Evidence-Based Reviews

When choosing psychopharmacologic agents for patients with bipolar disorder, the clinician lacks guidance from controlled clinical trials at virtually every therapeutic step. To help remedy this problem, we in the Stanley Foundation Bipolar Network (SFBN) evaluated compounds with potentially important therapeutic profiles. We began by documenting the demographics and illness characteristics of patients with bipolar disorder. Then we assessed some 16 treatments in naturalistic or formal studies, some of which are complete and others ongoing.

In this second installment, we report our current information about the efficacy of second-generation antidepressants, atypical antipsychotics, and anticonvulsant agents.

Mood stabilizers

As mood stabilizers, the anticonvulsants carbamazepine and valproate are well-accepted alternatives or adjuncts to lithium carbonate, which remains a mainstay treatment for acute episodes and long-term prophylaxis.¹

Valproate is approved by the FDA for treatment of acute mania but not for long-term prevention. Open studies in rapid-cycling, treatment-refractory patients demonstrate substantial improvement for both manic and depressive phases with valproate. In the most recent controlled study, valproate did not prevent manic episodes to a statistically significant degree, but it did show greater antidepressant effects than placebo or lithium.²

Carbamazepine has been widely studied in acute mania and compared with lithium for long-term prophylaxis. Most studies show nonsignificant differences between carbamazepine and lithium in preventing manic and depressive episodes, although several studies indicate less-robust antimanic effects of carbamazepine,³ particularly for patients with classic euphoric mania without psychosis, bipolar II, or associated substance abuse.⁴

In atypical patients, carbamazepine appeared to outperform lithium, suggesting clinical differences in these agents that have different mechanisms of action across neurotransmitter and peptide systems.

Low response rates Most randomized controlled trials and open adjunct studies suggest that 50% or more patients respond to lithium, valproate, or carbamazepine. Outcomes may be far less positive in clinical practice, however. Despite the use of mood stabilizers and a variety of antidepressants, benzodiazepines, and neuroleptics, our patients experienced substantial residual manic and depressive symptoms and functional impairment.

Similarly, clinician ratings on the National Institute of Mental Health Life Chart Method (NIMH-LCM) indicated a high rate of breakthrough episodes during carefully monitored and aggressive psychopharmacologic treatment.⁵ Two-thirds of the first 258 bipolar outpatients that we followed and rated daily for 1 year continued to be substantially impaired. One-quarter of them were ill for more than 75% of the year, despite using an average 4.1 psychopharmacologic agents per patient, including mood stabilizers, antidepressants, antipsychotics, and other agents.

Acute and long-term combination therapy appears more effective than monotherapy, particularly for treatment-refractory rapid cyclers.³ Even so, many patients do not respond to combination therapy. For example, in a 1-year prophylaxis study, 25% or fewer patients were rated “much improved” to “very much improved” on the Clinical Global Impressions (CGI) scale with lithium or carbamazepine as the baseline mood stabilizer and with antidepressants, neuroleptics, and benzodiazepines used as needed. In the third year of combination therapy, the overall response rate, including rapid cyclers, was roughly 50%.³

A low rate of response is apparent for lithium and valproate. While treating rapidly cycling patients, Calabrese and associates found that less than one-quarter of them responded well enough to the two-drug combination that they could be enrolled in a randomized double-blind comparison of each drug in monotherapy. Of those who were eligible, almost all relapsed with either lithium or valproate monotherapy and again required combination therapy.⁶

Table 1

RATE OF SWITCHING (%) INTO MANIA IN DEPRESSED BIPOLAR PATIENTS DURING ANTIDEPRESSANT TREATMENT*

Taken together, these studies indicate that even with our most effective and most studied agents, many patients respond inadequately. On the basis of this clinical reality, we began to explore additional options that might enhance clinical effectiveness.

Atypical antipsychotics

We assessed the addition of the atypical antipsychotic olanzapine in patients with treatment-refractory bipolar disorder⁷ and saw improvement in 57% of subjects with manic, mixed, and depressive components. These data foreshadowed more recent controlled findings of olanzapine’s usefulness in depression and mania.^8,9 Our preliminary open clinical trial experience allowed for more controlled studies and subsequent approval and wider clinical use of olanzapine in bipolar illness.

