Common reasons for nonadherence

The primary predictor of future nonadherence is a history of nonadherence. It is important to understand patients’ reasons for nonadherence so that practical and evidence-based solutions can be implemented into the treatment plans of individual patients.

The 2009 Expert Consensus Guidelines on Adherence Problems in Patients with Serious and Persistent Mental Illness divided variables related to nonadherence into 3 categories:

• those that lie within the patient (intrinsic)
• those that are related to the patient’s relationship with healthcare providers, family, or caregivers (extrinsic)
• those that are related to the healthcare delivery system (extrinsic).⁷

Among intrinsic variables, studies have shown a correlation between nonadherence and education level, lower socioeconomic status, homelessness, and male sex.⁷ (The Expert Consensus Guidelines considered homelessness to be an intrinsic factor because it was used as a demographic variable in the studies.)

Cognitive and negative symptoms associated with schizophrenia are an intrinsic risk factor for nonadherence because patients might not remember when or how to take medication.⁷ In a study by Freudenreich and co-workers⁸ of 81 outpatients who had a diagnosis of schizophrenia, the presence of negative symptoms predicted a negative attitude toward psychotropic medications. Poor insight might be the result of cognitive dysfunction associated with schizophrenia, and often is due to a lack of awareness of the importance of taking medications.

Limited insight into the need for treatment can be problematic early in the course of the illness when it may be directly related to positive symptoms. Perkins and colleagues⁹ demonstrated that patients recovering from a first psychotic episode who had limited insight into their illness and lacked desire to seek treatment were less adherent with medication. In another study, 5% of psychiatrists surveyed thought that many of their patients with schizophrenia were nonadherent because those patients did not believe that medications were effective or useful.¹⁰

Comorbid substance abuse disorders can contribute to medication nonadherence. In an analysis of 6,731 patients with schizophrenia, Novick and co-workers reported that alcohol dependence and substance abuse in the previous month predicted medication nonadherence.¹¹ Hunt and colleagues demonstrated that, among 99 nonadherent patients with schizophrenia, time to first readmission was shorter for patients with comorbid substance abuse disorders compared with patients who had a diagnosis of schizophrenia only. Over the 4-year study period, the 28 patients who had a dual diagnosis (schizophrenia and substance abuse) accounted for 57% of all hospital readmissions.¹²

Several variables that affect medication adherence are related to the patient’s relationship with healthcare providers, family, caregivers, and the service delivery system.⁷ These include:

• the perceived stigma of being given a diagnosis of a serious mental illness
• adverse effects related to medications
• poor social and family support
• difficulty gaining access to mental health services.^7,10

Societal stigma associated with seeking treatment from a mental health professional may contribute to nonadherence in some patients. In 1 study,¹³ 36% of people surveyed would not want to work closely with a person who has a serious mental illness.

Adverse effects contribute significantly to nonadherence

Limited treatment options (which may be expensive) can make it difficult to manage the adverse effects of antipsychotics. In a cross-sectional survey of 876 patients, investigators reported that: 1) <50% of patients were adherent with medication, and 2) 80% experienced ≥1 side effect that was reported to be “somewhat bothersome” in self-ratings (Table 1).¹⁴ Extrapyramidal symptoms (EPS) and agitation were most strongly associated with nonadherence; weight gain, akathisia, and sexual dysfunction also were associated with nonadherence.¹⁴ This study did not distinguish adverse effects associated with first-generation antipsychotics (FGAs) from those associated with second-generation antipsychotics (SGAs), even though 71.7% of patients studied were taking an SGA.

A meta-analysis by Leucht and co-workers¹⁵ compared 15 antipsychotics (the FGAs haloperidol and chlorpromazine and 13 SGAs) for efficacy and tolerability in schizophrenia. Haloperidol had the highest rate of discontinuation for any

Antipsychotic binding affinities to dopamine 2 (D2), serotonin 2A (5-HT2A), histamine (H1), and other receptors have an impact on a medication’s side-effect profile. Because of individual patient characteristics, you might be faced with choosing a medication that has a lower risk of EPS but a higher risk of weight gain and metabolic complications—or the inverse. Understanding binding affinities, side-effect profiles, and how to minimize or utilize adverse effects (ie, giving a drug that is approved to treat schizophrenia and is associated with weight gain to a patient with schizophrenia who has lost weight) may lead to greater adherence (Table 2¹⁶ and Table 3¹⁷).

