Current Psychiatry

In patients with treatment-resistant schizophrenia, lithium and anticonvulsants have become such common adjuncts to antipsychotics that 50% of inpatients may be receiving them.¹ Evidence supporting this practice is mixed:

• Initial case reports and open-label studies that showed benefit have not always been followed by randomized clinical trials.
• Lack of clear benefit also has been described (Table 1).

This article examines the extent of this prescribing pattern, its evidence base, and mechanisms of action that may help explain why some adjunctive mood stabilizers are more effective than others for treatment-resistant schizophrenia.

EXTENT OF USE

For 5 years, the rate at which inpatients with schizophrenia received adjunctive mood stabilizers has held steady at approximately 50% in New York State Office of Mental Health (NYSOMH) facilities (Figure1). These facilities provide intermediate and long-term care for the seriously, persistently mentally ill. Adjunctive mood stabilizers might not be used as often for outpatients or for inpatients treated in short-stay facilities.

Table 1

Evidence for adjunctive use of lithium or anticonvulsants for treating schizophrenia

Valproate is the most commonly used anticonvulsant, with one out of three patients with schizophrenia receiving it. Adjunctive gabapentin use is declining, probably because of inadequate efficacy—as will be discussed later. Use of adjunctive lamotrigine is expected to increase as more data become available on its usefulness in treatment-resistant schizophrenia.

Clinicians are using substantial dosages of adjunctive mood stabilizers. During first-quarter 2004, average daily dosages for 4,788 NYSOMH patients (80% with schizophrenia or schizoaffective disorder) receiving antipsychotics were:

• valproate, 1639 mg (n = 1921)
• gabapentin, 1524 mg (n = 303)
• oxcarbazepine, 1226 mg (n = 201)
• carbamazepine, 908 mg (n = 112)
• lithium, 894 mg (n = 715)
• topiramate, 234 mg (n = 269)
• lamotrigine, 204 mg (n = 231).²

Mood-stabilizer combinations were also used. Approximately one-half of patients receiving adjunctive mood stabilizers—with the exception of valproate—were receiving more than one. In patients receiving valproate, the rate of mood-stabilizer co-prescribing was about 25%.²

WHAT IS THE EVIDENCE?

Evidence supporting the use of adjunctive lithium or anticonvulsants to treat schizophrenia varies in quality and quantity (Table 1). Case reports and open studies offer the weakest evidence but can spur double-blind, randomized clinical trials (RCTs). Unfortunately, RCTs are not often done, and the published studies usually suffer from methodologic flaws such as:

• inadequate number of subjects (insufficient statistical power to detect differences)
• lack of control of confounds such as mood symptoms (seen when studies include patients with schizoaffective disorder)
• inadequate duration
• inappropriate target populations (patients with acute exacerbations of schizophrenia instead of persistent symptoms in treatment-resistant schizophrenia).

Because controlled trials of the use of adjunctive mood stabilizers are relatively scarce, clinical practice has transcended clinical research. Clinicians need effective regimens for treatment-resistant schizophrenia, and mood-stabilizer augmentation helps some patients.

Lithium is perhaps the best-known mood stabilizer. Although early studies showed adjunctive lithium useful in treating schizophrenia, later and better-designed trials did not. The authors of a recent meta-analysis of randomized clinical trials (n = 611 in 20 studies) concluded that despite some evidence supporting the efficacy of lithium augmentation, overall results were inconclusive. A large trial would be required to detect a small benefit in patients with schizophrenia who lack affective symptoms.³

Carbamazepine use among patients with schizophrenia is declining, primarily because this drug induces its own metabolism and can require frequent dose adjustments. Adjunctive carbamazepine has been used to manage persistent aggressive behavior in patients with schizophrenia and schizoaffective disorder. Evidence comes primarily from small trials or case reports (Table 2),^4-8 but results of a larger clinical trial (n = 162) by Okuma et al⁶ are also available

In the Okuma report—a double-blind, placebo-controlled trial of carbamazepine in patients with DSM-III schizophrenia or schizoaffective disorder—carbamazepine did not significantly improve patients’ total Brief Psychiatric Rating Scale (BPRS) scores. Compared with placebo, however, some benefit with carbamazepine did emerge in measures of suspiciousness, uncooperativeness, and excitement.

A systematic review and meta-analysis (n = 283 in 10 studies) detected a trend toward reduced psychopathology with carbamazepine augmentation for schizophrenia. BPRS scores declined by 20% and 35% in the six trials (n = 147) for which data were available (P = 0.08 and 0.09, respectively).⁹ Because the double-blind trial by Okuma et al⁶ was not randomized, it was not included in this meta-analysis.⁹

Figure 1 10-year trend in use of adjunctive mood stabilizers for schizophrenia

Initial double-blind, RCTs of adjunctive valproate in patients with schizophrenia were limited in size and failed to show benefit with adjunctive valproate^12-15 (Table 2). A more recent study¹⁶ showed that adjunctive valproate affects acute psychotic symptoms rather than mood. This study, however, did not answer whether adjunctive valproate would help patients with persistent symptoms of schizophrenia.

Table 2

Double-blind studies of adjunctive carbamazepine in schizophrenia

In this large (n = 249), multicenter, randomized, double-blind trial, hospitalized patients with an acute exacerbation of schizophrenia received olanzapine or risperidone plus divalproex or placebo for 28 days. Patients with schizoaffective disorder and treatment-resistant schizophrenia were excluded.

By day 6, dosages reached 6 mg/d for risperidone and 15 mg/d for olanzapine. Divalproex was started at 15 mg/kg and titrated to a maximum of 30 mg/kg by day 14. Mean divalproex dosage was approximately 2300 mg/d (mean plasma level approximately 100 mg/mL).

Positive and Negative Syndrome Scale (PANSS) total scores improved significantly in patients receiving adjunctive divalproex compared with those receiving antipsychotic monotherapy, and significant differences occurred as early as day 3. The major effect was seen on schizophrenia’s positive symptoms. A post-hoc analysis¹⁷ also showed greater reductions in hostility (as measured by the hostility item in the PANSS Positive Subscale) in patients receiving adjunctive divalproex compared with antipsychotic monotherapy. This effect was independent of the effect on positive symptoms or sedation.

A large, multi-site, 84-day acute schizophrenia RCT similar to the 28-day trial—but using extended-release divalproex—is being conducted. An extended-release preparation may be particularly helpful in encouraging medication adherence for patients taking complicated medication regimens.

Table 3

Double-blind studies of adjunctive valproate in schizophrenia

In a recent large (n = 10,262), retrospective, pharmacoepidemiologic analysis,¹⁸ valproate augmentation led to longer persistence of treatment than did the strategy of switching antipsychotics. Average valproate dosages were small, however (<425 mg/d), as were antipsychotic dosages (risperidone <1.7 mg/d, quetiapine <120 mg/d, and olanzapine <7.5 mg/d). Patients’ diagnostic categories were not available. One interpretation of this study is that valproate augmentation would be more successful than switching antipsychotics, assuming that treatment persistence can be viewed as a positive outcome.

Table 4

Double-blind studies of adjunctive lamotrigine in schizophrenia

Lamotrigine is the only other anticonvulsant for which published, double-blind, randomized evidence of use in patients with schizophrenia is available (Table 4).^19,20 Adjunctive lamotrigine may be effective in managing treatment-resistant schizophrenia, as was shown in a small (n = 34), double-blind, placebo-controlled, crossover trial.¹⁹ Hospitalized patients whose symptoms were inadequately controlled with clozapine monotherapy received lamotrigine, 200 mg/d, for up to 12 weeks. Adjunctive lamotrigine improved positive but not negative symptoms.

Similar results were seen in treatment-resistant inpatients with schizophrenia (n = 38) in a 10-week, double-blind, parallel group trial by Kremer et al.²⁰ Adjunctive lamotrigine improved PANSS positive, general psychopathology, and total symptom scores in the 31 patients who completed the trial. No differences were seen, however, in negative symptoms, total BPRS scores, or in the intent-to-treat analysis. These results have spurred the launch of a large, multi-site, RCT of adjunctive lamotrigine in patients with schizophrenia who have responded inadequately to antipsychotics alone.

Topiramate, one of the few psychotropics associated with weight loss, has attracted interest as an adjunct to second-generation antipsychotics to address weight gain. Although case reports have shown benefit,²¹ one showed deterioration in both positive and negative symptoms when topiramate was added to second-generation antipsychotics.²²

Table 5

Double-blind study of adjunctive topiramate in schizophrenia

An unpublished, randomized, crossover trial compared second-generation antipsychotics plus topiramate or placebo in 26 male inpatients with chronic schizophrenia. With adjunctive topiramate, the authors found a statistically significant improvement in the PANSS general psychopathology subscale but not in PANSS total, positive subscale, or negative subscale scores (Table 5) (Tiihonen J, personal communication 6/22/04).

Other agents. Very little information—all uncontrolled—supports adjunctive use of gabapentin or oxcarbazepine for patients with schizophrenia.^23-28 Of concern are reports of patients suffering worsening of psychosis with gabapentin²⁵ or of dysphoria and irritability with oxcarbazepine (attributed to a pharmacokinetic interaction).²⁶

Conclusion. More trials are needed to examine the use of adjunctive mood stabilizers in patients with schizophrenia—particularly in those with chronic symptoms. Although mood stabilizers are widely used in this population, important questions remain unanswered, including:

• characteristics of patients likely to require adjunctive treatment
• how long treatment should continue.

MECHANISMS OF ACTION

Unlike antipsychotics, mood stabilizers do not exert their therapeutic effects by acting directly on dopamine (D2) receptors. Differences in mechanism of action among the anticonvulsants may help explain why some—such as valproate and lamotrigine—have been useful for bipolar disorder or schizophrenia and others—such as gabapentin—have not.²⁹

One possibility is that anticonvulsants that affect voltage-gated sodium channels—such as valproate, lamotrigine, carbamazepine and oxcarbazepine—may be most useful for patients with bipolar disorder or schizophrenia. On the other hand, agents that affect voltage-gated calcium channels—such as gabapentin—may be efficacious as anticonvulsants but not as efficacious for bipolar disorder or schizophrenia.

Ketter et al³⁰ proposed an anticonvulsant classification system based on predominant psychotropic profiles:

• the “GABA-ergic” group predominantly potentiates the inhibitory neurotransmitter GABA, resulting in sedation, fatigue, cognitive slowing, and weight gain, as well as possible anxiolytic and antimanic effects
• the “anti-glutamate” group predominantly attenuates glutamate excitatory neurotransmission and is associated with activation, weight loss, and possibly anxiogenic and antidepressant effects.

In the GABA-ergic group are anticonvulsants such as barbiturates, benzodiazepines, valproate, gabapentin, tiagabine, and vigabatrin. The antiglutamate group includes agents such as felbamate and lamotrigine. A “mixed” category includes anticonvulsants with GABA-ergic and anti-glutaminergic actions such as topiramate, which has sedating and weight-loss properties.

Because GABA appears to modulate dopamine neurotransmission,³¹ this may explain valproate’s role as an adjunctive agent for schizophrenia. Similarly, mechanisms related to Nmethyl-D-aspartate (NMDA) and non-NMDA glutamate receptor function may explain lamotrigine’s usefulness in this setting.^19,20

SUMMARY

Clinicians resort to combination therapies when monotherapies fail to adequately control symptoms or maintain response. Co-prescribing of anticonvulsants with antipsychotics for inpatients with schizophrenia is common practice in New York State and most likely elsewhere. In general, antipsychotics’ and mood stabilizers’ different—and perhaps complementary—mechanisms of action explain the synergism between them. Mechanisms of action also may explain why some anticonvulsants help in schizophrenia (or bipolar disorder) whereas others do not.

Evidence for using adjunctive anticonvulsants is variable. The strongest data support using valproate (and perhaps lamotrigine), followed by carbamazepine and then topiramate. Gabapentin and oxcarbazepine have only anecdotal evidence, some of it negative. Well-designed, randomized clinical trials with the appropriate populations are needed.

Related resources

• Stahl SM. Essential psychopharmacology of antipsychotics and mood stabilizers. New York: Cambridge University Press, 2002.
• Harvard Medical School Department of Psychiatry’s psychopharmacology algorithm project. Osser DN, Patterson RD. Consultant for the pharmacotherapy of schizophrenia. Available at http://mhc.com/Algorithms/. Accessed Nov. 5, 2004.

Drug brand names

• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Gabapentin • Neurontin
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Lithium • Lithobid, Eskalith
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Topiramate • Topamax
• Valproate (valproic acid, divalproex sodium) • Depakene, Depakote

Disclosure

Dr. Citrome receives research grants/contracts from Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Eli Lilly & Co., Janssen Pharmaceutica, and Pfizer Inc. He is a consultant to and/or speaker for Bristol-Myers Squibb Co., Eli Lilly & Co., Pfizer Inc., Abbott Laboratories, AstraZeneca Pharmaceuticals, and Novartis Pharmaceuticals Corp.

Acknowledgment

Adapted from Citrome L. “Antipsychotic polypharmacy versus augmentation with anticonvulsants: the U.S. perspective” (presentation). Paris: Collegium Internationale Neuro-Psychopharmacologicum (CINP), June 2004 [abstract in Int J Neuropsychopharmacol. 2004; 7(suppl 1):S69], and from Citrome L. “Mood-stabilizer use in schizophrenia: 1994-2002” (NR350) (poster). New York: American Psychiatric Association annual meeting, May 2004.

In patients with treatment-resistant schizophrenia, lithium and anticonvulsants have become such common adjuncts to antipsychotics that 50% of inpatients may be receiving them.¹ Evidence supporting this practice is mixed:

• Initial case reports and open-label studies that showed benefit have not always been followed by randomized clinical trials.
• Lack of clear benefit also has been described (Table 1).

This article examines the extent of this prescribing pattern, its evidence base, and mechanisms of action that may help explain why some adjunctive mood stabilizers are more effective than others for treatment-resistant schizophrenia.

EXTENT OF USE

For 5 years, the rate at which inpatients with schizophrenia received adjunctive mood stabilizers has held steady at approximately 50% in New York State Office of Mental Health (NYSOMH) facilities (Figure1). These facilities provide intermediate and long-term care for the seriously, persistently mentally ill. Adjunctive mood stabilizers might not be used as often for outpatients or for inpatients treated in short-stay facilities.

Table 1

Evidence for adjunctive use of lithium or anticonvulsants for treating schizophrenia

Valproate is the most commonly used anticonvulsant, with one out of three patients with schizophrenia receiving it. Adjunctive gabapentin use is declining, probably because of inadequate efficacy—as will be discussed later. Use of adjunctive lamotrigine is expected to increase as more data become available on its usefulness in treatment-resistant schizophrenia.

Clinicians are using substantial dosages of adjunctive mood stabilizers. During first-quarter 2004, average daily dosages for 4,788 NYSOMH patients (80% with schizophrenia or schizoaffective disorder) receiving antipsychotics were:

• valproate, 1639 mg (n = 1921)
• gabapentin, 1524 mg (n = 303)
• oxcarbazepine, 1226 mg (n = 201)
• carbamazepine, 908 mg (n = 112)
• lithium, 894 mg (n = 715)
• topiramate, 234 mg (n = 269)
• lamotrigine, 204 mg (n = 231).²

Mood-stabilizer combinations were also used. Approximately one-half of patients receiving adjunctive mood stabilizers—with the exception of valproate—were receiving more than one. In patients receiving valproate, the rate of mood-stabilizer co-prescribing was about 25%.²

WHAT IS THE EVIDENCE?

Evidence supporting the use of adjunctive lithium or anticonvulsants to treat schizophrenia varies in quality and quantity (Table 1). Case reports and open studies offer the weakest evidence but can spur double-blind, randomized clinical trials (RCTs). Unfortunately, RCTs are not often done, and the published studies usually suffer from methodologic flaws such as:

• inadequate number of subjects (insufficient statistical power to detect differences)
• lack of control of confounds such as mood symptoms (seen when studies include patients with schizoaffective disorder)
• inadequate duration
• inappropriate target populations (patients with acute exacerbations of schizophrenia instead of persistent symptoms in treatment-resistant schizophrenia).

Because controlled trials of the use of adjunctive mood stabilizers are relatively scarce, clinical practice has transcended clinical research. Clinicians need effective regimens for treatment-resistant schizophrenia, and mood-stabilizer augmentation helps some patients.

Lithium is perhaps the best-known mood stabilizer. Although early studies showed adjunctive lithium useful in treating schizophrenia, later and better-designed trials did not. The authors of a recent meta-analysis of randomized clinical trials (n = 611 in 20 studies) concluded that despite some evidence supporting the efficacy of lithium augmentation, overall results were inconclusive. A large trial would be required to detect a small benefit in patients with schizophrenia who lack affective symptoms.³

Carbamazepine use among patients with schizophrenia is declining, primarily because this drug induces its own metabolism and can require frequent dose adjustments. Adjunctive carbamazepine has been used to manage persistent aggressive behavior in patients with schizophrenia and schizoaffective disorder. Evidence comes primarily from small trials or case reports (Table 2),^4-8 but results of a larger clinical trial (n = 162) by Okuma et al⁶ are also available

In the Okuma report—a double-blind, placebo-controlled trial of carbamazepine in patients with DSM-III schizophrenia or schizoaffective disorder—carbamazepine did not significantly improve patients’ total Brief Psychiatric Rating Scale (BPRS) scores. Compared with placebo, however, some benefit with carbamazepine did emerge in measures of suspiciousness, uncooperativeness, and excitement.