Our initial assessment of other atypical antipsychotics found that quetiapine was associated with significantly fewer depressive symptoms on the Inventory of Depressive Symptomatology (IDS) when used as part of the regular treatment regimen. This improvement, which was seen in the first month, was maintained over 4 months of treatment, whereas no significant improvement in depression severity was seen with the use of risperidone or clozapine.¹⁰

It would be highly preliminary to conclude from these uncontrolled data that quetiapine had greater effects on bipolar depressive symptoms than did risperidone or clozapine. We cannot rule out the possibility that patients with different degrees of treatment resistance were enrolled and treated with the different concomitant drugs. However, patients did not differ at baseline in severity of their depression.

In this initial look at the atypicals, the severity of depressive symptoms on the IDS was much greater than that of mania, as measured by the Young Mania Rating Scale (YMRS). Thus, the precise patterns of illness being treated and the impact of these antipsychotics on depressive cyclicity and duration await closer examination. We intend to look at the relative efficacy and side-effect profiles of each of the atypical antipsychotics as used in clinical practice.

Second-generation antidepressants

Bupropion, sertraline, and venlafaxine have different mechanisms of action but appear to be of value as adjuncts to bipolar disorder treatment. When we used them as adjuncts to mood stabilizers in a prospective study, we found a 40 to 50% acute response rate and some switching into hypomania and mania (Table 1).¹¹ Many switches appeared to involve only isolated brief bursts of hypomania or recurrent brief hypomanias, but more sustained episodes of hypomania (7 days) could be more clinically problematic. Only 13% of patients treated acutely with these antidepressants had more full-blown manic symptoms (i.e., those associated with moderate or greater dysfunction on the NIMH-LCM).

During the next year, when apparent acute antidepressant responders were offered continuation treatment, 18% switched into mania. However, most patients (about 80%) dropped out because of lack of efficacy (depressive recurrences), intolerance, or for administrative reasons. The 127 patients who were randomized received 175 acute antidepressant trials. Only 9% were associated with a switch into mania with moderate dysfunction, whereas another 9% showed periods of hypomania lasting longer than 1 week.¹²

Table 2

RELAPSE INTO DEPRESSION IN BIPOLAR PATIENTS AFTER 1 YEAR WITH OR WITHOUT ADJUNCTIVE ANTIDEPRESSANT TREATMENT*

We have entered 176 patients into this double-blind, randomized comparison of bupropion, sertraline, and venlafaxine, with another 27 randomized openly. The study will attempt to examine any possible between-drug differences. Even without the blind being broken, it appears that these antidepressants are associated with a somewhat lower-than-expected rate of switching into mania with dysfunction, but a direct comparison with a placebo is not available.

In two other series, patients who remained well for 2 months on antidepressants plus mood stabilizers and then continued on their antidepressants had a much lower incidence of depressive relapses over the following year than those who discontinued their antidepressants (Table 2).^13,14 Surprisingly, continuing the antidepressant was not associated with an increased rate of switching into mania.

Prospective randomized, controlled studies are required to confirm these findings. Even so, our studies appear to challenge conventional wisdom for the first time. Stopping antidepressant treatment in bipolar patients as soon as possible for fear of inducing a manic episode may not be the optimal recommendation in the admittedly small subgroup (about 15%) of patients who have responded well to an antidepressant for at least 2 months.

Table 3

SIX STUDIES COMPLETED BY SFBN INVESTIGATORS

Second-generation anticonvulsants

Based on our patients’ substantial residual symptoms, we explored a series of newly approved anticonvulsants for potential use as mood stabilizers.