Adequate support is essential

The therapeutic alliance plays a key role in patients’ attitudes toward taking medication. Magura and colleagues¹⁸ found that one-third of psychiatric patients (13% of whom had a diagnosis of schizophrenia) reported that their psychiatrist did not spend enough time with them explaining side effects, and felt “rushed.”

Patients with schizophrenia often require access to social support systems provided by family members, friends, and community agencies that provide case management and attendant care services. Patients who are adherent to medication tend to have greater perceived family involvement in medication treatment, and tend to have been raised in a family that had more of a positive attitude toward medication.¹⁹

In our practice, we have observed that recent state and federal budget cuts have resulted in patients having greater difficulty gaining access to case management and attendant care services, which then leads to increased rates of medication nonadherence. Be aware that variables such as limited office hours, financial hardship, and cultural and language barriers can compromise a patient’s ability to seek and continue care.

In the following section, we lay out techniques for improving adherence in patients with schizophrenia.

Employ general and specific strategies to boost adherence

How can you raise medication adherence concerns with patients, keeping in mind that they often overestimate their adherence?

Ask. Some clinicians ask questions such as “Are you taking your medication?”, although a more effective approach might be to ask how the patient is taking his (her) medication. Asking questions such as “When do you take your medication?” and “In the past week, how many doses do you think you missed?” might be more effective ways to inquire about adherence.⁷

The Expert Consensus Guidelines recommend asking patients about medication adherence monthly for those who are stable, doing well, and believed to be adherent. For those who are new to a practice or who are not doing well, inquire about medication adherence at least weekly.⁷

In our practice, patients who are unstable but do not require inpatient hospitalization typically are seen more often in the clinic, or are referred to intensive outpatient or partial hospitalization programs. If an unstable patient is unable to come in for more frequent appointments, we arrange phone conferences between her and her provider. If a patient is not doing well and has a case manager, we often ask that case manager to visit the patient, in person, more often than he (she) would otherwise.

Take a nonjudgmental approach when raising these issues with patients. Questions such as “We all forget to take our medication sometimes; do you?” help to normalize nonadherence, and improve the therapeutic alliance, and might result in the patient being more honest with the clinician.⁷ Because patients may be apprehensive about discussing adverse events, clinicians must be proactive about improving the therapeutic alliance and making patients feel comfortable when discussing sensitive topics. Clinicians should try to convey the idea that, although adherence is a concern, so is quality of life. A clinicians’ willingness to take a flexible approach that is nonpunitive nor authoritarian can aid the therapeutic alliance and improve overall adherence.

Be sensitive to financial, cultural, and language variables that can affect access to care. The Expert Consensus Guidelines recommend asking patients if they can afford their medication. In our practice, we have seen patients with schizophrenia discharged from the hospital only to be readmitted 1 month later because they could not afford to fill their prescriptions.

It is important to have translation services available, in person or by phone, for patients who do not speak English. Furthermore, it is important to understand the limitations that your practice might place on access to care. Ask patients if they have ever had trouble making an appointment when they needed to be seen, or if they called the office with a question and did not receive an answer in a timely fashion; doing so allows you to assess the practice’s ability to meet patients’ needs and helps you build a therapeutic alliance.

Make objective assessments. It is important for practitioners to not base their assessment of medication adherence solely on subjective findings. Asking patients to bring in their medication bottles for pill counts and checking with the patients’ pharmacies for information about refill frequency can provide some objective data. Electronic monitoring systems use microprocessors inserted into bottle caps to record the occurrence and timing of each bottle opening. Studies show that these electronic monitoring systems are the gold standard for determining medication adherence and could be used in cases where it is unclear if the patient is taking his (her) medication.^7,20 Such systems have successfully monitored medication adherence in clinical trials, but their use in clinical practice is complicated by ethical and legal considerations and cost issues.