A systematic review and meta-analysis (n = 283 in 10 studies) detected a trend toward reduced psychopathology with carbamazepine augmentation for schizophrenia. BPRS scores declined by 20% and 35% in the six trials (n = 147) for which data were available (P = 0.08 and 0.09, respectively).⁹ Because the double-blind trial by Okuma et al⁶ was not randomized, it was not included in this meta-analysis.⁹

Figure 1 10-year trend in use of adjunctive mood stabilizers for schizophrenia

Initial double-blind, RCTs of adjunctive valproate in patients with schizophrenia were limited in size and failed to show benefit with adjunctive valproate^12-15 (Table 2). A more recent study¹⁶ showed that adjunctive valproate affects acute psychotic symptoms rather than mood. This study, however, did not answer whether adjunctive valproate would help patients with persistent symptoms of schizophrenia.

Table 2

Double-blind studies of adjunctive carbamazepine in schizophrenia

In this large (n = 249), multicenter, randomized, double-blind trial, hospitalized patients with an acute exacerbation of schizophrenia received olanzapine or risperidone plus divalproex or placebo for 28 days. Patients with schizoaffective disorder and treatment-resistant schizophrenia were excluded.

By day 6, dosages reached 6 mg/d for risperidone and 15 mg/d for olanzapine. Divalproex was started at 15 mg/kg and titrated to a maximum of 30 mg/kg by day 14. Mean divalproex dosage was approximately 2300 mg/d (mean plasma level approximately 100 mg/mL).

Positive and Negative Syndrome Scale (PANSS) total scores improved significantly in patients receiving adjunctive divalproex compared with those receiving antipsychotic monotherapy, and significant differences occurred as early as day 3. The major effect was seen on schizophrenia’s positive symptoms. A post-hoc analysis¹⁷ also showed greater reductions in hostility (as measured by the hostility item in the PANSS Positive Subscale) in patients receiving adjunctive divalproex compared with antipsychotic monotherapy. This effect was independent of the effect on positive symptoms or sedation.

A large, multi-site, 84-day acute schizophrenia RCT similar to the 28-day trial—but using extended-release divalproex—is being conducted. An extended-release preparation may be particularly helpful in encouraging medication adherence for patients taking complicated medication regimens.

Table 3

Double-blind studies of adjunctive valproate in schizophrenia

In a recent large (n = 10,262), retrospective, pharmacoepidemiologic analysis,¹⁸ valproate augmentation led to longer persistence of treatment than did the strategy of switching antipsychotics. Average valproate dosages were small, however (<425 mg/d), as were antipsychotic dosages (risperidone <1.7 mg/d, quetiapine <120 mg/d, and olanzapine <7.5 mg/d). Patients’ diagnostic categories were not available. One interpretation of this study is that valproate augmentation would be more successful than switching antipsychotics, assuming that treatment persistence can be viewed as a positive outcome.

Table 4

Double-blind studies of adjunctive lamotrigine in schizophrenia

Lamotrigine is the only other anticonvulsant for which published, double-blind, randomized evidence of use in patients with schizophrenia is available (Table 4).^19,20 Adjunctive lamotrigine may be effective in managing treatment-resistant schizophrenia, as was shown in a small (n = 34), double-blind, placebo-controlled, crossover trial.¹⁹ Hospitalized patients whose symptoms were inadequately controlled with clozapine monotherapy received lamotrigine, 200 mg/d, for up to 12 weeks. Adjunctive lamotrigine improved positive but not negative symptoms.

Similar results were seen in treatment-resistant inpatients with schizophrenia (n = 38) in a 10-week, double-blind, parallel group trial by Kremer et al.²⁰ Adjunctive lamotrigine improved PANSS positive, general psychopathology, and total symptom scores in the 31 patients who completed the trial. No differences were seen, however, in negative symptoms, total BPRS scores, or in the intent-to-treat analysis. These results have spurred the launch of a large, multi-site, RCT of adjunctive lamotrigine in patients with schizophrenia who have responded inadequately to antipsychotics alone.

Topiramate, one of the few psychotropics associated with weight loss, has attracted interest as an adjunct to second-generation antipsychotics to address weight gain. Although case reports have shown benefit,²¹ one showed deterioration in both positive and negative symptoms when topiramate was added to second-generation antipsychotics.²²

Table 5

Double-blind study of adjunctive topiramate in schizophrenia

An unpublished, randomized, crossover trial compared second-generation antipsychotics plus topiramate or placebo in 26 male inpatients with chronic schizophrenia. With adjunctive topiramate, the authors found a statistically significant improvement in the PANSS general psychopathology subscale but not in PANSS total, positive subscale, or negative subscale scores (Table 5) (Tiihonen J, personal communication 6/22/04).

Other agents. Very little information—all uncontrolled—supports adjunctive use of gabapentin or oxcarbazepine for patients with schizophrenia.^23-28 Of concern are reports of patients suffering worsening of psychosis with gabapentin²⁵ or of dysphoria and irritability with oxcarbazepine (attributed to a pharmacokinetic interaction).²⁶

Conclusion. More trials are needed to examine the use of adjunctive mood stabilizers in patients with schizophrenia—particularly in those with chronic symptoms. Although mood stabilizers are widely used in this population, important questions remain unanswered, including:

• characteristics of patients likely to require adjunctive treatment
• how long treatment should continue.

MECHANISMS OF ACTION

Unlike antipsychotics, mood stabilizers do not exert their therapeutic effects by acting directly on dopamine (D2) receptors. Differences in mechanism of action among the anticonvulsants may help explain why some—such as valproate and lamotrigine—have been useful for bipolar disorder or schizophrenia and others—such as gabapentin—have not.²⁹

One possibility is that anticonvulsants that affect voltage-gated sodium channels—such as valproate, lamotrigine, carbamazepine and oxcarbazepine—may be most useful for patients with bipolar disorder or schizophrenia. On the other hand, agents that affect voltage-gated calcium channels—such as gabapentin—may be efficacious as anticonvulsants but not as efficacious for bipolar disorder or schizophrenia.

Ketter et al³⁰ proposed an anticonvulsant classification system based on predominant psychotropic profiles:

• the “GABA-ergic” group predominantly potentiates the inhibitory neurotransmitter GABA, resulting in sedation, fatigue, cognitive slowing, and weight gain, as well as possible anxiolytic and antimanic effects
• the “anti-glutamate” group predominantly attenuates glutamate excitatory neurotransmission and is associated with activation, weight loss, and possibly anxiogenic and antidepressant effects.

In the GABA-ergic group are anticonvulsants such as barbiturates, benzodiazepines, valproate, gabapentin, tiagabine, and vigabatrin. The antiglutamate group includes agents such as felbamate and lamotrigine. A “mixed” category includes anticonvulsants with GABA-ergic and anti-glutaminergic actions such as topiramate, which has sedating and weight-loss properties.

Because GABA appears to modulate dopamine neurotransmission,³¹ this may explain valproate’s role as an adjunctive agent for schizophrenia. Similarly, mechanisms related to Nmethyl-D-aspartate (NMDA) and non-NMDA glutamate receptor function may explain lamotrigine’s usefulness in this setting.^19,20

SUMMARY

Clinicians resort to combination therapies when monotherapies fail to adequately control symptoms or maintain response. Co-prescribing of anticonvulsants with antipsychotics for inpatients with schizophrenia is common practice in New York State and most likely elsewhere. In general, antipsychotics’ and mood stabilizers’ different—and perhaps complementary—mechanisms of action explain the synergism between them. Mechanisms of action also may explain why some anticonvulsants help in schizophrenia (or bipolar disorder) whereas others do not.

Evidence for using adjunctive anticonvulsants is variable. The strongest data support using valproate (and perhaps lamotrigine), followed by carbamazepine and then topiramate. Gabapentin and oxcarbazepine have only anecdotal evidence, some of it negative. Well-designed, randomized clinical trials with the appropriate populations are needed.

Related resources

• Stahl SM. Essential psychopharmacology of antipsychotics and mood stabilizers. New York: Cambridge University Press, 2002.
• Harvard Medical School Department of Psychiatry’s psychopharmacology algorithm project. Osser DN, Patterson RD. Consultant for the pharmacotherapy of schizophrenia. Available at http://mhc.com/Algorithms/. Accessed Nov. 5, 2004.

Drug brand names

• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Gabapentin • Neurontin
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Lithium • Lithobid, Eskalith
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Topiramate • Topamax
• Valproate (valproic acid, divalproex sodium) • Depakene, Depakote

Disclosure

Dr. Citrome receives research grants/contracts from Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Eli Lilly & Co., Janssen Pharmaceutica, and Pfizer Inc. He is a consultant to and/or speaker for Bristol-Myers Squibb Co., Eli Lilly & Co., Pfizer Inc., Abbott Laboratories, AstraZeneca Pharmaceuticals, and Novartis Pharmaceuticals Corp.

Acknowledgment

Adapted from Citrome L. “Antipsychotic polypharmacy versus augmentation with anticonvulsants: the U.S. perspective” (presentation). Paris: Collegium Internationale Neuro-Psychopharmacologicum (CINP), June 2004 [abstract in Int J Neuropsychopharmacol. 2004; 7(suppl 1):S69], and from Citrome L. “Mood-stabilizer use in schizophrenia: 1994-2002” (NR350) (poster). New York: American Psychiatric Association annual meeting, May 2004.

In patients with treatment-resistant schizophrenia, lithium and anticonvulsants have become such common adjuncts to antipsychotics that 50% of inpatients may be receiving them.¹ Evidence supporting this practice is mixed:

• Initial case reports and open-label studies that showed benefit have not always been followed by randomized clinical trials.
• Lack of clear benefit also has been described (Table 1).

This article examines the extent of this prescribing pattern, its evidence base, and mechanisms of action that may help explain why some adjunctive mood stabilizers are more effective than others for treatment-resistant schizophrenia.

EXTENT OF USE

For 5 years, the rate at which inpatients with schizophrenia received adjunctive mood stabilizers has held steady at approximately 50% in New York State Office of Mental Health (NYSOMH) facilities (Figure1). These facilities provide intermediate and long-term care for the seriously, persistently mentally ill. Adjunctive mood stabilizers might not be used as often for outpatients or for inpatients treated in short-stay facilities.

Table 1

Evidence for adjunctive use of lithium or anticonvulsants for treating schizophrenia

Valproate is the most commonly used anticonvulsant, with one out of three patients with schizophrenia receiving it. Adjunctive gabapentin use is declining, probably because of inadequate efficacy—as will be discussed later. Use of adjunctive lamotrigine is expected to increase as more data become available on its usefulness in treatment-resistant schizophrenia.

Clinicians are using substantial dosages of adjunctive mood stabilizers. During first-quarter 2004, average daily dosages for 4,788 NYSOMH patients (80% with schizophrenia or schizoaffective disorder) receiving antipsychotics were:

• valproate, 1639 mg (n = 1921)
• gabapentin, 1524 mg (n = 303)
• oxcarbazepine, 1226 mg (n = 201)
• carbamazepine, 908 mg (n = 112)
• lithium, 894 mg (n = 715)
• topiramate, 234 mg (n = 269)
• lamotrigine, 204 mg (n = 231).²

Mood-stabilizer combinations were also used. Approximately one-half of patients receiving adjunctive mood stabilizers—with the exception of valproate—were receiving more than one. In patients receiving valproate, the rate of mood-stabilizer co-prescribing was about 25%.²

WHAT IS THE EVIDENCE?

Evidence supporting the use of adjunctive lithium or anticonvulsants to treat schizophrenia varies in quality and quantity (Table 1). Case reports and open studies offer the weakest evidence but can spur double-blind, randomized clinical trials (RCTs). Unfortunately, RCTs are not often done, and the published studies usually suffer from methodologic flaws such as:

• inadequate number of subjects (insufficient statistical power to detect differences)
• lack of control of confounds such as mood symptoms (seen when studies include patients with schizoaffective disorder)
• inadequate duration
• inappropriate target populations (patients with acute exacerbations of schizophrenia instead of persistent symptoms in treatment-resistant schizophrenia).

Because controlled trials of the use of adjunctive mood stabilizers are relatively scarce, clinical practice has transcended clinical research. Clinicians need effective regimens for treatment-resistant schizophrenia, and mood-stabilizer augmentation helps some patients.

Lithium is perhaps the best-known mood stabilizer. Although early studies showed adjunctive lithium useful in treating schizophrenia, later and better-designed trials did not. The authors of a recent meta-analysis of randomized clinical trials (n = 611 in 20 studies) concluded that despite some evidence supporting the efficacy of lithium augmentation, overall results were inconclusive. A large trial would be required to detect a small benefit in patients with schizophrenia who lack affective symptoms.³

Carbamazepine use among patients with schizophrenia is declining, primarily because this drug induces its own metabolism and can require frequent dose adjustments. Adjunctive carbamazepine has been used to manage persistent aggressive behavior in patients with schizophrenia and schizoaffective disorder. Evidence comes primarily from small trials or case reports (Table 2),^4-8 but results of a larger clinical trial (n = 162) by Okuma et al⁶ are also available

In the Okuma report—a double-blind, placebo-controlled trial of carbamazepine in patients with DSM-III schizophrenia or schizoaffective disorder—carbamazepine did not significantly improve patients’ total Brief Psychiatric Rating Scale (BPRS) scores. Compared with placebo, however, some benefit with carbamazepine did emerge in measures of suspiciousness, uncooperativeness, and excitement.

A systematic review and meta-analysis (n = 283 in 10 studies) detected a trend toward reduced psychopathology with carbamazepine augmentation for schizophrenia. BPRS scores declined by 20% and 35% in the six trials (n = 147) for which data were available (P = 0.08 and 0.09, respectively).⁹ Because the double-blind trial by Okuma et al⁶ was not randomized, it was not included in this meta-analysis.⁹

Figure 1 10-year trend in use of adjunctive mood stabilizers for schizophrenia

Initial double-blind, RCTs of adjunctive valproate in patients with schizophrenia were limited in size and failed to show benefit with adjunctive valproate^12-15 (Table 2). A more recent study¹⁶ showed that adjunctive valproate affects acute psychotic symptoms rather than mood. This study, however, did not answer whether adjunctive valproate would help patients with persistent symptoms of schizophrenia.

Table 2

Double-blind studies of adjunctive carbamazepine in schizophrenia

In this large (n = 249), multicenter, randomized, double-blind trial, hospitalized patients with an acute exacerbation of schizophrenia received olanzapine or risperidone plus divalproex or placebo for 28 days. Patients with schizoaffective disorder and treatment-resistant schizophrenia were excluded.

By day 6, dosages reached 6 mg/d for risperidone and 15 mg/d for olanzapine. Divalproex was started at 15 mg/kg and titrated to a maximum of 30 mg/kg by day 14. Mean divalproex dosage was approximately 2300 mg/d (mean plasma level approximately 100 mg/mL).

Positive and Negative Syndrome Scale (PANSS) total scores improved significantly in patients receiving adjunctive divalproex compared with those receiving antipsychotic monotherapy, and significant differences occurred as early as day 3. The major effect was seen on schizophrenia’s positive symptoms. A post-hoc analysis¹⁷ also showed greater reductions in hostility (as measured by the hostility item in the PANSS Positive Subscale) in patients receiving adjunctive divalproex compared with antipsychotic monotherapy. This effect was independent of the effect on positive symptoms or sedation.

A large, multi-site, 84-day acute schizophrenia RCT similar to the 28-day trial—but using extended-release divalproex—is being conducted. An extended-release preparation may be particularly helpful in encouraging medication adherence for patients taking complicated medication regimens.

Table 3

Double-blind studies of adjunctive valproate in schizophrenia

In a recent large (n = 10,262), retrospective, pharmacoepidemiologic analysis,¹⁸ valproate augmentation led to longer persistence of treatment than did the strategy of switching antipsychotics. Average valproate dosages were small, however (<425 mg/d), as were antipsychotic dosages (risperidone <1.7 mg/d, quetiapine <120 mg/d, and olanzapine <7.5 mg/d). Patients’ diagnostic categories were not available. One interpretation of this study is that valproate augmentation would be more successful than switching antipsychotics, assuming that treatment persistence can be viewed as a positive outcome.

Table 4

Double-blind studies of adjunctive lamotrigine in schizophrenia

Lamotrigine is the only other anticonvulsant for which published, double-blind, randomized evidence of use in patients with schizophrenia is available (Table 4).^19,20 Adjunctive lamotrigine may be effective in managing treatment-resistant schizophrenia, as was shown in a small (n = 34), double-blind, placebo-controlled, crossover trial.¹⁹ Hospitalized patients whose symptoms were inadequately controlled with clozapine monotherapy received lamotrigine, 200 mg/d, for up to 12 weeks. Adjunctive lamotrigine improved positive but not negative symptoms.