Lamotrigine Consistent with other open and double-blind, placebo-controlled studies, lamotrigine showed promise as an adjunctive treatment, with improvement in depressive symptoms and cycling.¹⁵ One such study showed acute antidepressant effects of lamotrigine monotherapy compared with a placebo at dosages of 50 or 200 mg/d.¹⁶

Another double-blind, randomized, placebo-controlled NIMH study (partially funded by the Stanley Foundation) compared lamotrigine with gabapentin and a placebo in patients for whom lithium, carbamazepine, and valproate had failed.¹⁷ Most of these treatment-refractory patients received all three agents through three 6-week randomizations. Lamotrigine was much more effective in depression and overall illness than either a placebo or gabapentin. Men with bipolar compared with unipolar illness and patients with fewer unsuccessful clinical trials and hospitalizations for depression showed the greatest response.¹⁸

In two recent industry-sponsored controlled trials of long-term prophylaxis (following a recent manic or depressive episode), lamotrigine was significantly more effective than a placebo (Bowden et al and Calabrese et al, unpublished data). Lamotrigine was more effective than lithium in preventing depressive episodes, whereas lithium was more effective than lamotrigine for manic episodes, although lamotrigine was significantly better than the placebo.

These data suggest that lamotrigine may differ from valproate, carbamazepine, and lithium in being a more effective antidepressant than antimanic agent.

Topiramate Adjunctive use of topiramate in rapid-cycling and treatment-resistant patients has been examined in open studies, but controlled studies have not yet been published. In our open-label case series observations, 19 of 30 (63%) patients taking topiramate for mania or cycling were “much” or “very much” improved after 10 weeks, whereas only 3 of 11 (27%) patients taking topiramate for acute depression were so improved.¹⁹

Table 4

STUDIES IN PROGRESS BY SFBN INVESTIGATORS

An industry-sponsored double-blind, randomized trial of topiramate in acute mania looked promising in the first 67 patients, but not as encouraging in subsequent subjects. A positive drug effect re-emerged if one eliminated patients whose manic episodes were precipitated by antidepressants.

The acute antidepressant effects of topiramate did not appear promising in our study. On the other hand, a single-blind, randomized study of topiramate versus bupropion as adjunctive therapy for breakthrough bipolar depression suggested excellent acute response (approximately 56%) to both agents.²⁰ These data leave the potential antidepressant effects of topiramate undetermined.

In patients being treated with topiramate, we found significant weight loss (average –0.7 kg at 4 weeks, –1.6 kg at 10 weeks, –4.7 kg at 6 months, and –6.2 kg at 1 year).¹⁹ Average weight loss was 4.5±6.7 kg at the final evaluation (body mass index [BMI] change of –6.3% and –5% at 1 year and last evaluation, respectively).

We and others have thus seen substantial weight loss in one-third to one-half of patients taking topiramate for bipolar disorder.²¹ This weight loss is maintained over relatively long periods, which differentiates topiramate from other weight-loss regimens. Topiramate’s ability to decrease weight—even while it is in the early stages of evaluation as a mood stabilizer—is of considerable interest, given the substantial problem of overweight in the bipolar population and the fact that many drug therapies used in the illness are associated with weight gain.

We are proceeding with a randomized open comparison of the relative weight loss and psychotropic efficacy of topiramate versus the antiobesity agent sibutramine. Sibutramine has been reported to have antidepressant properties and is FDA-approved for weight loss.

Gabapentin and tiagabine Our group and many others have reported substantial overall clinical improvement when gabapentin was used as adjunctive therapy in an open study of patients with inadequate response to previous treatments.²² As monotherapy, however, gabapentin was not more effective than a placebo¹⁷ and was less effective than lamotrigine. Similarly, gabapentin was not an effective acute antimanic agent when compared with a placebo,²³ although other double-blind, controlled studies have indicated positive effects in anxiety disorders²⁴ and social phobias.²⁵ Thus, the gabapentin literature appears to be divergent—i.e., positive studies support its adjunctive use in bipolar patients, but controlled studies suggest that it is not directly antimanic or mood-stabilizing.

Gabapentin’s effect on syndromes that are highly comorbid with bipolar illness could account for its apparent success as open adjunctive therapy. For example, in addition to its antianxiety effects, gabapentin shows positive effects in alcohol withdrawal, pain syndromes, sleep disorders (including restless leg syndrome), and obsessive-compulsive disorder. Also, combining gabapentin with other psychotropics with other mechanisms of action may have a more robust therapeutic effect than monotherapy.