Simplify the regimen. Using medications with once-daily dosing, for example, can help improve adherence. Pfeiffer and co-workers²¹ found that patients whose medication regimens were changed from once daily to more than once daily experienced a decrease in medication adherence. Conversely, a decrease in dosing frequency was significantly associated with improved adherence. More than once-daily dosing was only weakly associated with poorer adherence among patients already on a stable regimen.

Discussing positive and negative aspects of past medication trials with a patient and inquiring if she prefers a specific medication can be an effective way to build the therapeutic relationship and help with adherence.

Direct patients to psychosocial interventions. These can be broadly classified as:

• educational approaches
• group therapy approaches
• family interventions
• cognitive treatments
• combination approaches.

Psychoeducational approaches have limited effect on improving adherence when delivered to individual patients. However, 1 study showed that psychoeducation was effective at improving adherence when extended to include the patient’s family.²²

Motivational interviewing techniques, behavioral approaches, and family interventions are effective at increasing medication adherence. One study looked at the value of training a patient-identified informant to supervise and administer medication. This person, usually a family member or close support, was responsible for obtaining medication from the pharmacy, administering the medication, and recording adherence. After 1 year, 67% of patients who used an informant were adherent, compared with only 45% in the group that did not have informant support.²² Case managers, attendant care workers, home health nurses, and assertive community treatment (ACT) teams also can participate in this manner; it is important, therefore, for you to be aware of the resources available in your community and to understand your role as patient advocate.

Substance abuse is a strong risk factor for nonadherence among patients with schizophrenia,¹⁸ which makes it important to assess patients for substance use and encourage those who do abuse to seek treatment. Although 1 study showed no correlation between Alcoholics Anonymous (AA) attendance and medication adherence,¹² many AA and Narcotics Anonymous groups do not discuss psychiatric medications during group meetings. Magura and colleagues encouraged the use of “dual focus” groups that involve mental health professionals and addiction treatment specialists discussing mental health and substance abuse issues at the same setting.¹⁸

Prescribe long-acting injectable antipsychotics. Typically, long-acting injectable antipsychotics (LAIs) are reserved for patients who have a history of nonadherence. In a small study (N = 97) comparing LAI risperidone and oral risperidone or oral haloperidol, patients treated with an LAI had significantly fewer all-cause discontinuations (26.0%, compared with 70.2%) at 24 months.²³ The Adherence to Treatment and Therapeutic Strategies in Schizophrenic Patients study examined 1,848 patients with schizophrenia and reached similar findings regarding LAI antipsychotics.²⁴ (Note: Aripiprazole, fluphenazine, haloperidol, olanzapine, and paliperidone also are available in an LAI formulation.)

Bottom Line

Antipsychotic nonadherence in schizophrenia is a major problem for patients, families, and society. Being able to identify patients at risk for nonadherence, understanding the reasons for their nonadherence, and seeking practical solutions to the problem are all the responsibility of the treating physician. Psychoeducation, addressing substance abuse, modifying dosing, and using long-acting injectable antipsychotics may help improve adherence.

Related Resources

• Velligan DI, Weiden PJ, Sajatovic M, et al; Expert Consensus Panel on Adherence Problems in Serious and Persistent Mental Illness. Assessment of adherence problems in patients with serious and persistent mental illness: recommendations from the Expert Consensus Guidelines. J Clin Psychiatry. 2009;70(suppl 4):1-46.
• National Alliance on Mental Illness. www.nami.org.
• Assertive Community Treatment (ACT) Organization. www.actassociation.org.

Drug Brand Names

Aripiprazole • Abilify        Chlorpromazine • Thorazine      Clozapine • Clozaril       Fluphenazine • Permitil    Haloperidol • Haldol                  Iloperidone • Fanapt       Olanzapine • Zyprexa      Paliperidone • Invega               Perphenazine • Trilafon    Quetiapine • Seroquel      Risperidone • Risperdal            Ziprasidone • Geodon

Disclosures

Dr. Macaluso has been the principal investigator for clinical trials for AbbVie, Eisai, Envivo, Janssen, Naurex, and Pfizer. All clinical trial and study contracts and payments were made through the Kansas University Medical Center Research Institute. Dr. McKnight reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

HISTORY: ‘Not himself’

Mr. C, age 69, presents to the emergency department complaining of intermittent fever of about 100°F, hematuria, headache, weakness, fatigue, and decreased appetite over 2 months. Testing shows acute renal failure, elevated C-reactive protein, and increased sedimentation rate. The attending internist admits Mr. C with a working diagnosis of temporal arteritis and acute renal failure, administers corticosteroids for headache, and orders a right temporal artery biopsy, which shows no signs of vasculitis.