Similar results were seen in treatment-resistant inpatients with schizophrenia (n = 38) in a 10-week, double-blind, parallel group trial by Kremer et al.²⁰ Adjunctive lamotrigine improved PANSS positive, general psychopathology, and total symptom scores in the 31 patients who completed the trial. No differences were seen, however, in negative symptoms, total BPRS scores, or in the intent-to-treat analysis. These results have spurred the launch of a large, multi-site, RCT of adjunctive lamotrigine in patients with schizophrenia who have responded inadequately to antipsychotics alone.

Topiramate, one of the few psychotropics associated with weight loss, has attracted interest as an adjunct to second-generation antipsychotics to address weight gain. Although case reports have shown benefit,²¹ one showed deterioration in both positive and negative symptoms when topiramate was added to second-generation antipsychotics.²²

Table 5

Double-blind study of adjunctive topiramate in schizophrenia

An unpublished, randomized, crossover trial compared second-generation antipsychotics plus topiramate or placebo in 26 male inpatients with chronic schizophrenia. With adjunctive topiramate, the authors found a statistically significant improvement in the PANSS general psychopathology subscale but not in PANSS total, positive subscale, or negative subscale scores (Table 5) (Tiihonen J, personal communication 6/22/04).

Other agents. Very little information—all uncontrolled—supports adjunctive use of gabapentin or oxcarbazepine for patients with schizophrenia.^23-28 Of concern are reports of patients suffering worsening of psychosis with gabapentin²⁵ or of dysphoria and irritability with oxcarbazepine (attributed to a pharmacokinetic interaction).²⁶

Conclusion. More trials are needed to examine the use of adjunctive mood stabilizers in patients with schizophrenia—particularly in those with chronic symptoms. Although mood stabilizers are widely used in this population, important questions remain unanswered, including:

• characteristics of patients likely to require adjunctive treatment
• how long treatment should continue.

MECHANISMS OF ACTION

Unlike antipsychotics, mood stabilizers do not exert their therapeutic effects by acting directly on dopamine (D2) receptors. Differences in mechanism of action among the anticonvulsants may help explain why some—such as valproate and lamotrigine—have been useful for bipolar disorder or schizophrenia and others—such as gabapentin—have not.²⁹

One possibility is that anticonvulsants that affect voltage-gated sodium channels—such as valproate, lamotrigine, carbamazepine and oxcarbazepine—may be most useful for patients with bipolar disorder or schizophrenia. On the other hand, agents that affect voltage-gated calcium channels—such as gabapentin—may be efficacious as anticonvulsants but not as efficacious for bipolar disorder or schizophrenia.

Ketter et al³⁰ proposed an anticonvulsant classification system based on predominant psychotropic profiles:

• the “GABA-ergic” group predominantly potentiates the inhibitory neurotransmitter GABA, resulting in sedation, fatigue, cognitive slowing, and weight gain, as well as possible anxiolytic and antimanic effects
• the “anti-glutamate” group predominantly attenuates glutamate excitatory neurotransmission and is associated with activation, weight loss, and possibly anxiogenic and antidepressant effects.

In the GABA-ergic group are anticonvulsants such as barbiturates, benzodiazepines, valproate, gabapentin, tiagabine, and vigabatrin. The antiglutamate group includes agents such as felbamate and lamotrigine. A “mixed” category includes anticonvulsants with GABA-ergic and anti-glutaminergic actions such as topiramate, which has sedating and weight-loss properties.

Because GABA appears to modulate dopamine neurotransmission,³¹ this may explain valproate’s role as an adjunctive agent for schizophrenia. Similarly, mechanisms related to Nmethyl-D-aspartate (NMDA) and non-NMDA glutamate receptor function may explain lamotrigine’s usefulness in this setting.^19,20

SUMMARY

Clinicians resort to combination therapies when monotherapies fail to adequately control symptoms or maintain response. Co-prescribing of anticonvulsants with antipsychotics for inpatients with schizophrenia is common practice in New York State and most likely elsewhere. In general, antipsychotics’ and mood stabilizers’ different—and perhaps complementary—mechanisms of action explain the synergism between them. Mechanisms of action also may explain why some anticonvulsants help in schizophrenia (or bipolar disorder) whereas others do not.

Evidence for using adjunctive anticonvulsants is variable. The strongest data support using valproate (and perhaps lamotrigine), followed by carbamazepine and then topiramate. Gabapentin and oxcarbazepine have only anecdotal evidence, some of it negative. Well-designed, randomized clinical trials with the appropriate populations are needed.

Related resources

• Stahl SM. Essential psychopharmacology of antipsychotics and mood stabilizers. New York: Cambridge University Press, 2002.
• Harvard Medical School Department of Psychiatry’s psychopharmacology algorithm project. Osser DN, Patterson RD. Consultant for the pharmacotherapy of schizophrenia. Available at http://mhc.com/Algorithms/. Accessed Nov. 5, 2004.

Drug brand names

• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Gabapentin • Neurontin
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Lithium • Lithobid, Eskalith
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Topiramate • Topamax
• Valproate (valproic acid, divalproex sodium) • Depakene, Depakote

Disclosure

Dr. Citrome receives research grants/contracts from Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Eli Lilly & Co., Janssen Pharmaceutica, and Pfizer Inc. He is a consultant to and/or speaker for Bristol-Myers Squibb Co., Eli Lilly & Co., Pfizer Inc., Abbott Laboratories, AstraZeneca Pharmaceuticals, and Novartis Pharmaceuticals Corp.

Acknowledgment

Adapted from Citrome L. “Antipsychotic polypharmacy versus augmentation with anticonvulsants: the U.S. perspective” (presentation). Paris: Collegium Internationale Neuro-Psychopharmacologicum (CINP), June 2004 [abstract in Int J Neuropsychopharmacol. 2004; 7(suppl 1):S69], and from Citrome L. “Mood-stabilizer use in schizophrenia: 1994-2002” (NR350) (poster). New York: American Psychiatric Association annual meeting, May 2004.

Anabolic steroid use by athletes and body-builders has captured public attention but remains poorly understood by most physicians. This is not surprising because users of anabolic-androgenic steroids (AAS):

• rarely seek treatment or disclose their drug use
• frequently distrust professionals.

If you are a clinician who regularly sees male adolescents and young men, you need to become familiar with—and watch for—this often-secret form of substance abuse. This article provides the groundwork for that understanding, starting with the story of “Aaron”—a composite patient whose case represents experiences and verbatim quotes from AAS users known to the authors.

CASE REPORT: ‘I FEEL INVINCIBLE’

At his first visit, Aaron, age 18, told the psychiatrist he had no complaints but was coming to please his parents. “I have a lot of arguments with my Dad,” he said, “and they keep thinking something’s wrong with me.”

The patient was very muscular and dressed in baggy sweats that masked his body proportions. He was appropriately groomed and darkly tanned but displayed some acne. The clinician guessed he weighed about 175 lbs and stood at about 65 inches, with very low body fat. Although superficially confident, he seemed restless, somewhat anxious, and guarded as the interview progressed.

Aaron admitted he experienced prominent mood swings. During rage outbursts, he had damaged objects and put his fist through the wall. “There’s holes all over the wall of my room,” he joked.

He also had assaulted a motorist in a traffic altercation, then left the scene. “Did you hurt him?” the clinician asked. Somewhat sheepishly, Aaron responded, “Well, I bought the newspaper and kept checking the obituaries for about 2 weeks afterwards.”

He spoke with pride about his weightlifting, which was the focus of his life. He revealed that he was preparing for a body-building contest in 2 months. The psychiatrist asked him about use of supplements—protein shakes, creatine, and “andro” (androstenedione)—all of which Aaron acknowledged. The psychiatrist then gently asked about anabolic steroid use (Box 1).

Initially, Aaron strongly denied using AAS. The psychiatrist persisted, pointing out that no information would be disclosed to his parents, and asked again using colloquial terms from the AAS subculture: “Anybody who is prepping for an untested contest in a couple of months is going to be on a cycle. Come on, what are you taking?”

Box 1

Eventually it emerged that Aaron had taken five 8- to 20-week AAS “cycles” (courses), during which he had “stacked” (combined) various “injectables” such as IM testosterone and “orals” such as methyltestosterone (Table 1). His current cycle included:

• a blend of testosterone esters (Sustanon), 500 mg IM once a week
• boldenone (Equipoise), a veterinary AAS normally used for horses, 200 mg IM per week
• oxymetholone (Anadrol), 50 mg orally per day.

Table 1

Commonly used anabolic-androgenic steroids

His friends had taught him to self-inject AAS at age 15; he admitted that he was also occasionally self-injecting the opioid analgesic nalbuphine intravenously because of “pain in my ‘delts’ from military presses.”

During his cycles, Aaron experienced hypomanic symptoms, including euphoria, prominent irritability, increased libido, decreased need for sleep, and grandiosity. “I feel invincible,” he said. His aggressive outbursts had worsened with increasing AAS doses; in addition to attacking the motorist, he also had been physically violent with his girlfriend. “She’s scared of me when I’m on juice,” he conceded.

During the withdrawal phase after stopping each cycle, Aaron described prominent depression with anhedonia, hypersomnia, loss of libido, and suicidal ideation. “I once almost jumped off a bridge after my fourth cycle,” he admitted. “I couldn’t wait to get on my next cycle to feel good again.” His depressions were also characterized by body-image obsessions; he would regularly spend at least 1 hour a day examining his musculature in a mirror, and sometimes refused to go out in public because he “was getting too small.”

Perhaps most disturbing was his increasing use of opioids. In addition to self-injecting nalbuphine, he also ingested oral opioids such as oxycodone almost daily. He mentioned that several of his friends in the gym had progressed from injecting nalbuphine to injecting morphine or heroin, and he knew two bodybuilders who had died from apparently unintentional opioid overdoses.

Aaron said his parents, teachers, and non-bodybuilding friends were unaware of this history. He claimed his parents were proud that their son had apparently eschewed drugs and alcohol to pursue a healthy athletic lifestyle.

RECOGNIZING AAS USE

In our experience with treating substance abusers, we find that AAS users may be the least likely to disclose their drug use to clinicians. In a recent study,¹ 20 of 36 AAS users (56%) reported they had never revealed their AAS use to any physician. When asked to rate their trust in sources of information about AAS, 17 of 42 AAS users (40%) said they trusted information from their drug dealers at least as much as information from any physician they had seen.

Some expressed contempt for physicians as “geeks” or “pencil-necks” who could not comprehend the body-building lifestyle. They gave doctors high marks on knowledge of tobacco, alcohol, and ordinary “street drugs” but much lower ratings on AAS knowledge. Other investigators have shown that many clinicians are unfamiliar with AAS.^2,3

AAS users embrace these beliefs for two other reasons. First, to admit to AAS use is to admit that one’s muscularity and physical prowess is the result of taking a drug; there is no comparable motivation to withhold information about, say, one’s use of marijuana or cocaine.

Second, AAS users are much less likely than other substance abusers to view their behavior as pathologic. We have argued that our culture is partially to blame.⁴ Americans pay to watch 300-lb football linemen and AAS-using movie stars. Makers of cars, computers, and electronics do not hesitate to advertise their products as “on steroids,” but they would never claim their products were “on cocaine.” In this climate, it is easy to forget that AAS use is an illicit substance abuse.

Box 2

Table 2

Clues to possible AAS use in men

To overcome these treatment obstacles, we recommend that you:

• Become as knowledgeable about AAS use as you are about other forms of substance abuse (see Related resources).
• Approach AAS users as you would any other substance abusers—as individuals at risk for potentially serious medical and psychiatric consequences.
• Maintain a high index of suspicion when evaluating any muscular young male patient, even if he initially denies AAS use.

AAS use can often be suspected by looking at the patient as he walks in the door. Using what we call the “fat-free mass index” (FFMI) to calculate muscularity (Box 2), we have shown that a lean man can achieve only a certain amount of muscularity without using drugs.⁵ Although this finding needs to be replicated elsewhere, in our experience a man is almost certainly lying if he:

• is relatively lean (with approximately 10% body fat)
• displays an FFMI >26
• and claims he has not used drugs.

If a patient has an elevated FFMI and other cues suggesting AAS use (Table 2), gently but persistently question him if he denies using these drugs.

TREATING AAS-ASSOCIATED SYNDROMES

When you have established a history of AAS use, you will be far better prepared to anticipate and possibly treat its associated syndromes. Discussion of these effects is beyond the scope of this paper; for details, see reviews of AAS-associated medical effects,^3,6 psychiatric effects,^6,7 and general treatment principles.⁸ We focus here on the four scenarios clinicians encounter most often in practice and offer some pragmatic suggestions.

Forensic cases. AAS users almost never voluntarily seek help to stop their drug use. Such a request would be somewhat analogous to a girl with anorexia nervosa voluntarily asking for help to gain weight. We are unaware of any rehabilitation centers, clinics, 12-step programs, or the like for AAS users—there is no demand for them.

Thus, an AAS user may first come to clinical attention through legal channels. For example, if an AAS user committed a violent crime while experiencing hypomanic effects from these drugs, he might be required to undergo random urine testing as a condition of probation. This may be reasonable, provided that the tests are unannounced and urine is always collected under direct observation.

Monitoring clinicians may serve as little better than policemen, although sometimes it is possible to forge an alliance with the patient.

Depression. Exogenous AAS administration suppresses endogenous testosterone production through feedback mechanisms involving the hypothalamic-pituitary-testicular axis.^3,6 Thus, during a long cycle, the user’s testes may shrink to half their normal size and stop producing testosterone and spermatozoa.

If the user then stops AAS rapidly, he may plunge into a profoundly hypogonadal state associated with symptoms of major depression. In a field study of 77 steroid users (71 male and 6 female), 6 (7.8%) reported they attempted suicide during AAS withdrawal.⁹ Depression associated with AAS withdrawal may prompt users to resume AAS quickly, triggering a syndrome of AAS dependence.^6,10,11

Fortunately, AAS-withdrawal depression is usually self-limited and responds—in our experience and that of others¹²—to standard antidepressants. We recommend aggressively treating such depressions, as doing so may prevent resumption of AAS use and eventual AAS dependence.

Body-image disorders. AAS users often report body-image disorders, especially muscle dysmorphia—a form of body dysmorphic disorder where individuals become preoccupied with the belief that they are not adequately muscular.^13,14 Anxieties about muscularity are a risk factor for subsequent AAS use¹⁵ and a major contributor to AAS dependence.^8,11

Body dysmorphic disorder responds to pharmacologic and cognitive-behavioral interventions.^3,16 Young men showing pathologic concerns about their muscularity or displaying related body-image pathology may benefit from prompt treatment before they are tempted to use AAS.

Progression to opioid dependence. An ominous development among American¹⁷ and British¹⁸ AAS users is a growing tendency to use opioids. In two studies of individuals with opioid dependence,^19,20 7% to 9% reported beginning as AAS users, then learning about opioids from fellow bodybuilders and often buying their first illicit opioids from the person who had sold them AAS. Most learned as teenagers to use needles to inject AAS intramuscularly, so beginning to using opioids intravenously was only a small step.

In the last 5 years, we have become anecdotally aware of numerous AAS users who developed heroin addiction requiring repeated inpatient detoxification or who died of unintentional opioid overdoses. We suspect this phenomenon is under-recognized and urge clinicians to watch for it.

Related resources

• Pope HG Jr, Brower KJ. Anabolic-androgenic steroid abuse. In: Sadock BJ, Sadock VA (eds). Comprehensive textbook of psychiatry (8th ed). Philadelphia: Lippincott Williams & Wilkins (in press).
• Yesalis CE (ed). Anabolic steroids in sport and exercise (2nd ed). Champaign, IL: Human Kinetics, 2000.
• The Taylor Hooton Foundation. Started by the father of a high school athlete who committed suicide during a depressive episode apparently precipitated by AAS withdrawal. Includes links to related Web sites. http://www.taylorhooton.org/about.asp. Accessed Nov. 10, 2004.

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Anabolic steroid use by athletes and body-builders has captured public attention but remains poorly understood by most physicians. This is not surprising because users of anabolic-androgenic steroids (AAS):

• rarely seek treatment or disclose their drug use
• frequently distrust professionals.

If you are a clinician who regularly sees male adolescents and young men, you need to become familiar with—and watch for—this often-secret form of substance abuse. This article provides the groundwork for that understanding, starting with the story of “Aaron”—a composite patient whose case represents experiences and verbatim quotes from AAS users known to the authors.

CASE REPORT: ‘I FEEL INVINCIBLE’

At his first visit, Aaron, age 18, told the psychiatrist he had no complaints but was coming to please his parents. “I have a lot of arguments with my Dad,” he said, “and they keep thinking something’s wrong with me.”

The patient was very muscular and dressed in baggy sweats that masked his body proportions. He was appropriately groomed and darkly tanned but displayed some acne. The clinician guessed he weighed about 175 lbs and stood at about 65 inches, with very low body fat. Although superficially confident, he seemed restless, somewhat anxious, and guarded as the interview progressed.