Our preliminary observations with the selective GABA-reuptake inhibitor tiagabine were not promising. In an open study, only 3 of the first 17 SFBN patients with treatment-resistant affective disorders showed a partial response (moderate improvement on the Clinical Global Impressions Scale for Bipolar Illness [CGI-BP]) to adjunctive tiagabine treatment when the dosage was gradually increased. Serious side effects, including two patients with possible seizures, were noted.²⁶ Similar results were seen when tiagabine doses were rapidly increased in eight patients with acute mania; none responded, and one had a major motor seizure.²⁷

Thus, our initial observations led us to discontinue use of tiagabine and suggest any further clinical consideration of this agent for treatment-resistant affective disorders would require great care. This perspective contrasts with several previous positive case reports. It is unknown whether selected patients or those treated with lower dosages would be more responsive to this agent.

Like valproate, gabapentin and tiagabine increase brain GABA, but their apparent lack of antimanic efficacy strongly suggests that raising brain GABA alone does little to counter mania. These data further support the viewpoint already offered that all anticonvulsants are not alike and that anticonvulsants as a class are not necessarily mood stabilizers.

Zonisamide and levetiracetam Open studies of these two other anticonvulsants are near completion. Each has an interesting mechanistic profile, good tolerability, and the (potentially positive) side effect of inducing some weight loss, based on studies of neurologic patients.

Omega-3 fatty acids Based on positive reports of antidepressant effects of omega-3 fatty acids,^28-30 we recently recruited more than 120 patients with bipolar disorder for two double-blind, randomized, controlled trials. Those patients with either an acute depression or a cyclic course will receive 6 grams of omega-3 fatty acid (the eicosapentaenoate form) or a placebo for 4 months of double-blind treatment, followed by an 8-month open, active continuation phase.

If results are positive, omega-3 fatty acids would represent the much-needed addition of a well-tolerated dietary agent to the therapeutic armamentarium directed at bipolar illness.

Conclusion

The Stanley Foundation Bipolar Network has begun to evaluate the usefulness of numerous older and new compounds for patients with bipolar disorder, including second-generation antidepressants, anticonvulsants, atypical antipsychotic agents, and omega-3 fatty acids. Based on initial observations from 16 treatment studies (Table 3), we have drawn these conclusions:

• Second-generation antidepressants such as bupropion, sertraline, and venlafaxine appear to have a lower-than-expected switch rate into mania, compared with the use of the older tricyclic antidepressants.
• If the addition of a second-generation antidepressant results in good antidepressant response for 2 months and no switches into mania, one should consider continuing the antidepressant in this small minority of patients, rather than stopping it as soon as possible as previously recommended.
• Adjunctive use of lamotrigine appears to be of value, particularly for acute depression and prophylaxis, for many patients who have not responded to other treatments.
• While our group and others have reported improvement with adjunctive gabapentin in bipolar patients in uncontrolled case series, its primary antimanic or mood-stabilizing utility (as well as that of tiagabine) does not appear promising.
• Topiramate’s ability to induce substantial weight loss may emerge as clinically therapeutic for patients with problematic weight gain related to other psychotropic drugs, independent of its ultimate utility as a possible mood stabilizer.

We are preparing to analyze other open case series assessing acute and long-term treatment outcomes as well as randomized, double-blind clinical trials. Even though the funding of this unique collaborative network is ending, we look forward to more effective treatment of bipolar disorder in the future with continued development of new psychotropic agents and data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) and the VA Cooperative studies.³¹

Related resources

• National Alliance for the Mentally Ill (NAMI). www.nami.org
• National Depressive and Manic-Depressive Association (NDMDA). www.ndmda.org

Drug brand names

• Bupropion • Wellbutrin
• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Sibutramine • Meridia
• Tiagabine • Gabitril
• Topiramate • Topamax
• Valproate • Depakote
• Venlafaxine • Effexor
• Zonisamide • Zonegran

Acknowledgement

The authors are particularly indebted to the generosity of The Stanley Foundation in making funds available for this series of studies and several about to be completed.

Disclosure

Financial disclosure statements have been provided by all authors and are available upon request at [email protected].

When choosing psychopharmacologic agents for patients with bipolar disorder, the clinician lacks guidance from controlled clinical trials at virtually every therapeutic step. To help remedy this problem, we in the Stanley Foundation Bipolar Network (SFBN) evaluated compounds with potentially important therapeutic profiles. We began by documenting the demographics and illness characteristics of patients with bipolar disorder. Then we assessed some 16 treatments in naturalistic or formal studies, some of which are complete and others ongoing.