Family members report that Mr. C has not been himself—he has become increasingly withdrawn and “emotionless.” Mr. C’s wife says her husband has needed help with dressing and eating because of short-term memory loss over 9 months. She says he has lost 20 to 30 lb.

The patient’s cognitive function appears to have worsened since he developed these physical symptoms. Mrs. C also reports that he has had weakness and fatigue for 8 months.

One month earlier, the patient was admitted to a different hospital and treated for 2 weeks with IV antibiotics for fever of unknown origin. Results of lumbar puncture and extensive rheumatologic, infectious disease, urologic, and gastroenterologic evaluations were normal.

The internal medicine physician requests a psychiatric consultation. During our interview, Mr. C is cooperative, shows no signs of acute distress, is well groomed and dressed appropriately, and maintains eye contact. Speech rate and volume are low, with normal articulation and coherence, diminished spontaneity, and paucity of language. Mrs. C tells us her husband was lively and talkative before his recent illness. His mood is euthymic, and he is pleasant and cheerful during the evaluation.

The authors’ observations

Initially, we suspect an underlying medical condition is causing Mr. C’s psychiatric symptoms.

Mr. C’s wife reports that her husband stopped drinking 2 years ago after his family expressed concern about his health. Mr. C’s past alcohol use could not be quantified. He has not abused illicit drugs and has no personal or family history of dementia, trauma, or psychiatric or neurologic disorders.

EVALUATION: Impaired memory

Mr. C is afebrile during the initial physical examination, but fever returns within several days. Neurologic examination is normal, and negative rapid plasma reagin rules out syphilis. Vitamin B₁₂ and folate levels are normal, as is thyroid function. Other laboratory findings are outside normal limits (Table).

Urine is cloudy with 2+ protein, 3+ blood, and trace leukocyte esterase. The presence of protein and blood suggests a glomerular disease such as a glomerulonephritis.

A positive leukocyte esterase test results from the presence of white blood cells, either as whole cells or as lysed cells. An abnormal number of leukocytes may appear with upper or lower urinary tract infection or in acute glomerulonephritis.

Chest radiography shows increased bilateral pulmonary vasculature, which can indicate pulmonary hypertension.

Mr. C has fair attention and concentration but impaired recent memory. He cannot recall yesterday’s events without help.

Mr. C’s Mini-Mental State Examination score of 21/30 suggests markedly impaired executive functioning and cognitive deficits. The attending psychiatrist recommends brain MRI.

Table

Mr. C’s laboratory findings

The authors’ observations

Mr. C shows markedly impaired cognitive function without significant impairment of attention and concentration despite his progressive deterioration and increasing disability. Urine toxicology shows no illicit substances. Given his lack of a previous mood disorder and his family’s description of him as formerly vibrant and cheerful, he likely does not have a mood disorder.

Based on the history of events, including the symptom pattern, we rule out delirium. We suspect that Mr. C has dementia secondary to a general medical condition. His symptoms seem to be directly related to his medical complaints and do not have a waxing and waning course. The internal medicine physician orders additional laboratory tests.

TESTING: Kidney, lung damage

Over 5 days, Mr. C’s intermittent low-grade fevers continue. Laboratory tests are negative for HIV antibody, hepatitis panel, and antinuclear antibodies (ANA). C-reactive protein is elevated at 27.8 mg/dL (normal range,

Renal ultrasound is normal, but preliminary renal biopsy shows rapidly progressive glomerulonephritis. The internist immediately starts dialysis, cyclophosphamide at 1.5 mg/kg, and prednisone, 1 mg/kg. The pathology report on the renal biopsy describes extensive crescentic glomerular destruction, with inflammatory cells present.