Aaron admitted he experienced prominent mood swings. During rage outbursts, he had damaged objects and put his fist through the wall. “There’s holes all over the wall of my room,” he joked.

He also had assaulted a motorist in a traffic altercation, then left the scene. “Did you hurt him?” the clinician asked. Somewhat sheepishly, Aaron responded, “Well, I bought the newspaper and kept checking the obituaries for about 2 weeks afterwards.”

He spoke with pride about his weightlifting, which was the focus of his life. He revealed that he was preparing for a body-building contest in 2 months. The psychiatrist asked him about use of supplements—protein shakes, creatine, and “andro” (androstenedione)—all of which Aaron acknowledged. The psychiatrist then gently asked about anabolic steroid use (Box 1).

Initially, Aaron strongly denied using AAS. The psychiatrist persisted, pointing out that no information would be disclosed to his parents, and asked again using colloquial terms from the AAS subculture: “Anybody who is prepping for an untested contest in a couple of months is going to be on a cycle. Come on, what are you taking?”

Box 1

Eventually it emerged that Aaron had taken five 8- to 20-week AAS “cycles” (courses), during which he had “stacked” (combined) various “injectables” such as IM testosterone and “orals” such as methyltestosterone (Table 1). His current cycle included:

• a blend of testosterone esters (Sustanon), 500 mg IM once a week
• boldenone (Equipoise), a veterinary AAS normally used for horses, 200 mg IM per week
• oxymetholone (Anadrol), 50 mg orally per day.

Table 1

Commonly used anabolic-androgenic steroids

His friends had taught him to self-inject AAS at age 15; he admitted that he was also occasionally self-injecting the opioid analgesic nalbuphine intravenously because of “pain in my ‘delts’ from military presses.”

During his cycles, Aaron experienced hypomanic symptoms, including euphoria, prominent irritability, increased libido, decreased need for sleep, and grandiosity. “I feel invincible,” he said. His aggressive outbursts had worsened with increasing AAS doses; in addition to attacking the motorist, he also had been physically violent with his girlfriend. “She’s scared of me when I’m on juice,” he conceded.

During the withdrawal phase after stopping each cycle, Aaron described prominent depression with anhedonia, hypersomnia, loss of libido, and suicidal ideation. “I once almost jumped off a bridge after my fourth cycle,” he admitted. “I couldn’t wait to get on my next cycle to feel good again.” His depressions were also characterized by body-image obsessions; he would regularly spend at least 1 hour a day examining his musculature in a mirror, and sometimes refused to go out in public because he “was getting too small.”

Perhaps most disturbing was his increasing use of opioids. In addition to self-injecting nalbuphine, he also ingested oral opioids such as oxycodone almost daily. He mentioned that several of his friends in the gym had progressed from injecting nalbuphine to injecting morphine or heroin, and he knew two bodybuilders who had died from apparently unintentional opioid overdoses.

Aaron said his parents, teachers, and non-bodybuilding friends were unaware of this history. He claimed his parents were proud that their son had apparently eschewed drugs and alcohol to pursue a healthy athletic lifestyle.

RECOGNIZING AAS USE

In our experience with treating substance abusers, we find that AAS users may be the least likely to disclose their drug use to clinicians. In a recent study,¹ 20 of 36 AAS users (56%) reported they had never revealed their AAS use to any physician. When asked to rate their trust in sources of information about AAS, 17 of 42 AAS users (40%) said they trusted information from their drug dealers at least as much as information from any physician they had seen.

Some expressed contempt for physicians as “geeks” or “pencil-necks” who could not comprehend the body-building lifestyle. They gave doctors high marks on knowledge of tobacco, alcohol, and ordinary “street drugs” but much lower ratings on AAS knowledge. Other investigators have shown that many clinicians are unfamiliar with AAS.^2,3

AAS users embrace these beliefs for two other reasons. First, to admit to AAS use is to admit that one’s muscularity and physical prowess is the result of taking a drug; there is no comparable motivation to withhold information about, say, one’s use of marijuana or cocaine.

Second, AAS users are much less likely than other substance abusers to view their behavior as pathologic. We have argued that our culture is partially to blame.⁴ Americans pay to watch 300-lb football linemen and AAS-using movie stars. Makers of cars, computers, and electronics do not hesitate to advertise their products as “on steroids,” but they would never claim their products were “on cocaine.” In this climate, it is easy to forget that AAS use is an illicit substance abuse.

Box 2

Table 2

Clues to possible AAS use in men

To overcome these treatment obstacles, we recommend that you:

• Become as knowledgeable about AAS use as you are about other forms of substance abuse (see Related resources).
• Approach AAS users as you would any other substance abusers—as individuals at risk for potentially serious medical and psychiatric consequences.
• Maintain a high index of suspicion when evaluating any muscular young male patient, even if he initially denies AAS use.

AAS use can often be suspected by looking at the patient as he walks in the door. Using what we call the “fat-free mass index” (FFMI) to calculate muscularity (Box 2), we have shown that a lean man can achieve only a certain amount of muscularity without using drugs.⁵ Although this finding needs to be replicated elsewhere, in our experience a man is almost certainly lying if he:

• is relatively lean (with approximately 10% body fat)
• displays an FFMI >26
• and claims he has not used drugs.

If a patient has an elevated FFMI and other cues suggesting AAS use (Table 2), gently but persistently question him if he denies using these drugs.

TREATING AAS-ASSOCIATED SYNDROMES

When you have established a history of AAS use, you will be far better prepared to anticipate and possibly treat its associated syndromes. Discussion of these effects is beyond the scope of this paper; for details, see reviews of AAS-associated medical effects,^3,6 psychiatric effects,^6,7 and general treatment principles.⁸ We focus here on the four scenarios clinicians encounter most often in practice and offer some pragmatic suggestions.

Forensic cases. AAS users almost never voluntarily seek help to stop their drug use. Such a request would be somewhat analogous to a girl with anorexia nervosa voluntarily asking for help to gain weight. We are unaware of any rehabilitation centers, clinics, 12-step programs, or the like for AAS users—there is no demand for them.

Thus, an AAS user may first come to clinical attention through legal channels. For example, if an AAS user committed a violent crime while experiencing hypomanic effects from these drugs, he might be required to undergo random urine testing as a condition of probation. This may be reasonable, provided that the tests are unannounced and urine is always collected under direct observation.

Monitoring clinicians may serve as little better than policemen, although sometimes it is possible to forge an alliance with the patient.

Depression. Exogenous AAS administration suppresses endogenous testosterone production through feedback mechanisms involving the hypothalamic-pituitary-testicular axis.^3,6 Thus, during a long cycle, the user’s testes may shrink to half their normal size and stop producing testosterone and spermatozoa.

If the user then stops AAS rapidly, he may plunge into a profoundly hypogonadal state associated with symptoms of major depression. In a field study of 77 steroid users (71 male and 6 female), 6 (7.8%) reported they attempted suicide during AAS withdrawal.⁹ Depression associated with AAS withdrawal may prompt users to resume AAS quickly, triggering a syndrome of AAS dependence.^6,10,11

Fortunately, AAS-withdrawal depression is usually self-limited and responds—in our experience and that of others¹²—to standard antidepressants. We recommend aggressively treating such depressions, as doing so may prevent resumption of AAS use and eventual AAS dependence.

Body-image disorders. AAS users often report body-image disorders, especially muscle dysmorphia—a form of body dysmorphic disorder where individuals become preoccupied with the belief that they are not adequately muscular.^13,14 Anxieties about muscularity are a risk factor for subsequent AAS use¹⁵ and a major contributor to AAS dependence.^8,11

Body dysmorphic disorder responds to pharmacologic and cognitive-behavioral interventions.^3,16 Young men showing pathologic concerns about their muscularity or displaying related body-image pathology may benefit from prompt treatment before they are tempted to use AAS.

Progression to opioid dependence. An ominous development among American¹⁷ and British¹⁸ AAS users is a growing tendency to use opioids. In two studies of individuals with opioid dependence,^19,20 7% to 9% reported beginning as AAS users, then learning about opioids from fellow bodybuilders and often buying their first illicit opioids from the person who had sold them AAS. Most learned as teenagers to use needles to inject AAS intramuscularly, so beginning to using opioids intravenously was only a small step.

In the last 5 years, we have become anecdotally aware of numerous AAS users who developed heroin addiction requiring repeated inpatient detoxification or who died of unintentional opioid overdoses. We suspect this phenomenon is under-recognized and urge clinicians to watch for it.

Related resources

• Pope HG Jr, Brower KJ. Anabolic-androgenic steroid abuse. In: Sadock BJ, Sadock VA (eds). Comprehensive textbook of psychiatry (8th ed). Philadelphia: Lippincott Williams & Wilkins (in press).
• Yesalis CE (ed). Anabolic steroids in sport and exercise (2nd ed). Champaign, IL: Human Kinetics, 2000.
• The Taylor Hooton Foundation. Started by the father of a high school athlete who committed suicide during a depressive episode apparently precipitated by AAS withdrawal. Includes links to related Web sites. http://www.taylorhooton.org/about.asp. Accessed Nov. 10, 2004.

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Anabolic steroid use by athletes and body-builders has captured public attention but remains poorly understood by most physicians. This is not surprising because users of anabolic-androgenic steroids (AAS):

• rarely seek treatment or disclose their drug use
• frequently distrust professionals.

If you are a clinician who regularly sees male adolescents and young men, you need to become familiar with—and watch for—this often-secret form of substance abuse. This article provides the groundwork for that understanding, starting with the story of “Aaron”—a composite patient whose case represents experiences and verbatim quotes from AAS users known to the authors.

CASE REPORT: ‘I FEEL INVINCIBLE’

At his first visit, Aaron, age 18, told the psychiatrist he had no complaints but was coming to please his parents. “I have a lot of arguments with my Dad,” he said, “and they keep thinking something’s wrong with me.”

The patient was very muscular and dressed in baggy sweats that masked his body proportions. He was appropriately groomed and darkly tanned but displayed some acne. The clinician guessed he weighed about 175 lbs and stood at about 65 inches, with very low body fat. Although superficially confident, he seemed restless, somewhat anxious, and guarded as the interview progressed.

Aaron admitted he experienced prominent mood swings. During rage outbursts, he had damaged objects and put his fist through the wall. “There’s holes all over the wall of my room,” he joked.

He also had assaulted a motorist in a traffic altercation, then left the scene. “Did you hurt him?” the clinician asked. Somewhat sheepishly, Aaron responded, “Well, I bought the newspaper and kept checking the obituaries for about 2 weeks afterwards.”

He spoke with pride about his weightlifting, which was the focus of his life. He revealed that he was preparing for a body-building contest in 2 months. The psychiatrist asked him about use of supplements—protein shakes, creatine, and “andro” (androstenedione)—all of which Aaron acknowledged. The psychiatrist then gently asked about anabolic steroid use (Box 1).

Initially, Aaron strongly denied using AAS. The psychiatrist persisted, pointing out that no information would be disclosed to his parents, and asked again using colloquial terms from the AAS subculture: “Anybody who is prepping for an untested contest in a couple of months is going to be on a cycle. Come on, what are you taking?”

Box 1

Eventually it emerged that Aaron had taken five 8- to 20-week AAS “cycles” (courses), during which he had “stacked” (combined) various “injectables” such as IM testosterone and “orals” such as methyltestosterone (Table 1). His current cycle included:

• a blend of testosterone esters (Sustanon), 500 mg IM once a week
• boldenone (Equipoise), a veterinary AAS normally used for horses, 200 mg IM per week
• oxymetholone (Anadrol), 50 mg orally per day.

Table 1

Commonly used anabolic-androgenic steroids

His friends had taught him to self-inject AAS at age 15; he admitted that he was also occasionally self-injecting the opioid analgesic nalbuphine intravenously because of “pain in my ‘delts’ from military presses.”

During his cycles, Aaron experienced hypomanic symptoms, including euphoria, prominent irritability, increased libido, decreased need for sleep, and grandiosity. “I feel invincible,” he said. His aggressive outbursts had worsened with increasing AAS doses; in addition to attacking the motorist, he also had been physically violent with his girlfriend. “She’s scared of me when I’m on juice,” he conceded.

During the withdrawal phase after stopping each cycle, Aaron described prominent depression with anhedonia, hypersomnia, loss of libido, and suicidal ideation. “I once almost jumped off a bridge after my fourth cycle,” he admitted. “I couldn’t wait to get on my next cycle to feel good again.” His depressions were also characterized by body-image obsessions; he would regularly spend at least 1 hour a day examining his musculature in a mirror, and sometimes refused to go out in public because he “was getting too small.”

Perhaps most disturbing was his increasing use of opioids. In addition to self-injecting nalbuphine, he also ingested oral opioids such as oxycodone almost daily. He mentioned that several of his friends in the gym had progressed from injecting nalbuphine to injecting morphine or heroin, and he knew two bodybuilders who had died from apparently unintentional opioid overdoses.

Aaron said his parents, teachers, and non-bodybuilding friends were unaware of this history. He claimed his parents were proud that their son had apparently eschewed drugs and alcohol to pursue a healthy athletic lifestyle.

RECOGNIZING AAS USE

In our experience with treating substance abusers, we find that AAS users may be the least likely to disclose their drug use to clinicians. In a recent study,¹ 20 of 36 AAS users (56%) reported they had never revealed their AAS use to any physician. When asked to rate their trust in sources of information about AAS, 17 of 42 AAS users (40%) said they trusted information from their drug dealers at least as much as information from any physician they had seen.

Some expressed contempt for physicians as “geeks” or “pencil-necks” who could not comprehend the body-building lifestyle. They gave doctors high marks on knowledge of tobacco, alcohol, and ordinary “street drugs” but much lower ratings on AAS knowledge. Other investigators have shown that many clinicians are unfamiliar with AAS.^2,3

AAS users embrace these beliefs for two other reasons. First, to admit to AAS use is to admit that one’s muscularity and physical prowess is the result of taking a drug; there is no comparable motivation to withhold information about, say, one’s use of marijuana or cocaine.

Second, AAS users are much less likely than other substance abusers to view their behavior as pathologic. We have argued that our culture is partially to blame.⁴ Americans pay to watch 300-lb football linemen and AAS-using movie stars. Makers of cars, computers, and electronics do not hesitate to advertise their products as “on steroids,” but they would never claim their products were “on cocaine.” In this climate, it is easy to forget that AAS use is an illicit substance abuse.

Box 2

Table 2

Clues to possible AAS use in men

To overcome these treatment obstacles, we recommend that you:

• Become as knowledgeable about AAS use as you are about other forms of substance abuse (see Related resources).
• Approach AAS users as you would any other substance abusers—as individuals at risk for potentially serious medical and psychiatric consequences.
• Maintain a high index of suspicion when evaluating any muscular young male patient, even if he initially denies AAS use.

AAS use can often be suspected by looking at the patient as he walks in the door. Using what we call the “fat-free mass index” (FFMI) to calculate muscularity (Box 2), we have shown that a lean man can achieve only a certain amount of muscularity without using drugs.⁵ Although this finding needs to be replicated elsewhere, in our experience a man is almost certainly lying if he:

• is relatively lean (with approximately 10% body fat)
• displays an FFMI >26
• and claims he has not used drugs.

If a patient has an elevated FFMI and other cues suggesting AAS use (Table 2), gently but persistently question him if he denies using these drugs.

TREATING AAS-ASSOCIATED SYNDROMES

When you have established a history of AAS use, you will be far better prepared to anticipate and possibly treat its associated syndromes. Discussion of these effects is beyond the scope of this paper; for details, see reviews of AAS-associated medical effects,^3,6 psychiatric effects,^6,7 and general treatment principles.⁸ We focus here on the four scenarios clinicians encounter most often in practice and offer some pragmatic suggestions.

Forensic cases. AAS users almost never voluntarily seek help to stop their drug use. Such a request would be somewhat analogous to a girl with anorexia nervosa voluntarily asking for help to gain weight. We are unaware of any rehabilitation centers, clinics, 12-step programs, or the like for AAS users—there is no demand for them.

Thus, an AAS user may first come to clinical attention through legal channels. For example, if an AAS user committed a violent crime while experiencing hypomanic effects from these drugs, he might be required to undergo random urine testing as a condition of probation. This may be reasonable, provided that the tests are unannounced and urine is always collected under direct observation.

Monitoring clinicians may serve as little better than policemen, although sometimes it is possible to forge an alliance with the patient.

Depression. Exogenous AAS administration suppresses endogenous testosterone production through feedback mechanisms involving the hypothalamic-pituitary-testicular axis.^3,6 Thus, during a long cycle, the user’s testes may shrink to half their normal size and stop producing testosterone and spermatozoa.

If the user then stops AAS rapidly, he may plunge into a profoundly hypogonadal state associated with symptoms of major depression. In a field study of 77 steroid users (71 male and 6 female), 6 (7.8%) reported they attempted suicide during AAS withdrawal.⁹ Depression associated with AAS withdrawal may prompt users to resume AAS quickly, triggering a syndrome of AAS dependence.^6,10,11

Fortunately, AAS-withdrawal depression is usually self-limited and responds—in our experience and that of others¹²—to standard antidepressants. We recommend aggressively treating such depressions, as doing so may prevent resumption of AAS use and eventual AAS dependence.

Body-image disorders. AAS users often report body-image disorders, especially muscle dysmorphia—a form of body dysmorphic disorder where individuals become preoccupied with the belief that they are not adequately muscular.^13,14 Anxieties about muscularity are a risk factor for subsequent AAS use¹⁵ and a major contributor to AAS dependence.^8,11

Body dysmorphic disorder responds to pharmacologic and cognitive-behavioral interventions.^3,16 Young men showing pathologic concerns about their muscularity or displaying related body-image pathology may benefit from prompt treatment before they are tempted to use AAS.

Progression to opioid dependence. An ominous development among American¹⁷ and British¹⁸ AAS users is a growing tendency to use opioids. In two studies of individuals with opioid dependence,^19,20 7% to 9% reported beginning as AAS users, then learning about opioids from fellow bodybuilders and often buying their first illicit opioids from the person who had sold them AAS. Most learned as teenagers to use needles to inject AAS intramuscularly, so beginning to using opioids intravenously was only a small step.

In the last 5 years, we have become anecdotally aware of numerous AAS users who developed heroin addiction requiring repeated inpatient detoxification or who died of unintentional opioid overdoses. We suspect this phenomenon is under-recognized and urge clinicians to watch for it.

Related resources

• Pope HG Jr, Brower KJ. Anabolic-androgenic steroid abuse. In: Sadock BJ, Sadock VA (eds). Comprehensive textbook of psychiatry (8th ed). Philadelphia: Lippincott Williams & Wilkins (in press).
• Yesalis CE (ed). Anabolic steroids in sport and exercise (2nd ed). Champaign, IL: Human Kinetics, 2000.
• The Taylor Hooton Foundation. Started by the father of a high school athlete who committed suicide during a depressive episode apparently precipitated by AAS withdrawal. Includes links to related Web sites. http://www.taylorhooton.org/about.asp. Accessed Nov. 10, 2004.

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

It’s the holiday season. You’ve got better things to think about than your computers’ security and data accessibility.

Many “tech toys” can help secure your computers and let you August 2004.)

Still, notebook computers are easy to steal, and desktop computers can be stolen or infiltrated. To secure your data, you need encryption to supplement password-restricted access. Also, you should regularly save and copy data in an alternate location.

Solutions. The Authenex HDLock is a universal serial bus (USB) key that encrypts your hard drive’s contents. The device uses “two-factor authentication,” a security method that blocks access until you provide something you have (the key) and something you know (the password). Without both the key and password, encrypted data cannot be accessed. If you lose the key or forget the password, an online support section provides a one-time password.

If more than one person needs access, the Silex Technology FUS-200N USB fingerprint reader is more appropriate. This device and its accompanying software:

• provide secured access for multiple users
• encrypt files and folders
• and force users to show their fingerprints before allowing access to selected programs, such as your medical records program.

The FUS-200N is more accurate than other fingerprint recognition devices because it uses electricity rather than light patterns to record fingerprints.

Another option, the DiskOnKey Classic 2.0 USB flash drive, includes a small built-in microprocessor that lets you run your electronic medical records program or other applications from the key. CapMed uses this key to allow consumers to store their medical information on the Personal HealthKey device.

See Table 1 for more information on these security enhancement programs.

Storage

Problem. When shuttling between home and office, it makes sense to carry files on a USB flash drive. These devices are great for transporting documents because the computer sees a flash drive as just another disk drive.

Flash drives, however, are easily lost—and no psychiatrist wants to be sued for losing sensitive information.

Solutions. Some USB flash drives, such as the Sony Micro Vault, offer password protection for files and folders. Another option, the Trek Thumbdrive Touch, has a built-in fingerprint reader to guard your data (Table 2).

If you already have a favorite USB flash drive, add quick- and easy-to-use encryption software to your home and office computers. AxCrypt, a free Windows-compatible program, lets you encrypt and decrypt files with a simple right-mouse click. A similar program, Fairly Good Privacy, is Mac OS-compatible (Table 1).

Synchronization/remote access

Problem. You need to access critical files in both your office and home computer from either location.

Solutions. Internet-based synchronization services can simultaneously update files on both computers (Table 3). fusionOne Plus, for example, keeps files, contacts, e-mail, and calendars in sync. Contacts and calendars can also be accessed and synchronized via some mobile phones. What’s more, FusionOne Plus provides an online backup copy of your files.

LogMeIn provides free secured remote access to your office files from any computer. After your install a server program on the host computer, you can run programs and open files via a Web browser. The LogMeIn Pro version, which costs $12.95 per month, adds the ability to synchronize computers, transfer files, and distribute them over the Internet.

GoToMyPC allows you to access files and programs on a host computer and also allows Pocket PC PDA viewing as well as remote printing, but it does not provide file synchronization.

For direct computer-to-computer connection, pcAnywhere and RealVNC allow you to access files and programs on the host computer. Unlike GoToMyPC and LogMeIn, however, these programs do not offer additional password protection by verifying the user’s account.

The $200 PC Anywhere program will encrypt data between computers, whereas the free RealVNC program only provides password security. PC Anywhere synchronizes file, whereas RealVNC only helps you run the remote computer. RealVNC has enterprise versions and is developing a personal version with additional features.

Online storage can help you avoid synchronization issues. Xdrive has desktop software that creates a virtual drive for storage. When starting your computer, the software will automatically connect via the Internet to your Xdrive account. You can also change the settings of your electronic medical records program or document editing software to save data only to this Internet drive. This way, your data will always be backed up to a safe location even if your home or office computer is stolen.

Table 1

Programs, services that enhance data security

Table 2

Secure flash drives

Table 3

Programs, services that facilitate remote data access

Disclosure

Dr. Luo reports no financial relationship with any company whose products are mentioned in this article. The opinions expressed by Dr. Luo in this column are his own and do not necessarily reflect those of Current Psychiatry.

poll here

It’s the holiday season. You’ve got better things to think about than your computers’ security and data accessibility.

Many “tech toys” can help secure your computers and let you August 2004.)

Still, notebook computers are easy to steal, and desktop computers can be stolen or infiltrated. To secure your data, you need encryption to supplement password-restricted access. Also, you should regularly save and copy data in an alternate location.

Solutions. The Authenex HDLock is a universal serial bus (USB) key that encrypts your hard drive’s contents. The device uses “two-factor authentication,” a security method that blocks access until you provide something you have (the key) and something you know (the password). Without both the key and password, encrypted data cannot be accessed. If you lose the key or forget the password, an online support section provides a one-time password.

If more than one person needs access, the Silex Technology FUS-200N USB fingerprint reader is more appropriate. This device and its accompanying software:

• provide secured access for multiple users
• encrypt files and folders
• and force users to show their fingerprints before allowing access to selected programs, such as your medical records program.

The FUS-200N is more accurate than other fingerprint recognition devices because it uses electricity rather than light patterns to record fingerprints.

Another option, the DiskOnKey Classic 2.0 USB flash drive, includes a small built-in microprocessor that lets you run your electronic medical records program or other applications from the key. CapMed uses this key to allow consumers to store their medical information on the Personal HealthKey device.

See Table 1 for more information on these security enhancement programs.

Storage

Problem. When shuttling between home and office, it makes sense to carry files on a USB flash drive. These devices are great for transporting documents because the computer sees a flash drive as just another disk drive.

Flash drives, however, are easily lost—and no psychiatrist wants to be sued for losing sensitive information.

Solutions. Some USB flash drives, such as the Sony Micro Vault, offer password protection for files and folders. Another option, the Trek Thumbdrive Touch, has a built-in fingerprint reader to guard your data (Table 2).

If you already have a favorite USB flash drive, add quick- and easy-to-use encryption software to your home and office computers. AxCrypt, a free Windows-compatible program, lets you encrypt and decrypt files with a simple right-mouse click. A similar program, Fairly Good Privacy, is Mac OS-compatible (Table 1).

Synchronization/remote access

Problem. You need to access critical files in both your office and home computer from either location.

Solutions. Internet-based synchronization services can simultaneously update files on both computers (Table 3). fusionOne Plus, for example, keeps files, contacts, e-mail, and calendars in sync. Contacts and calendars can also be accessed and synchronized via some mobile phones. What’s more, FusionOne Plus provides an online backup copy of your files.

LogMeIn provides free secured remote access to your office files from any computer. After your install a server program on the host computer, you can run programs and open files via a Web browser. The LogMeIn Pro version, which costs $12.95 per month, adds the ability to synchronize computers, transfer files, and distribute them over the Internet.

GoToMyPC allows you to access files and programs on a host computer and also allows Pocket PC PDA viewing as well as remote printing, but it does not provide file synchronization.

For direct computer-to-computer connection, pcAnywhere and RealVNC allow you to access files and programs on the host computer. Unlike GoToMyPC and LogMeIn, however, these programs do not offer additional password protection by verifying the user’s account.

The $200 PC Anywhere program will encrypt data between computers, whereas the free RealVNC program only provides password security. PC Anywhere synchronizes file, whereas RealVNC only helps you run the remote computer. RealVNC has enterprise versions and is developing a personal version with additional features.

Online storage can help you avoid synchronization issues. Xdrive has desktop software that creates a virtual drive for storage. When starting your computer, the software will automatically connect via the Internet to your Xdrive account. You can also change the settings of your electronic medical records program or document editing software to save data only to this Internet drive. This way, your data will always be backed up to a safe location even if your home or office computer is stolen.

Table 1

Programs, services that enhance data security

Table 2

Secure flash drives

Table 3

Programs, services that facilitate remote data access

Disclosure

Dr. Luo reports no financial relationship with any company whose products are mentioned in this article. The opinions expressed by Dr. Luo in this column are his own and do not necessarily reflect those of Current Psychiatry.

poll here

It’s the holiday season. You’ve got better things to think about than your computers’ security and data accessibility.

Many “tech toys” can help secure your computers and let you August 2004.)

Still, notebook computers are easy to steal, and desktop computers can be stolen or infiltrated. To secure your data, you need encryption to supplement password-restricted access. Also, you should regularly save and copy data in an alternate location.

Solutions. The Authenex HDLock is a universal serial bus (USB) key that encrypts your hard drive’s contents. The device uses “two-factor authentication,” a security method that blocks access until you provide something you have (the key) and something you know (the password). Without both the key and password, encrypted data cannot be accessed. If you lose the key or forget the password, an online support section provides a one-time password.

If more than one person needs access, the Silex Technology FUS-200N USB fingerprint reader is more appropriate. This device and its accompanying software:

• provide secured access for multiple users
• encrypt files and folders
• and force users to show their fingerprints before allowing access to selected programs, such as your medical records program.

The FUS-200N is more accurate than other fingerprint recognition devices because it uses electricity rather than light patterns to record fingerprints.

Another option, the DiskOnKey Classic 2.0 USB flash drive, includes a small built-in microprocessor that lets you run your electronic medical records program or other applications from the key. CapMed uses this key to allow consumers to store their medical information on the Personal HealthKey device.

See Table 1 for more information on these security enhancement programs.

Storage

Problem. When shuttling between home and office, it makes sense to carry files on a USB flash drive. These devices are great for transporting documents because the computer sees a flash drive as just another disk drive.

Flash drives, however, are easily lost—and no psychiatrist wants to be sued for losing sensitive information.

Solutions. Some USB flash drives, such as the Sony Micro Vault, offer password protection for files and folders. Another option, the Trek Thumbdrive Touch, has a built-in fingerprint reader to guard your data (Table 2).

If you already have a favorite USB flash drive, add quick- and easy-to-use encryption software to your home and office computers. AxCrypt, a free Windows-compatible program, lets you encrypt and decrypt files with a simple right-mouse click. A similar program, Fairly Good Privacy, is Mac OS-compatible (Table 1).

Synchronization/remote access

Problem. You need to access critical files in both your office and home computer from either location.

Solutions. Internet-based synchronization services can simultaneously update files on both computers (Table 3). fusionOne Plus, for example, keeps files, contacts, e-mail, and calendars in sync. Contacts and calendars can also be accessed and synchronized via some mobile phones. What’s more, FusionOne Plus provides an online backup copy of your files.

LogMeIn provides free secured remote access to your office files from any computer. After your install a server program on the host computer, you can run programs and open files via a Web browser. The LogMeIn Pro version, which costs $12.95 per month, adds the ability to synchronize computers, transfer files, and distribute them over the Internet.

GoToMyPC allows you to access files and programs on a host computer and also allows Pocket PC PDA viewing as well as remote printing, but it does not provide file synchronization.

For direct computer-to-computer connection, pcAnywhere and RealVNC allow you to access files and programs on the host computer. Unlike GoToMyPC and LogMeIn, however, these programs do not offer additional password protection by verifying the user’s account.

The $200 PC Anywhere program will encrypt data between computers, whereas the free RealVNC program only provides password security. PC Anywhere synchronizes file, whereas RealVNC only helps you run the remote computer. RealVNC has enterprise versions and is developing a personal version with additional features.

Online storage can help you avoid synchronization issues. Xdrive has desktop software that creates a virtual drive for storage. When starting your computer, the software will automatically connect via the Internet to your Xdrive account. You can also change the settings of your electronic medical records program or document editing software to save data only to this Internet drive. This way, your data will always be backed up to a safe location even if your home or office computer is stolen.

Table 1

Programs, services that enhance data security

Table 2

Secure flash drives

Table 3

Programs, services that facilitate remote data access

Disclosure

Dr. Luo reports no financial relationship with any company whose products are mentioned in this article. The opinions expressed by Dr. Luo in this column are his own and do not necessarily reflect those of Current Psychiatry.

poll here

Can knowing a patient’s environmental stressors and family history help us more quickly diagnose bipolar mania?

Kessing et al¹ studied patients who were diagnosed as having mania or a mixed episode during their first psychiatric hospitalization. They found that certain life events were associated with these diagnoses, reinforcing the belief that environment to some extent influences psychiatric illness.

Although more research is needed, this finding may help psychiatrists reach a diagnosis of bipolar mania when the clinical course is unclear. Life events that may contribute to bipolar mania are remembered with the mnemonic MANIAS:

• Marital status change. The patient recently was married, divorced, or lost a significant other to death.
• Family Admission. The patient’s mother, father, or sibling was hospitalized at some point for a psychiatric disorder. It does not seem to matter whether the patient remembers the family member’s hospitalization.
• No work. The patient is unemployed.
• Inability to work. The patient is disabled or collects disability benefits.
• Abstaining from relationships. The patient does not have a significant other.
• Suicide was completed by the patient’s mother, father, or sibling. It does not matter how long ago or at what point in the patient’s life the suicide happened.

Can knowing a patient’s environmental stressors and family history help us more quickly diagnose bipolar mania?

Kessing et al¹ studied patients who were diagnosed as having mania or a mixed episode during their first psychiatric hospitalization. They found that certain life events were associated with these diagnoses, reinforcing the belief that environment to some extent influences psychiatric illness.

Although more research is needed, this finding may help psychiatrists reach a diagnosis of bipolar mania when the clinical course is unclear. Life events that may contribute to bipolar mania are remembered with the mnemonic MANIAS:

• Marital status change. The patient recently was married, divorced, or lost a significant other to death.
• Family Admission. The patient’s mother, father, or sibling was hospitalized at some point for a psychiatric disorder. It does not seem to matter whether the patient remembers the family member’s hospitalization.
• No work. The patient is unemployed.
• Inability to work. The patient is disabled or collects disability benefits.
• Abstaining from relationships. The patient does not have a significant other.
• Suicide was completed by the patient’s mother, father, or sibling. It does not matter how long ago or at what point in the patient’s life the suicide happened.

Can knowing a patient’s environmental stressors and family history help us more quickly diagnose bipolar mania?

Kessing et al¹ studied patients who were diagnosed as having mania or a mixed episode during their first psychiatric hospitalization. They found that certain life events were associated with these diagnoses, reinforcing the belief that environment to some extent influences psychiatric illness.

Although more research is needed, this finding may help psychiatrists reach a diagnosis of bipolar mania when the clinical course is unclear. Life events that may contribute to bipolar mania are remembered with the mnemonic MANIAS:

• Marital status change. The patient recently was married, divorced, or lost a significant other to death.
• Family Admission. The patient’s mother, father, or sibling was hospitalized at some point for a psychiatric disorder. It does not seem to matter whether the patient remembers the family member’s hospitalization.
• No work. The patient is unemployed.
• Inability to work. The patient is disabled or collects disability benefits.
• Abstaining from relationships. The patient does not have a significant other.
• Suicide was completed by the patient’s mother, father, or sibling. It does not matter how long ago or at what point in the patient’s life the suicide happened.

“Prudent prescribing: Intelligent use of lab tests and other diagnostics” (Current Psychiatry, October 2004) effectively reviewed key principles for using diagnostic and monitoring tools in psychiatry.

At a time when psychologists in some states have gained or may soon gain prescribing privileges, we as psychiatrists must embrace our medical training and apply our understanding of laboratory testing and diagnostic studies to our patients’ advantage. Outpatient laboratory testing is often difficult to coordinate, mostly because we traditionally have saved such tests for rare and unusual cases. As our use of such testing expands, we will more efficiently coordinate sample collection and report results to provide safe, effective medical care.