Ten days after admission, Mr. C develops hemoptysis, and chest radiography shows increasing alveolar infiltrates. The attending internist consults pulmonary and critical care services.

The consultant suspects a pulmonary-renal syndrome because of bilateral alveolar infiltrates (diffuse alveolar hemorrhage). The internal medicine team continues high-dose corticosteroids, followed by plasmapheresis.

Brain MRI shows subacute to chronic infarcts involving the right basal ganglia and corona radiate and mild to moderate small vessel ischemic changes. Old areas of hemorrhage are noted within both cerebellar lobes, left temporal lobe, right basal ganglia, right parietal lobe, and right frontal lobe.

During follow-up interviews, Mr. C often cannot recall recent dialysis or plasmapheresis and reports no physical symptoms. His short-term memory continues to deteriorate; he would forget to eat if not cued by family or nursing staff. He shows global cognitive deficits and is increasingly withdrawn and flat.

The authors’ observations

Although few case reports have associated Goodpasture’s syndrome with neurobehavioral changes, the apparent relationship of Mr. C’s medical symptoms with the worsening of his cognitive impairment suggests a link.

Mr. C’s MRI findings also might suggest CNS vasculitis, which affects small arteries of the cerebral and spinal cord leptomeninges and parenchyma, leading to CNS dys-function.^6-8 CNS vasculitis can result from primary nervous system involvement or from a secondary systemic process such as Goodpasture’s syndrome.⁹

We rule out lupus because Mr. C is ANA-negative; this test has 99% sensitivity for lupus.¹⁰

Box

OUTCOME: Ongoing disability

Mr. C is hospitalized for 6 weeks. He receives cyclophosphamide, prednisone, and 10 sessions of plasmapheresis. We prescribe mirtazapine, 15 mg at bedtime, to treat mood symptoms. We chose mirtazapine because of the drug’s sleep-restoring and appetite-stimulating properties.

Mr. C’s fever resolves and pulmonary function soon improves, but his cognitive impairment persists. He has difficulties preparing meals, taking medications, and managing his money.

Mr. C is discharged with a referral to a psychiatrist. He continues taking mirtazapine and a lower dose of prednisone. He requires ongoing hemodialysis and assistance with activities of daily living.

The authors’ observations

Prompt multidisciplinary intervention is critical when patients present with concurrent cognitive and medical symptoms. A thorough psychiatric evaluation can help piece together the illness’ course. The psychiatrist’s role in a multidisciplinary assessment is to:

• document neurocognitive changes
  
• verify them through collateral information
  
• correlate these changes with the timing of medical symptoms.
  

An underlying psychiatric condition can complicate the diagnosis. In these cases, careful interviewing and collateral information can help you discern the chronology of events.

HISTORY: ‘Not himself’

Mr. C, age 69, presents to the emergency department complaining of intermittent fever of about 100°F, hematuria, headache, weakness, fatigue, and decreased appetite over 2 months. Testing shows acute renal failure, elevated C-reactive protein, and increased sedimentation rate. The attending internist admits Mr. C with a working diagnosis of temporal arteritis and acute renal failure, administers corticosteroids for headache, and orders a right temporal artery biopsy, which shows no signs of vasculitis.

Family members report that Mr. C has not been himself—he has become increasingly withdrawn and “emotionless.” Mr. C’s wife says her husband has needed help with dressing and eating because of short-term memory loss over 9 months. She says he has lost 20 to 30 lb.

The patient’s cognitive function appears to have worsened since he developed these physical symptoms. Mrs. C also reports that he has had weakness and fatigue for 8 months.

One month earlier, the patient was admitted to a different hospital and treated for 2 weeks with IV antibiotics for fever of unknown origin. Results of lumbar puncture and extensive rheumatologic, infectious disease, urologic, and gastroenterologic evaluations were normal.

The internal medicine physician requests a psychiatric consultation. During our interview, Mr. C is cooperative, shows no signs of acute distress, is well groomed and dressed appropriately, and maintains eye contact. Speech rate and volume are low, with normal articulation and coherence, diminished spontaneity, and paucity of language. Mrs. C tells us her husband was lively and talkative before his recent illness. His mood is euthymic, and he is pleasant and cheerful during the evaluation.