Also, more laboratory tests will soon be available. For example, the FDA recently approved a carbohydrate-deficient transferrin test to help clinicians detect or monitor an alcohol use disorder.

Regular and substantial alcohol use affects liver metabolism and transferrin synthesis, causing an abnormal, carbohydrate-deficient form of transferrin to be released into the bloodstream. Abnormal transferrin is measured as a percentage of overall transferrin in the bloodstream (%CDT). Any increase in %CDT above the normal range indicates a clinically significant increase in drinking. We consider 2.6 the upper limit of normal.

The test detects %CDT elevations in patients who have consumed 60 to 80 grams of alcohol (4 to 6 standard drinks) daily for 2 to 3 weeks. The test offers 90% to 95% specificity, with false elevations coming from inborn errors of glycoprotein metabolism (1% to 2% of the population) and in some cases from severe liver disease. Sensitivity is approximately 60% but improves significantly when the test is correlated with gamma-glutamyltransferase (GGT) testing and other serum markers.

Jeffrey S. Cluver, MD
Assistant professor of psychiatry
Ralph H. Johnson Veterans Affairs
Medical Center Medical University of South Carolina,
Charleston

References

1. Anton RF, Lieber C, Tabakoff B, for the CDTect Study Group. Carbohydrate-deficient transferrin and gamma-glutamyltransferase for the detection and monitoring of alcohol use: results from a multisite study. Alcohol Clin Exp Res 2002;26:1215–22.
   
2. Conigrave KM, Degenhardt LJ, Whitfield JB, et al, for the WHO/ ISBRA Study Group. CDT, GGT, and AST as markers of alcohol use: the WHO/ISBRA Collaborative Project. Alcohol Clin Exp Res 2002;26:332–9.
   

“Prudent prescribing: Intelligent use of lab tests and other diagnostics” (Current Psychiatry, October 2004) effectively reviewed key principles for using diagnostic and monitoring tools in psychiatry.

At a time when psychologists in some states have gained or may soon gain prescribing privileges, we as psychiatrists must embrace our medical training and apply our understanding of laboratory testing and diagnostic studies to our patients’ advantage. Outpatient laboratory testing is often difficult to coordinate, mostly because we traditionally have saved such tests for rare and unusual cases. As our use of such testing expands, we will more efficiently coordinate sample collection and report results to provide safe, effective medical care.

Also, more laboratory tests will soon be available. For example, the FDA recently approved a carbohydrate-deficient transferrin test to help clinicians detect or monitor an alcohol use disorder.

Regular and substantial alcohol use affects liver metabolism and transferrin synthesis, causing an abnormal, carbohydrate-deficient form of transferrin to be released into the bloodstream. Abnormal transferrin is measured as a percentage of overall transferrin in the bloodstream (%CDT). Any increase in %CDT above the normal range indicates a clinically significant increase in drinking. We consider 2.6 the upper limit of normal.

The test detects %CDT elevations in patients who have consumed 60 to 80 grams of alcohol (4 to 6 standard drinks) daily for 2 to 3 weeks. The test offers 90% to 95% specificity, with false elevations coming from inborn errors of glycoprotein metabolism (1% to 2% of the population) and in some cases from severe liver disease. Sensitivity is approximately 60% but improves significantly when the test is correlated with gamma-glutamyltransferase (GGT) testing and other serum markers.

Jeffrey S. Cluver, MD
Assistant professor of psychiatry
Ralph H. Johnson Veterans Affairs
Medical Center Medical University of South Carolina,
Charleston

References

1. Anton RF, Lieber C, Tabakoff B, for the CDTect Study Group. Carbohydrate-deficient transferrin and gamma-glutamyltransferase for the detection and monitoring of alcohol use: results from a multisite study. Alcohol Clin Exp Res 2002;26:1215–22.
   
2. Conigrave KM, Degenhardt LJ, Whitfield JB, et al, for the WHO/ ISBRA Study Group. CDT, GGT, and AST as markers of alcohol use: the WHO/ISBRA Collaborative Project. Alcohol Clin Exp Res 2002;26:332–9.
   

“Prudent prescribing: Intelligent use of lab tests and other diagnostics” (Current Psychiatry, October 2004) effectively reviewed key principles for using diagnostic and monitoring tools in psychiatry.

At a time when psychologists in some states have gained or may soon gain prescribing privileges, we as psychiatrists must embrace our medical training and apply our understanding of laboratory testing and diagnostic studies to our patients’ advantage. Outpatient laboratory testing is often difficult to coordinate, mostly because we traditionally have saved such tests for rare and unusual cases. As our use of such testing expands, we will more efficiently coordinate sample collection and report results to provide safe, effective medical care.

Also, more laboratory tests will soon be available. For example, the FDA recently approved a carbohydrate-deficient transferrin test to help clinicians detect or monitor an alcohol use disorder.

Regular and substantial alcohol use affects liver metabolism and transferrin synthesis, causing an abnormal, carbohydrate-deficient form of transferrin to be released into the bloodstream. Abnormal transferrin is measured as a percentage of overall transferrin in the bloodstream (%CDT). Any increase in %CDT above the normal range indicates a clinically significant increase in drinking. We consider 2.6 the upper limit of normal.

The test detects %CDT elevations in patients who have consumed 60 to 80 grams of alcohol (4 to 6 standard drinks) daily for 2 to 3 weeks. The test offers 90% to 95% specificity, with false elevations coming from inborn errors of glycoprotein metabolism (1% to 2% of the population) and in some cases from severe liver disease. Sensitivity is approximately 60% but improves significantly when the test is correlated with gamma-glutamyltransferase (GGT) testing and other serum markers.

Jeffrey S. Cluver, MD
Assistant professor of psychiatry
Ralph H. Johnson Veterans Affairs
Medical Center Medical University of South Carolina,
Charleston

References

1. Anton RF, Lieber C, Tabakoff B, for the CDTect Study Group. Carbohydrate-deficient transferrin and gamma-glutamyltransferase for the detection and monitoring of alcohol use: results from a multisite study. Alcohol Clin Exp Res 2002;26:1215–22.
   
2. Conigrave KM, Degenhardt LJ, Whitfield JB, et al, for the WHO/ ISBRA Study Group. CDT, GGT, and AST as markers of alcohol use: the WHO/ISBRA Collaborative Project. Alcohol Clin Exp Res 2002;26:332–9.
   

When Confucius was asked what he would do first should he become minister of the Kingdom of Wei, he replied: “What is necessary is to rectify names.” He further stated, “If names be not correct, language is not in accordance with the truth of things. If language be not in accordance with the truth of things, affairs cannot be carried on to success” (from The Analects of Confucius, James R. Ware translation, 1980: book 13, verse 3).

I am reminded of this aphorism by Dr. Leslie Citrome’s article, “Treatment-resistant schizophrenia: What role for mood stabilizers?”. This article highlights several psychotropic classes whose names badly need rectification, including “mood stabilizers,” “anticonvulsants,” and “antipsychotics.”

A compound’s first use tends to give it its functional name. Sodium valproate was first used to treat seizures, so it is called an anticonvulsant. Lithium was first used to stabilize mood, so it is called a mood stabilizer. Sometimes valproate is now called a mood stabilizer as well. As Dr. Citrome demonstrates, both compounds also may have efficacy as adjuncts in treating schizophrenia. So do we call them antipsychotics, too?

Each compound has a variety of effects, of course, and we start to diverge from the “truth of things” when we get locked into thinking of a compound in just one way. We also make it less likely that affairs can “be carried on to success” for our patients.

When Confucius was asked what he would do first should he become minister of the Kingdom of Wei, he replied: “What is necessary is to rectify names.” He further stated, “If names be not correct, language is not in accordance with the truth of things. If language be not in accordance with the truth of things, affairs cannot be carried on to success” (from The Analects of Confucius, James R. Ware translation, 1980: book 13, verse 3).

I am reminded of this aphorism by Dr. Leslie Citrome’s article, “Treatment-resistant schizophrenia: What role for mood stabilizers?”. This article highlights several psychotropic classes whose names badly need rectification, including “mood stabilizers,” “anticonvulsants,” and “antipsychotics.”

A compound’s first use tends to give it its functional name. Sodium valproate was first used to treat seizures, so it is called an anticonvulsant. Lithium was first used to stabilize mood, so it is called a mood stabilizer. Sometimes valproate is now called a mood stabilizer as well. As Dr. Citrome demonstrates, both compounds also may have efficacy as adjuncts in treating schizophrenia. So do we call them antipsychotics, too?

Each compound has a variety of effects, of course, and we start to diverge from the “truth of things” when we get locked into thinking of a compound in just one way. We also make it less likely that affairs can “be carried on to success” for our patients.

When Confucius was asked what he would do first should he become minister of the Kingdom of Wei, he replied: “What is necessary is to rectify names.” He further stated, “If names be not correct, language is not in accordance with the truth of things. If language be not in accordance with the truth of things, affairs cannot be carried on to success” (from The Analects of Confucius, James R. Ware translation, 1980: book 13, verse 3).

I am reminded of this aphorism by Dr. Leslie Citrome’s article, “Treatment-resistant schizophrenia: What role for mood stabilizers?”. This article highlights several psychotropic classes whose names badly need rectification, including “mood stabilizers,” “anticonvulsants,” and “antipsychotics.”

A compound’s first use tends to give it its functional name. Sodium valproate was first used to treat seizures, so it is called an anticonvulsant. Lithium was first used to stabilize mood, so it is called a mood stabilizer. Sometimes valproate is now called a mood stabilizer as well. As Dr. Citrome demonstrates, both compounds also may have efficacy as adjuncts in treating schizophrenia. So do we call them antipsychotics, too?

Each compound has a variety of effects, of course, and we start to diverge from the “truth of things” when we get locked into thinking of a compound in just one way. We also make it less likely that affairs can “be carried on to success” for our patients.

Patients with schizophrenia or bipolar disorder face a higher risk of premature death, compared with the general population. Their overall mortality rate is elevated not only by higher suicide rates but also by higher rates of medical comorbidities, including obesity, diabetes mellitus, cardiovascular and pulmonary diseases, HIV infection, and cancer.^1,2

Schizophrenia and bipolar disorder are also frequently complicated by psychiatric comorbidities including alcohol and substance use disorders (such as nicotine dependence), anxiety disorders, and eating disorders (such as binge eating).^3,4 Even so, the impact of psychiatric comorbidity on medical morbidity and mortality has not been adequately investigated and has—until rather recently—received little attention from clinical researchers.

Within the past 5 years or so, epidemiologic and population studies have shown increased morbidity and mortality from medical illnesses in patients with serious and persistent mental illness.^5,6 These findings have sparked renewed interest in behavioral, biological, and psychosocial factors associated with schizophrenia and bipolar disorder that may contribute to comorbid medical illnesses. These factors include:

• negative and depressive symptoms
• physical inactivity and poor diet
• hypothalamic-pituitary-adrenal axis dysregulation associated with acute psychotic and affective episodes
• amotivation
• social isolation
• limited access to primary and preventive health care.⁷

The degree to which these factors may elevate medical comorbidity rates in patients with Commentary these serious psychiatric illnesses has not been well-studied or described.

TREATMENT IMPLICATIONS

These observations raise concerns about safe and effective use of medications by patients with schizophrenia or bipolar disorder as well as medical illness. Issues for clinicians to consider include:

• possible pharmacokinetic and pharmacodynamic interactions in patients taking concomitant medications for psychiatric and medical illnesses
• potential beneficial and adverse effects of psychotropics on medical illnesses
• and—conversely—potential beneficial and adverse effects on mood and psychotic disorders of medications used to treat medical illnesses.

Being aware of metabolic effects when prescribing psychotropics is not a new idea. Lithium, for example, has long been known to cause weight gain, suppress thyroid hormone, and interact with thiazide diuretics when used to treat bipolar disorder. Thus, therapeutic blood monitoring is recommended for patients receiving acute and maintenance lithium therapy.

More recently, atypical antipsychotics such as olanzapine and clozapine (and risperidone and quetiapine to a lesser extent) have been shown to produce substantial weight gain and other metabolic effects that increase the risk of diabetes and cardiovascular disease.⁷ As a result, the American Diabetes Association—along with the American Psychiatric Association and other groups—now recommends that psychiatrists and other physicians monitor patients’ body weight and body mass index, vital signs, serum glucose, and lipids when prescribing these agents.^7-11 Careful monitoring should improve the medical care of patients with schizophrenia and bipolar disorder and help protect them from the medical risks associated with overweight and obesity.

Similar precautions are needed when schizophrenia and bipolar disorder co-occur with other medical illnesses treated by complex pharmacologic regimens, such as pulmonary disease, cancer, and HIV. Three points to keep in mind are:

• careful selection of treatments for co-occurring medical illnesses, considering potential effects on the primary psychiatric disorder
• the impact of psychotropics on patients’ medical illnesses
• and the potential for drug interactions.

Patients with schizophrenia or bipolar disorder face a higher risk of premature death, compared with the general population. Their overall mortality rate is elevated not only by higher suicide rates but also by higher rates of medical comorbidities, including obesity, diabetes mellitus, cardiovascular and pulmonary diseases, HIV infection, and cancer.^1,2

Schizophrenia and bipolar disorder are also frequently complicated by psychiatric comorbidities including alcohol and substance use disorders (such as nicotine dependence), anxiety disorders, and eating disorders (such as binge eating).^3,4 Even so, the impact of psychiatric comorbidity on medical morbidity and mortality has not been adequately investigated and has—until rather recently—received little attention from clinical researchers.

Within the past 5 years or so, epidemiologic and population studies have shown increased morbidity and mortality from medical illnesses in patients with serious and persistent mental illness.^5,6 These findings have sparked renewed interest in behavioral, biological, and psychosocial factors associated with schizophrenia and bipolar disorder that may contribute to comorbid medical illnesses. These factors include:

• negative and depressive symptoms
• physical inactivity and poor diet
• hypothalamic-pituitary-adrenal axis dysregulation associated with acute psychotic and affective episodes
• amotivation
• social isolation
• limited access to primary and preventive health care.⁷

The degree to which these factors may elevate medical comorbidity rates in patients with Commentary these serious psychiatric illnesses has not been well-studied or described.

TREATMENT IMPLICATIONS

These observations raise concerns about safe and effective use of medications by patients with schizophrenia or bipolar disorder as well as medical illness. Issues for clinicians to consider include:

• possible pharmacokinetic and pharmacodynamic interactions in patients taking concomitant medications for psychiatric and medical illnesses
• potential beneficial and adverse effects of psychotropics on medical illnesses
• and—conversely—potential beneficial and adverse effects on mood and psychotic disorders of medications used to treat medical illnesses.

Being aware of metabolic effects when prescribing psychotropics is not a new idea. Lithium, for example, has long been known to cause weight gain, suppress thyroid hormone, and interact with thiazide diuretics when used to treat bipolar disorder. Thus, therapeutic blood monitoring is recommended for patients receiving acute and maintenance lithium therapy.

More recently, atypical antipsychotics such as olanzapine and clozapine (and risperidone and quetiapine to a lesser extent) have been shown to produce substantial weight gain and other metabolic effects that increase the risk of diabetes and cardiovascular disease.⁷ As a result, the American Diabetes Association—along with the American Psychiatric Association and other groups—now recommends that psychiatrists and other physicians monitor patients’ body weight and body mass index, vital signs, serum glucose, and lipids when prescribing these agents.^7-11 Careful monitoring should improve the medical care of patients with schizophrenia and bipolar disorder and help protect them from the medical risks associated with overweight and obesity.

Similar precautions are needed when schizophrenia and bipolar disorder co-occur with other medical illnesses treated by complex pharmacologic regimens, such as pulmonary disease, cancer, and HIV. Three points to keep in mind are:

• careful selection of treatments for co-occurring medical illnesses, considering potential effects on the primary psychiatric disorder
• the impact of psychotropics on patients’ medical illnesses
• and the potential for drug interactions.

Patients with schizophrenia or bipolar disorder face a higher risk of premature death, compared with the general population. Their overall mortality rate is elevated not only by higher suicide rates but also by higher rates of medical comorbidities, including obesity, diabetes mellitus, cardiovascular and pulmonary diseases, HIV infection, and cancer.^1,2

Schizophrenia and bipolar disorder are also frequently complicated by psychiatric comorbidities including alcohol and substance use disorders (such as nicotine dependence), anxiety disorders, and eating disorders (such as binge eating).^3,4 Even so, the impact of psychiatric comorbidity on medical morbidity and mortality has not been adequately investigated and has—until rather recently—received little attention from clinical researchers.

Within the past 5 years or so, epidemiologic and population studies have shown increased morbidity and mortality from medical illnesses in patients with serious and persistent mental illness.^5,6 These findings have sparked renewed interest in behavioral, biological, and psychosocial factors associated with schizophrenia and bipolar disorder that may contribute to comorbid medical illnesses. These factors include:

• negative and depressive symptoms
• physical inactivity and poor diet
• hypothalamic-pituitary-adrenal axis dysregulation associated with acute psychotic and affective episodes
• amotivation
• social isolation
• limited access to primary and preventive health care.⁷

The degree to which these factors may elevate medical comorbidity rates in patients with Commentary these serious psychiatric illnesses has not been well-studied or described.

TREATMENT IMPLICATIONS

These observations raise concerns about safe and effective use of medications by patients with schizophrenia or bipolar disorder as well as medical illness. Issues for clinicians to consider include:

• possible pharmacokinetic and pharmacodynamic interactions in patients taking concomitant medications for psychiatric and medical illnesses
• potential beneficial and adverse effects of psychotropics on medical illnesses
• and—conversely—potential beneficial and adverse effects on mood and psychotic disorders of medications used to treat medical illnesses.

Being aware of metabolic effects when prescribing psychotropics is not a new idea. Lithium, for example, has long been known to cause weight gain, suppress thyroid hormone, and interact with thiazide diuretics when used to treat bipolar disorder. Thus, therapeutic blood monitoring is recommended for patients receiving acute and maintenance lithium therapy.

More recently, atypical antipsychotics such as olanzapine and clozapine (and risperidone and quetiapine to a lesser extent) have been shown to produce substantial weight gain and other metabolic effects that increase the risk of diabetes and cardiovascular disease.⁷ As a result, the American Diabetes Association—along with the American Psychiatric Association and other groups—now recommends that psychiatrists and other physicians monitor patients’ body weight and body mass index, vital signs, serum glucose, and lipids when prescribing these agents.^7-11 Careful monitoring should improve the medical care of patients with schizophrenia and bipolar disorder and help protect them from the medical risks associated with overweight and obesity.

Similar precautions are needed when schizophrenia and bipolar disorder co-occur with other medical illnesses treated by complex pharmacologic regimens, such as pulmonary disease, cancer, and HIV. Three points to keep in mind are:

• careful selection of treatments for co-occurring medical illnesses, considering potential effects on the primary psychiatric disorder
• the impact of psychotropics on patients’ medical illnesses
• and the potential for drug interactions.

Antidepressants’ sexual side effects can often be managed—while preserving the antidepressant effect—by altering dosages, switching to another drug class, or adding an “antidote.” Understanding the benefits and risks of each strategy can help you:

• base treatment choices on your patient’s history and side-effect experience
• improve long-term compliance with antidepressant regimens.

EFFECTS VARY BY ANTIDEPRESSANT CLASS

Antidepressants may affect one or more phases of sexual functioning:

• desire (libido)
• arousal (erection or vaginal lubrication)
• orgasm/ejaculation.

Sexual symptoms linked to antidepressants range from diminished interest/arousal and delayed orgasm to heightened sexual functioning (Table 1). Resulting sexual dysfunction can impair quality of life and intimate relationships and discourage patients from taking antidepressants (Box) ^1,2

Table 1

Sexual side effects linked to antidepressants

Although most reports have focused on SSRIs, all antidepressant classes have been associated with sexual dysfunction, with prevalence likely influenced by differences in neurotransmitter modulation (Table 2).^1,3,4 The highest rates of sexual side effects have been reported with SSRIs, certain tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs).

A recent study reported similarly high rates with mirtazapine, but its small sample size limits conclusions about side effect prevalence with this drug.¹ Other studies have found significantly lower rates with bupropion and nefazodone.

TCAs’ sexual side-effect rates and types depend on how much each drug inhibits serotonin reuptake. Clomipramine appears to have the highest rates of sexual dysfunction—particularly anorgasmia—probably because it inhibits the serotonin transporter more than do other TCAs.⁵ In TCAs with lesser effects on serotonergic neurotransmission, alpha-adrenergic and cholinergic receptor blockade may cause sexual side effects—particularly erectile dysfunction (ED).

Cholinergic agonists such as bethanechol, 10 to 50 mg/d, may reverse sexual dysfunction caused by anticholinergic effects.⁶ Cyproheptadine—a nonselective serotonin receptor antagonist—has also shown benefit at 4 to 12 mg/d in treating TCA-related sexual side effects.⁷

MAOIs. Sexual side effects appear to be more prevalent with MAOIs than with TCAs,⁴ perhaps similar to the rate seen with SSRIs. MAOIs directly increase serotonergic neurotransmission, and their substantial alpha-adrenergic antagonist effects may also produce sexual side effects.

Waiting for symptoms to subside may be appropriate, as anorgasmia caused by MAOIs may remit spontaneously. Sildenafil⁸ and cyproheptadine⁹ may reverse MAOI sexual side effects, although serious toxicity has been reported in a patient taking cyproheptadine and an MAOI.¹⁰

SSRIs. Increased serotonergic neurotransmission is widely believed to cause SSRI sexual side effects. Resulting secondary effects—such as inhibited central dopamine release, increased prolactin secretion, and inhibited nitric oxide synthesis—may also play important roles.

In general, SSRIs appear to alter sexual functioning in 40% to 60% of patients—both men and women. Anorgasmia is the most commonly reported sexual symptom.

Although all SSRIs are associated with sexual dysfunction, some studies have found higher rates with paroxetine. One study associated paroxetine with significantly higher rates of ED compared with other SSRIs. The authors attributed this finding to paroxetine’s greater anticholinergic effects or to its directly decreasing nitric oxide synthesis.³

SSRI MANAGEMENT STRATEGIES

Waiting. The simplest, safest way to manage SSRI-related sexual dysfunction is to wait and see if side effects resolve spontaneously. Sexual side effects improve without treatment in approximately 20% of cases,³ although improvement is often incomplete. Moreover, several months may pass before symptoms diminish adequately, making this strategy impractical for patients with substantial sexual dysfunction.

Dosing changes. Because SSRIs’ sexual side effects appear to be dose-related,¹¹ carefully reducing the dosage may reduce sexual dysfunction without compromising antidepressant efficacy. This strategy is most likely to sustain remission when you avoid dosages that have proven ineffective. For example, consider a patient who achieves remission of depressive symptoms when fluoxetine is increased from 20 to 40 mg/d. If sexual side effects emerge at 40 mg/d, relapse may be less likely at 30 mg/d than at 20 mg/d.

Box

Other strategies that lessen sexual side effects for some patients include:

• dividing the dosage
• delaying dosing until after sexual activity
• allowing 2- to 3-day “drug holidays” over weekends, when sexual activity is more likely to occur.¹²

Drug holidays probably would not help patients taking fluoxetine, as plasma concentrations would not drop sufficiently in 2 to 3 days to alleviate sexual side effects. Also, drug holidays are presumably safest for patients who are in maintenance treatment, are asymptomatic, and have no history of rapid symptom recurrence or withdrawal effects when discontinuing SSRIs.¹²

Switching medications. When sexual side effects do not resolve spontaneously or with dose reduction, consider switching to an antidepressant with a lower incidence of sexual dysfunction.

Table 2

Prevalence of antidepressant sexual side effects

Bupropion has been shown to improve sexual functioning in patients treated for depression. One study reported improved sexual functioning in patients with SSRI-induced sexual side effects who were switched to bupropion.¹³ Similar studies have shown benefits with substituting nefazodone or mirtazapine for an SSRI.

These uncontrolled studies suggest that switching some patients to a non-SSRI antidepressant may diminish sexual side effects while continuing antidepressant efficacy. Bupropion or nefazodone may be more effective for this purpose, as mirtazapine showed a high rate of sexual side effects in a large observational study.¹

Use caution when switching from an SSRI to nefazodone, as cytochrome P-450 2D6 isoenzyme inhibition may increase levels of mCPP—a nefazodone metabolite with anxiogenic properties. To avoid this interaction, taper the SSRI before starting nefazodone.

Switching medications may not be ideal for patients with an unacceptable depression relapse risk, characterized by severe dysfunction, suicidal ideation, or past treatment resistance.

USING AN ANTIDOTE

Adding a second medication to antidepressant therapy is another strategy to consider. An antidote seems most practical when:

• a patient clearly benefits from an antidepressant regimen
• the risk of losing efficacy with a new medication is high
• reducing the dosage or waiting for sexual dysfunction to resolve spontaneously are impractical or have failed.

Most reports of sexual side effect antidotes have been open-label trials of drugs thought to:

• improve some aspect of sexual functioning as with dopamine or noradrenergic agonists)
• or block antidepressant mechanisms suspected of contributing to sexual side effects (as with serotonin receptor antagonists or cholinergic agonists).

Unfortunately, controlled trials with many of these strategies have been less than promising (Table 3).^5,14-28 Several trials reported high placebo-response rates—which may complicate assessment of any sexual side effect treatment—and most produced negative results. Two notable exceptions have been sildenafil and bupropion.

Sildenafil, a phosphodiesterase-5 inhibitor, showed greater benefit than placebo in a prospective trial of 90 depressed men (mean age 45) diagnosed with sexual dysfunction caused by an SSRI.²⁸ The men took sildenafil, 50 to 100 mg, 1 hour before sexual activity.

After 6 weeks, 55% of sildenafil-treated patients were rated as much/very much improved on the Clinical Global Impression Scale adapted for Sexual Function, compared with 4% of those taking placebo, a statistically significant difference. Measures used to assess sexual function showed that arousal, erectile function, and orgasm improved significantly, with a lesser effect on desire. This suggests that adjunctive sildenafil reduces SSRIs’ sexual side effects, and this benefit may extend beyond improving ED.

Table 3

Evidence for antidotes used to treat antidepressant sexual side effects

Sildenafil improves peripheral vasodilatation due to smooth muscle relaxation caused by enhanced nitric oxide release. Other sexual side effects—such as delayed orgasm/ejaculation—may improve because of indirect effects of increased penile and clitoral blood flow caused by vasodilatation.²⁹

Sildenafil treatment was well-tolerated; the most common side effects were headache (40.5%), flushing (16.7%), dyspepsia (7.1%), nasal congestion (11.9%), and transient visual disturbances (11.9%).

Bupropion has also shown therapeutic efficacy for SSRI-related sexual dysfunction in a 4-week, placebo-controlled trial of 55 patients (mean age 39) diagnosed with SSRI-induced sexual dysfunction.¹⁵ Compared with the placebo group, those receiving add-on bupropion SR, 150 mg bid, improved significantly more in sexual desire and frequency of sexual activity, as measured by the Changes in Sexual Functioning Questionnaire.

Measures of arousal, orgasm, and global sexual functioning did not differ significantly between the two groups. Bupropion added to SSRI treatment was well-tolerated; most-commonly reported side effects were irritability (12%), dry mouth (12%), and headache (15%).

Other ED treatments. Two additional phosphodiesterase-5 inhibitors have become available in the past year. Like sildenafil, tadalafil and vardenafil are indicated for treating ED. They may be useful as alternatives for patients who do not respond to or tolerate sildenafil, although no published studies have examined their use in antidepressant-induced sexual dysfunction.

Recommendation. Based on the evidence, it seems reasonable to start with bupropion or sildenafil when considering an antidote for sexual side effects caused by SSRIs or other medications with strong serotonergic effects. Determining which agent would be “first-line” depends on patient factors, as summarized in Table 1^30,31For example:

• Bupropion has been reported to augment SSRIs’ antidepressant effects³² and thus may provide added benefit in patients with residual depressive symptoms.
• Bupropion is more effective than sildenafil for improving sexual desire and thus would be preferred for patients in whom this sexual dysfunction symptom is prominent.
• Sildenafil appears to be more effective than bupropion for improving overall sexual satisfaction for men experiencing substantial erectile dysfunction.

Table 4

Bupropion vs. sildenafil as antidote therapy for antidepressant sexual side effects

Related resources

• Worthington JJ 3rd, Peters PM. Treatment of antidepressant-induced sexual dysfunction. Drugs Today (Barc) 2003;39(11):887-96.
• Montgomery SA, Baldwin DS, Riley A. Antidepressant medications: a review of the evidence for drug-induced sexual dysfunction. J Affect Disord 2002;69(1-3):119-40.

Drug brand names

• Amantadine • Symmetrel
• Bethanechol • Duvoid, Urecholine, Urabeth
• Bupropion SR • Wellbutrin SR
• Buspirone • Buspar
• Citalopram • Celexa
• Clomipramine • Anafranil
• Cyproheptadine • Periactin
• Fluoxetine • Prozac
• Granisetron • Kytril
• Methyphenidate • Ritalin
• Mianserin • Bolvidon, Norval
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Paroxetine • Paxil
• Pramipexole • Mirapex
• Ropinirole • Requip
• Sertraline • Zoloft
• Sildenafil • Viagra
• Tadalafil • Cialis
• Vardenafil • Levitra
• Venlafaxine • Effexor

Disclosure

Dr. Nelson receives research support from Eli Lilly and Co. and Forest Laboratories and is a speaker for Pfizer Inc. and Wyeth Pharmaceuticals.

Antidepressants’ sexual side effects can often be managed—while preserving the antidepressant effect—by altering dosages, switching to another drug class, or adding an “antidote.” Understanding the benefits and risks of each strategy can help you:

• base treatment choices on your patient’s history and side-effect experience
• improve long-term compliance with antidepressant regimens.

EFFECTS VARY BY ANTIDEPRESSANT CLASS

Antidepressants may affect one or more phases of sexual functioning:

• desire (libido)
• arousal (erection or vaginal lubrication)
• orgasm/ejaculation.

Sexual symptoms linked to antidepressants range from diminished interest/arousal and delayed orgasm to heightened sexual functioning (Table 1). Resulting sexual dysfunction can impair quality of life and intimate relationships and discourage patients from taking antidepressants (Box) ^1,2

Table 1

Sexual side effects linked to antidepressants

Although most reports have focused on SSRIs, all antidepressant classes have been associated with sexual dysfunction, with prevalence likely influenced by differences in neurotransmitter modulation (Table 2).^1,3,4 The highest rates of sexual side effects have been reported with SSRIs, certain tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs).

A recent study reported similarly high rates with mirtazapine, but its small sample size limits conclusions about side effect prevalence with this drug.¹ Other studies have found significantly lower rates with bupropion and nefazodone.

TCAs’ sexual side-effect rates and types depend on how much each drug inhibits serotonin reuptake. Clomipramine appears to have the highest rates of sexual dysfunction—particularly anorgasmia—probably because it inhibits the serotonin transporter more than do other TCAs.⁵ In TCAs with lesser effects on serotonergic neurotransmission, alpha-adrenergic and cholinergic receptor blockade may cause sexual side effects—particularly erectile dysfunction (ED).

Cholinergic agonists such as bethanechol, 10 to 50 mg/d, may reverse sexual dysfunction caused by anticholinergic effects.⁶ Cyproheptadine—a nonselective serotonin receptor antagonist—has also shown benefit at 4 to 12 mg/d in treating TCA-related sexual side effects.⁷

MAOIs. Sexual side effects appear to be more prevalent with MAOIs than with TCAs,⁴ perhaps similar to the rate seen with SSRIs. MAOIs directly increase serotonergic neurotransmission, and their substantial alpha-adrenergic antagonist effects may also produce sexual side effects.

Waiting for symptoms to subside may be appropriate, as anorgasmia caused by MAOIs may remit spontaneously. Sildenafil⁸ and cyproheptadine⁹ may reverse MAOI sexual side effects, although serious toxicity has been reported in a patient taking cyproheptadine and an MAOI.¹⁰

SSRIs. Increased serotonergic neurotransmission is widely believed to cause SSRI sexual side effects. Resulting secondary effects—such as inhibited central dopamine release, increased prolactin secretion, and inhibited nitric oxide synthesis—may also play important roles.

In general, SSRIs appear to alter sexual functioning in 40% to 60% of patients—both men and women. Anorgasmia is the most commonly reported sexual symptom.

Although all SSRIs are associated with sexual dysfunction, some studies have found higher rates with paroxetine. One study associated paroxetine with significantly higher rates of ED compared with other SSRIs. The authors attributed this finding to paroxetine’s greater anticholinergic effects or to its directly decreasing nitric oxide synthesis.³

SSRI MANAGEMENT STRATEGIES

Waiting. The simplest, safest way to manage SSRI-related sexual dysfunction is to wait and see if side effects resolve spontaneously. Sexual side effects improve without treatment in approximately 20% of cases,³ although improvement is often incomplete. Moreover, several months may pass before symptoms diminish adequately, making this strategy impractical for patients with substantial sexual dysfunction.

Dosing changes. Because SSRIs’ sexual side effects appear to be dose-related,¹¹ carefully reducing the dosage may reduce sexual dysfunction without compromising antidepressant efficacy. This strategy is most likely to sustain remission when you avoid dosages that have proven ineffective. For example, consider a patient who achieves remission of depressive symptoms when fluoxetine is increased from 20 to 40 mg/d. If sexual side effects emerge at 40 mg/d, relapse may be less likely at 30 mg/d than at 20 mg/d.