The authors’ observations

Initially, we suspect an underlying medical condition is causing Mr. C’s psychiatric symptoms.

Mr. C’s wife reports that her husband stopped drinking 2 years ago after his family expressed concern about his health. Mr. C’s past alcohol use could not be quantified. He has not abused illicit drugs and has no personal or family history of dementia, trauma, or psychiatric or neurologic disorders.

EVALUATION: Impaired memory

Mr. C is afebrile during the initial physical examination, but fever returns within several days. Neurologic examination is normal, and negative rapid plasma reagin rules out syphilis. Vitamin B₁₂ and folate levels are normal, as is thyroid function. Other laboratory findings are outside normal limits (Table).

Urine is cloudy with 2+ protein, 3+ blood, and trace leukocyte esterase. The presence of protein and blood suggests a glomerular disease such as a glomerulonephritis.

A positive leukocyte esterase test results from the presence of white blood cells, either as whole cells or as lysed cells. An abnormal number of leukocytes may appear with upper or lower urinary tract infection or in acute glomerulonephritis.

Chest radiography shows increased bilateral pulmonary vasculature, which can indicate pulmonary hypertension.

Mr. C has fair attention and concentration but impaired recent memory. He cannot recall yesterday’s events without help.

Mr. C’s Mini-Mental State Examination score of 21/30 suggests markedly impaired executive functioning and cognitive deficits. The attending psychiatrist recommends brain MRI.

Table

Mr. C’s laboratory findings

The authors’ observations

Mr. C shows markedly impaired cognitive function without significant impairment of attention and concentration despite his progressive deterioration and increasing disability. Urine toxicology shows no illicit substances. Given his lack of a previous mood disorder and his family’s description of him as formerly vibrant and cheerful, he likely does not have a mood disorder.

Based on the history of events, including the symptom pattern, we rule out delirium. We suspect that Mr. C has dementia secondary to a general medical condition. His symptoms seem to be directly related to his medical complaints and do not have a waxing and waning course. The internal medicine physician orders additional laboratory tests.

TESTING: Kidney, lung damage

Over 5 days, Mr. C’s intermittent low-grade fevers continue. Laboratory tests are negative for HIV antibody, hepatitis panel, and antinuclear antibodies (ANA). C-reactive protein is elevated at 27.8 mg/dL (normal range,

Renal ultrasound is normal, but preliminary renal biopsy shows rapidly progressive glomerulonephritis. The internist immediately starts dialysis, cyclophosphamide at 1.5 mg/kg, and prednisone, 1 mg/kg. The pathology report on the renal biopsy describes extensive crescentic glomerular destruction, with inflammatory cells present.

Ten days after admission, Mr. C develops hemoptysis, and chest radiography shows increasing alveolar infiltrates. The attending internist consults pulmonary and critical care services.

The consultant suspects a pulmonary-renal syndrome because of bilateral alveolar infiltrates (diffuse alveolar hemorrhage). The internal medicine team continues high-dose corticosteroids, followed by plasmapheresis.

Brain MRI shows subacute to chronic infarcts involving the right basal ganglia and corona radiate and mild to moderate small vessel ischemic changes. Old areas of hemorrhage are noted within both cerebellar lobes, left temporal lobe, right basal ganglia, right parietal lobe, and right frontal lobe.

During follow-up interviews, Mr. C often cannot recall recent dialysis or plasmapheresis and reports no physical symptoms. His short-term memory continues to deteriorate; he would forget to eat if not cued by family or nursing staff. He shows global cognitive deficits and is increasingly withdrawn and flat.

The authors’ observations

Although few case reports have associated Goodpasture’s syndrome with neurobehavioral changes, the apparent relationship of Mr. C’s medical symptoms with the worsening of his cognitive impairment suggests a link.