Box

Other strategies that lessen sexual side effects for some patients include:

• dividing the dosage
• delaying dosing until after sexual activity
• allowing 2- to 3-day “drug holidays” over weekends, when sexual activity is more likely to occur.¹²

Drug holidays probably would not help patients taking fluoxetine, as plasma concentrations would not drop sufficiently in 2 to 3 days to alleviate sexual side effects. Also, drug holidays are presumably safest for patients who are in maintenance treatment, are asymptomatic, and have no history of rapid symptom recurrence or withdrawal effects when discontinuing SSRIs.¹²

Switching medications. When sexual side effects do not resolve spontaneously or with dose reduction, consider switching to an antidepressant with a lower incidence of sexual dysfunction.

Table 2

Prevalence of antidepressant sexual side effects

Bupropion has been shown to improve sexual functioning in patients treated for depression. One study reported improved sexual functioning in patients with SSRI-induced sexual side effects who were switched to bupropion.¹³ Similar studies have shown benefits with substituting nefazodone or mirtazapine for an SSRI.

These uncontrolled studies suggest that switching some patients to a non-SSRI antidepressant may diminish sexual side effects while continuing antidepressant efficacy. Bupropion or nefazodone may be more effective for this purpose, as mirtazapine showed a high rate of sexual side effects in a large observational study.¹

Use caution when switching from an SSRI to nefazodone, as cytochrome P-450 2D6 isoenzyme inhibition may increase levels of mCPP—a nefazodone metabolite with anxiogenic properties. To avoid this interaction, taper the SSRI before starting nefazodone.

Switching medications may not be ideal for patients with an unacceptable depression relapse risk, characterized by severe dysfunction, suicidal ideation, or past treatment resistance.

USING AN ANTIDOTE

Adding a second medication to antidepressant therapy is another strategy to consider. An antidote seems most practical when:

• a patient clearly benefits from an antidepressant regimen
• the risk of losing efficacy with a new medication is high
• reducing the dosage or waiting for sexual dysfunction to resolve spontaneously are impractical or have failed.

Most reports of sexual side effect antidotes have been open-label trials of drugs thought to:

• improve some aspect of sexual functioning as with dopamine or noradrenergic agonists)
• or block antidepressant mechanisms suspected of contributing to sexual side effects (as with serotonin receptor antagonists or cholinergic agonists).

Unfortunately, controlled trials with many of these strategies have been less than promising (Table 3).^5,14-28 Several trials reported high placebo-response rates—which may complicate assessment of any sexual side effect treatment—and most produced negative results. Two notable exceptions have been sildenafil and bupropion.

Sildenafil, a phosphodiesterase-5 inhibitor, showed greater benefit than placebo in a prospective trial of 90 depressed men (mean age 45) diagnosed with sexual dysfunction caused by an SSRI.²⁸ The men took sildenafil, 50 to 100 mg, 1 hour before sexual activity.

After 6 weeks, 55% of sildenafil-treated patients were rated as much/very much improved on the Clinical Global Impression Scale adapted for Sexual Function, compared with 4% of those taking placebo, a statistically significant difference. Measures used to assess sexual function showed that arousal, erectile function, and orgasm improved significantly, with a lesser effect on desire. This suggests that adjunctive sildenafil reduces SSRIs’ sexual side effects, and this benefit may extend beyond improving ED.

Table 3

Evidence for antidotes used to treat antidepressant sexual side effects

Sildenafil improves peripheral vasodilatation due to smooth muscle relaxation caused by enhanced nitric oxide release. Other sexual side effects—such as delayed orgasm/ejaculation—may improve because of indirect effects of increased penile and clitoral blood flow caused by vasodilatation.²⁹

Sildenafil treatment was well-tolerated; the most common side effects were headache (40.5%), flushing (16.7%), dyspepsia (7.1%), nasal congestion (11.9%), and transient visual disturbances (11.9%).

Bupropion has also shown therapeutic efficacy for SSRI-related sexual dysfunction in a 4-week, placebo-controlled trial of 55 patients (mean age 39) diagnosed with SSRI-induced sexual dysfunction.¹⁵ Compared with the placebo group, those receiving add-on bupropion SR, 150 mg bid, improved significantly more in sexual desire and frequency of sexual activity, as measured by the Changes in Sexual Functioning Questionnaire.

Measures of arousal, orgasm, and global sexual functioning did not differ significantly between the two groups. Bupropion added to SSRI treatment was well-tolerated; most-commonly reported side effects were irritability (12%), dry mouth (12%), and headache (15%).

Other ED treatments. Two additional phosphodiesterase-5 inhibitors have become available in the past year. Like sildenafil, tadalafil and vardenafil are indicated for treating ED. They may be useful as alternatives for patients who do not respond to or tolerate sildenafil, although no published studies have examined their use in antidepressant-induced sexual dysfunction.

Recommendation. Based on the evidence, it seems reasonable to start with bupropion or sildenafil when considering an antidote for sexual side effects caused by SSRIs or other medications with strong serotonergic effects. Determining which agent would be “first-line” depends on patient factors, as summarized in Table 1^30,31For example:

• Bupropion has been reported to augment SSRIs’ antidepressant effects³² and thus may provide added benefit in patients with residual depressive symptoms.
• Bupropion is more effective than sildenafil for improving sexual desire and thus would be preferred for patients in whom this sexual dysfunction symptom is prominent.
• Sildenafil appears to be more effective than bupropion for improving overall sexual satisfaction for men experiencing substantial erectile dysfunction.

Table 4

Bupropion vs. sildenafil as antidote therapy for antidepressant sexual side effects

Related resources

• Worthington JJ 3rd, Peters PM. Treatment of antidepressant-induced sexual dysfunction. Drugs Today (Barc) 2003;39(11):887-96.
• Montgomery SA, Baldwin DS, Riley A. Antidepressant medications: a review of the evidence for drug-induced sexual dysfunction. J Affect Disord 2002;69(1-3):119-40.

Drug brand names

• Amantadine • Symmetrel
• Bethanechol • Duvoid, Urecholine, Urabeth
• Bupropion SR • Wellbutrin SR
• Buspirone • Buspar
• Citalopram • Celexa
• Clomipramine • Anafranil
• Cyproheptadine • Periactin
• Fluoxetine • Prozac
• Granisetron • Kytril
• Methyphenidate • Ritalin
• Mianserin • Bolvidon, Norval
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Paroxetine • Paxil
• Pramipexole • Mirapex
• Ropinirole • Requip
• Sertraline • Zoloft
• Sildenafil • Viagra
• Tadalafil • Cialis
• Vardenafil • Levitra
• Venlafaxine • Effexor

Disclosure

Dr. Nelson receives research support from Eli Lilly and Co. and Forest Laboratories and is a speaker for Pfizer Inc. and Wyeth Pharmaceuticals.

Antidepressants’ sexual side effects can often be managed—while preserving the antidepressant effect—by altering dosages, switching to another drug class, or adding an “antidote.” Understanding the benefits and risks of each strategy can help you:

• base treatment choices on your patient’s history and side-effect experience
• improve long-term compliance with antidepressant regimens.

EFFECTS VARY BY ANTIDEPRESSANT CLASS

Antidepressants may affect one or more phases of sexual functioning:

• desire (libido)
• arousal (erection or vaginal lubrication)
• orgasm/ejaculation.

Sexual symptoms linked to antidepressants range from diminished interest/arousal and delayed orgasm to heightened sexual functioning (Table 1). Resulting sexual dysfunction can impair quality of life and intimate relationships and discourage patients from taking antidepressants (Box) ^1,2

Table 1

Sexual side effects linked to antidepressants

Although most reports have focused on SSRIs, all antidepressant classes have been associated with sexual dysfunction, with prevalence likely influenced by differences in neurotransmitter modulation (Table 2).^1,3,4 The highest rates of sexual side effects have been reported with SSRIs, certain tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs).

A recent study reported similarly high rates with mirtazapine, but its small sample size limits conclusions about side effect prevalence with this drug.¹ Other studies have found significantly lower rates with bupropion and nefazodone.

TCAs’ sexual side-effect rates and types depend on how much each drug inhibits serotonin reuptake. Clomipramine appears to have the highest rates of sexual dysfunction—particularly anorgasmia—probably because it inhibits the serotonin transporter more than do other TCAs.⁵ In TCAs with lesser effects on serotonergic neurotransmission, alpha-adrenergic and cholinergic receptor blockade may cause sexual side effects—particularly erectile dysfunction (ED).

Cholinergic agonists such as bethanechol, 10 to 50 mg/d, may reverse sexual dysfunction caused by anticholinergic effects.⁶ Cyproheptadine—a nonselective serotonin receptor antagonist—has also shown benefit at 4 to 12 mg/d in treating TCA-related sexual side effects.⁷

MAOIs. Sexual side effects appear to be more prevalent with MAOIs than with TCAs,⁴ perhaps similar to the rate seen with SSRIs. MAOIs directly increase serotonergic neurotransmission, and their substantial alpha-adrenergic antagonist effects may also produce sexual side effects.

Waiting for symptoms to subside may be appropriate, as anorgasmia caused by MAOIs may remit spontaneously. Sildenafil⁸ and cyproheptadine⁹ may reverse MAOI sexual side effects, although serious toxicity has been reported in a patient taking cyproheptadine and an MAOI.¹⁰

SSRIs. Increased serotonergic neurotransmission is widely believed to cause SSRI sexual side effects. Resulting secondary effects—such as inhibited central dopamine release, increased prolactin secretion, and inhibited nitric oxide synthesis—may also play important roles.

In general, SSRIs appear to alter sexual functioning in 40% to 60% of patients—both men and women. Anorgasmia is the most commonly reported sexual symptom.

Although all SSRIs are associated with sexual dysfunction, some studies have found higher rates with paroxetine. One study associated paroxetine with significantly higher rates of ED compared with other SSRIs. The authors attributed this finding to paroxetine’s greater anticholinergic effects or to its directly decreasing nitric oxide synthesis.³

SSRI MANAGEMENT STRATEGIES

Waiting. The simplest, safest way to manage SSRI-related sexual dysfunction is to wait and see if side effects resolve spontaneously. Sexual side effects improve without treatment in approximately 20% of cases,³ although improvement is often incomplete. Moreover, several months may pass before symptoms diminish adequately, making this strategy impractical for patients with substantial sexual dysfunction.

Dosing changes. Because SSRIs’ sexual side effects appear to be dose-related,¹¹ carefully reducing the dosage may reduce sexual dysfunction without compromising antidepressant efficacy. This strategy is most likely to sustain remission when you avoid dosages that have proven ineffective. For example, consider a patient who achieves remission of depressive symptoms when fluoxetine is increased from 20 to 40 mg/d. If sexual side effects emerge at 40 mg/d, relapse may be less likely at 30 mg/d than at 20 mg/d.

Box

Other strategies that lessen sexual side effects for some patients include:

• dividing the dosage
• delaying dosing until after sexual activity
• allowing 2- to 3-day “drug holidays” over weekends, when sexual activity is more likely to occur.¹²

Drug holidays probably would not help patients taking fluoxetine, as plasma concentrations would not drop sufficiently in 2 to 3 days to alleviate sexual side effects. Also, drug holidays are presumably safest for patients who are in maintenance treatment, are asymptomatic, and have no history of rapid symptom recurrence or withdrawal effects when discontinuing SSRIs.¹²

Switching medications. When sexual side effects do not resolve spontaneously or with dose reduction, consider switching to an antidepressant with a lower incidence of sexual dysfunction.

Table 2

Prevalence of antidepressant sexual side effects

Bupropion has been shown to improve sexual functioning in patients treated for depression. One study reported improved sexual functioning in patients with SSRI-induced sexual side effects who were switched to bupropion.¹³ Similar studies have shown benefits with substituting nefazodone or mirtazapine for an SSRI.

These uncontrolled studies suggest that switching some patients to a non-SSRI antidepressant may diminish sexual side effects while continuing antidepressant efficacy. Bupropion or nefazodone may be more effective for this purpose, as mirtazapine showed a high rate of sexual side effects in a large observational study.¹

Use caution when switching from an SSRI to nefazodone, as cytochrome P-450 2D6 isoenzyme inhibition may increase levels of mCPP—a nefazodone metabolite with anxiogenic properties. To avoid this interaction, taper the SSRI before starting nefazodone.

Switching medications may not be ideal for patients with an unacceptable depression relapse risk, characterized by severe dysfunction, suicidal ideation, or past treatment resistance.

USING AN ANTIDOTE

Adding a second medication to antidepressant therapy is another strategy to consider. An antidote seems most practical when:

• a patient clearly benefits from an antidepressant regimen
• the risk of losing efficacy with a new medication is high
• reducing the dosage or waiting for sexual dysfunction to resolve spontaneously are impractical or have failed.

Most reports of sexual side effect antidotes have been open-label trials of drugs thought to:

• improve some aspect of sexual functioning as with dopamine or noradrenergic agonists)
• or block antidepressant mechanisms suspected of contributing to sexual side effects (as with serotonin receptor antagonists or cholinergic agonists).

Unfortunately, controlled trials with many of these strategies have been less than promising (Table 3).^5,14-28 Several trials reported high placebo-response rates—which may complicate assessment of any sexual side effect treatment—and most produced negative results. Two notable exceptions have been sildenafil and bupropion.

Sildenafil, a phosphodiesterase-5 inhibitor, showed greater benefit than placebo in a prospective trial of 90 depressed men (mean age 45) diagnosed with sexual dysfunction caused by an SSRI.²⁸ The men took sildenafil, 50 to 100 mg, 1 hour before sexual activity.

After 6 weeks, 55% of sildenafil-treated patients were rated as much/very much improved on the Clinical Global Impression Scale adapted for Sexual Function, compared with 4% of those taking placebo, a statistically significant difference. Measures used to assess sexual function showed that arousal, erectile function, and orgasm improved significantly, with a lesser effect on desire. This suggests that adjunctive sildenafil reduces SSRIs’ sexual side effects, and this benefit may extend beyond improving ED.

Table 3

Evidence for antidotes used to treat antidepressant sexual side effects

Sildenafil improves peripheral vasodilatation due to smooth muscle relaxation caused by enhanced nitric oxide release. Other sexual side effects—such as delayed orgasm/ejaculation—may improve because of indirect effects of increased penile and clitoral blood flow caused by vasodilatation.²⁹

Sildenafil treatment was well-tolerated; the most common side effects were headache (40.5%), flushing (16.7%), dyspepsia (7.1%), nasal congestion (11.9%), and transient visual disturbances (11.9%).

Bupropion has also shown therapeutic efficacy for SSRI-related sexual dysfunction in a 4-week, placebo-controlled trial of 55 patients (mean age 39) diagnosed with SSRI-induced sexual dysfunction.¹⁵ Compared with the placebo group, those receiving add-on bupropion SR, 150 mg bid, improved significantly more in sexual desire and frequency of sexual activity, as measured by the Changes in Sexual Functioning Questionnaire.

Measures of arousal, orgasm, and global sexual functioning did not differ significantly between the two groups. Bupropion added to SSRI treatment was well-tolerated; most-commonly reported side effects were irritability (12%), dry mouth (12%), and headache (15%).

Other ED treatments. Two additional phosphodiesterase-5 inhibitors have become available in the past year. Like sildenafil, tadalafil and vardenafil are indicated for treating ED. They may be useful as alternatives for patients who do not respond to or tolerate sildenafil, although no published studies have examined their use in antidepressant-induced sexual dysfunction.

Recommendation. Based on the evidence, it seems reasonable to start with bupropion or sildenafil when considering an antidote for sexual side effects caused by SSRIs or other medications with strong serotonergic effects. Determining which agent would be “first-line” depends on patient factors, as summarized in Table 1^30,31For example:

• Bupropion has been reported to augment SSRIs’ antidepressant effects³² and thus may provide added benefit in patients with residual depressive symptoms.
• Bupropion is more effective than sildenafil for improving sexual desire and thus would be preferred for patients in whom this sexual dysfunction symptom is prominent.
• Sildenafil appears to be more effective than bupropion for improving overall sexual satisfaction for men experiencing substantial erectile dysfunction.

Table 4

Bupropion vs. sildenafil as antidote therapy for antidepressant sexual side effects

Related resources

• Worthington JJ 3rd, Peters PM. Treatment of antidepressant-induced sexual dysfunction. Drugs Today (Barc) 2003;39(11):887-96.
• Montgomery SA, Baldwin DS, Riley A. Antidepressant medications: a review of the evidence for drug-induced sexual dysfunction. J Affect Disord 2002;69(1-3):119-40.

Drug brand names

• Amantadine • Symmetrel
• Bethanechol • Duvoid, Urecholine, Urabeth
• Bupropion SR • Wellbutrin SR
• Buspirone • Buspar
• Citalopram • Celexa
• Clomipramine • Anafranil
• Cyproheptadine • Periactin
• Fluoxetine • Prozac
• Granisetron • Kytril
• Methyphenidate • Ritalin
• Mianserin • Bolvidon, Norval
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Paroxetine • Paxil
• Pramipexole • Mirapex
• Ropinirole • Requip
• Sertraline • Zoloft
• Sildenafil • Viagra
• Tadalafil • Cialis
• Vardenafil • Levitra
• Venlafaxine • Effexor

Disclosure

Dr. Nelson receives research support from Eli Lilly and Co. and Forest Laboratories and is a speaker for Pfizer Inc. and Wyeth Pharmaceuticals.