Mr. C’s MRI findings also might suggest CNS vasculitis, which affects small arteries of the cerebral and spinal cord leptomeninges and parenchyma, leading to CNS dys-function.^6-8 CNS vasculitis can result from primary nervous system involvement or from a secondary systemic process such as Goodpasture’s syndrome.⁹

We rule out lupus because Mr. C is ANA-negative; this test has 99% sensitivity for lupus.¹⁰

Box

OUTCOME: Ongoing disability

Mr. C is hospitalized for 6 weeks. He receives cyclophosphamide, prednisone, and 10 sessions of plasmapheresis. We prescribe mirtazapine, 15 mg at bedtime, to treat mood symptoms. We chose mirtazapine because of the drug’s sleep-restoring and appetite-stimulating properties.

Mr. C’s fever resolves and pulmonary function soon improves, but his cognitive impairment persists. He has difficulties preparing meals, taking medications, and managing his money.

Mr. C is discharged with a referral to a psychiatrist. He continues taking mirtazapine and a lower dose of prednisone. He requires ongoing hemodialysis and assistance with activities of daily living.

The authors’ observations

Prompt multidisciplinary intervention is critical when patients present with concurrent cognitive and medical symptoms. A thorough psychiatric evaluation can help piece together the illness’ course. The psychiatrist’s role in a multidisciplinary assessment is to:

• document neurocognitive changes
  
• verify them through collateral information
  
• correlate these changes with the timing of medical symptoms.
  

An underlying psychiatric condition can complicate the diagnosis. In these cases, careful interviewing and collateral information can help you discern the chronology of events.

HISTORY: ‘Not himself’

Mr. C, age 69, presents to the emergency department complaining of intermittent fever of about 100°F, hematuria, headache, weakness, fatigue, and decreased appetite over 2 months. Testing shows acute renal failure, elevated C-reactive protein, and increased sedimentation rate. The attending internist admits Mr. C with a working diagnosis of temporal arteritis and acute renal failure, administers corticosteroids for headache, and orders a right temporal artery biopsy, which shows no signs of vasculitis.

Family members report that Mr. C has not been himself—he has become increasingly withdrawn and “emotionless.” Mr. C’s wife says her husband has needed help with dressing and eating because of short-term memory loss over 9 months. She says he has lost 20 to 30 lb.

The patient’s cognitive function appears to have worsened since he developed these physical symptoms. Mrs. C also reports that he has had weakness and fatigue for 8 months.

One month earlier, the patient was admitted to a different hospital and treated for 2 weeks with IV antibiotics for fever of unknown origin. Results of lumbar puncture and extensive rheumatologic, infectious disease, urologic, and gastroenterologic evaluations were normal.

The internal medicine physician requests a psychiatric consultation. During our interview, Mr. C is cooperative, shows no signs of acute distress, is well groomed and dressed appropriately, and maintains eye contact. Speech rate and volume are low, with normal articulation and coherence, diminished spontaneity, and paucity of language. Mrs. C tells us her husband was lively and talkative before his recent illness. His mood is euthymic, and he is pleasant and cheerful during the evaluation.

The authors’ observations

Initially, we suspect an underlying medical condition is causing Mr. C’s psychiatric symptoms.

Mr. C’s wife reports that her husband stopped drinking 2 years ago after his family expressed concern about his health. Mr. C’s past alcohol use could not be quantified. He has not abused illicit drugs and has no personal or family history of dementia, trauma, or psychiatric or neurologic disorders.

EVALUATION: Impaired memory

Mr. C is afebrile during the initial physical examination, but fever returns within several days. Neurologic examination is normal, and negative rapid plasma reagin rules out syphilis. Vitamin B₁₂ and folate levels are normal, as is thyroid function. Other laboratory findings are outside normal limits (Table).

Urine is cloudy with 2+ protein, 3+ blood, and trace leukocyte esterase. The presence of protein and blood suggests a glomerular disease such as a glomerulonephritis.

A positive leukocyte esterase test results from the presence of white blood cells, either as whole cells or as lysed cells. An abnormal number of leukocytes may appear with upper or lower urinary tract infection or in acute glomerulonephritis.

Chest radiography shows increased bilateral pulmonary vasculature, which can indicate pulmonary hypertension.

Mr. C has fair attention and concentration but impaired recent memory. He cannot recall yesterday’s events without help.

Mr. C’s Mini-Mental State Examination score of 21/30 suggests markedly impaired executive functioning and cognitive deficits. The attending psychiatrist recommends brain MRI.

Table

Mr. C’s laboratory findings

The authors’ observations

Mr. C shows markedly impaired cognitive function without significant impairment of attention and concentration despite his progressive deterioration and increasing disability. Urine toxicology shows no illicit substances. Given his lack of a previous mood disorder and his family’s description of him as formerly vibrant and cheerful, he likely does not have a mood disorder.

Based on the history of events, including the symptom pattern, we rule out delirium. We suspect that Mr. C has dementia secondary to a general medical condition. His symptoms seem to be directly related to his medical complaints and do not have a waxing and waning course. The internal medicine physician orders additional laboratory tests.

TESTING: Kidney, lung damage

Over 5 days, Mr. C’s intermittent low-grade fevers continue. Laboratory tests are negative for HIV antibody, hepatitis panel, and antinuclear antibodies (ANA). C-reactive protein is elevated at 27.8 mg/dL (normal range,

Renal ultrasound is normal, but preliminary renal biopsy shows rapidly progressive glomerulonephritis. The internist immediately starts dialysis, cyclophosphamide at 1.5 mg/kg, and prednisone, 1 mg/kg. The pathology report on the renal biopsy describes extensive crescentic glomerular destruction, with inflammatory cells present.

Ten days after admission, Mr. C develops hemoptysis, and chest radiography shows increasing alveolar infiltrates. The attending internist consults pulmonary and critical care services.

The consultant suspects a pulmonary-renal syndrome because of bilateral alveolar infiltrates (diffuse alveolar hemorrhage). The internal medicine team continues high-dose corticosteroids, followed by plasmapheresis.

Brain MRI shows subacute to chronic infarcts involving the right basal ganglia and corona radiate and mild to moderate small vessel ischemic changes. Old areas of hemorrhage are noted within both cerebellar lobes, left temporal lobe, right basal ganglia, right parietal lobe, and right frontal lobe.

During follow-up interviews, Mr. C often cannot recall recent dialysis or plasmapheresis and reports no physical symptoms. His short-term memory continues to deteriorate; he would forget to eat if not cued by family or nursing staff. He shows global cognitive deficits and is increasingly withdrawn and flat.

The authors’ observations

Although few case reports have associated Goodpasture’s syndrome with neurobehavioral changes, the apparent relationship of Mr. C’s medical symptoms with the worsening of his cognitive impairment suggests a link.

Mr. C’s MRI findings also might suggest CNS vasculitis, which affects small arteries of the cerebral and spinal cord leptomeninges and parenchyma, leading to CNS dys-function.^6-8 CNS vasculitis can result from primary nervous system involvement or from a secondary systemic process such as Goodpasture’s syndrome.⁹

We rule out lupus because Mr. C is ANA-negative; this test has 99% sensitivity for lupus.¹⁰

Box

OUTCOME: Ongoing disability

Mr. C is hospitalized for 6 weeks. He receives cyclophosphamide, prednisone, and 10 sessions of plasmapheresis. We prescribe mirtazapine, 15 mg at bedtime, to treat mood symptoms. We chose mirtazapine because of the drug’s sleep-restoring and appetite-stimulating properties.

Mr. C’s fever resolves and pulmonary function soon improves, but his cognitive impairment persists. He has difficulties preparing meals, taking medications, and managing his money.

Mr. C is discharged with a referral to a psychiatrist. He continues taking mirtazapine and a lower dose of prednisone. He requires ongoing hemodialysis and assistance with activities of daily living.

The authors’ observations

Prompt multidisciplinary intervention is critical when patients present with concurrent cognitive and medical symptoms. A thorough psychiatric evaluation can help piece together the illness’ course. The psychiatrist’s role in a multidisciplinary assessment is to:

• document neurocognitive changes
  
• verify them through collateral information
  
• correlate these changes with the timing of medical symptoms.
  

An underlying psychiatric condition can complicate the diagnosis. In these cases, careful interviewing and collateral information can help you discern the chronology of events.