In this second installment, we report our current information about the efficacy of second-generation antidepressants, atypical antipsychotics, and anticonvulsant agents.

Mood stabilizers

As mood stabilizers, the anticonvulsants carbamazepine and valproate are well-accepted alternatives or adjuncts to lithium carbonate, which remains a mainstay treatment for acute episodes and long-term prophylaxis.¹

Valproate is approved by the FDA for treatment of acute mania but not for long-term prevention. Open studies in rapid-cycling, treatment-refractory patients demonstrate substantial improvement for both manic and depressive phases with valproate. In the most recent controlled study, valproate did not prevent manic episodes to a statistically significant degree, but it did show greater antidepressant effects than placebo or lithium.²

Carbamazepine has been widely studied in acute mania and compared with lithium for long-term prophylaxis. Most studies show nonsignificant differences between carbamazepine and lithium in preventing manic and depressive episodes, although several studies indicate less-robust antimanic effects of carbamazepine,³ particularly for patients with classic euphoric mania without psychosis, bipolar II, or associated substance abuse.⁴

In atypical patients, carbamazepine appeared to outperform lithium, suggesting clinical differences in these agents that have different mechanisms of action across neurotransmitter and peptide systems.

Low response rates Most randomized controlled trials and open adjunct studies suggest that 50% or more patients respond to lithium, valproate, or carbamazepine. Outcomes may be far less positive in clinical practice, however. Despite the use of mood stabilizers and a variety of antidepressants, benzodiazepines, and neuroleptics, our patients experienced substantial residual manic and depressive symptoms and functional impairment.

Similarly, clinician ratings on the National Institute of Mental Health Life Chart Method (NIMH-LCM) indicated a high rate of breakthrough episodes during carefully monitored and aggressive psychopharmacologic treatment.⁵ Two-thirds of the first 258 bipolar outpatients that we followed and rated daily for 1 year continued to be substantially impaired. One-quarter of them were ill for more than 75% of the year, despite using an average 4.1 psychopharmacologic agents per patient, including mood stabilizers, antidepressants, antipsychotics, and other agents.

Acute and long-term combination therapy appears more effective than monotherapy, particularly for treatment-refractory rapid cyclers.³ Even so, many patients do not respond to combination therapy. For example, in a 1-year prophylaxis study, 25% or fewer patients were rated “much improved” to “very much improved” on the Clinical Global Impressions (CGI) scale with lithium or carbamazepine as the baseline mood stabilizer and with antidepressants, neuroleptics, and benzodiazepines used as needed. In the third year of combination therapy, the overall response rate, including rapid cyclers, was roughly 50%.³

A low rate of response is apparent for lithium and valproate. While treating rapidly cycling patients, Calabrese and associates found that less than one-quarter of them responded well enough to the two-drug combination that they could be enrolled in a randomized double-blind comparison of each drug in monotherapy. Of those who were eligible, almost all relapsed with either lithium or valproate monotherapy and again required combination therapy.⁶

Table 1

RATE OF SWITCHING (%) INTO MANIA IN DEPRESSED BIPOLAR PATIENTS DURING ANTIDEPRESSANT TREATMENT*

Taken together, these studies indicate that even with our most effective and most studied agents, many patients respond inadequately. On the basis of this clinical reality, we began to explore additional options that might enhance clinical effectiveness.

Atypical antipsychotics

We assessed the addition of the atypical antipsychotic olanzapine in patients with treatment-refractory bipolar disorder⁷ and saw improvement in 57% of subjects with manic, mixed, and depressive components. These data foreshadowed more recent controlled findings of olanzapine’s usefulness in depression and mania.^8,9 Our preliminary open clinical trial experience allowed for more controlled studies and subsequent approval and wider clinical use of olanzapine in bipolar illness.

Our initial assessment of other atypical antipsychotics found that quetiapine was associated with significantly fewer depressive symptoms on the Inventory of Depressive Symptomatology (IDS) when used as part of the regular treatment regimen. This improvement, which was seen in the first month, was maintained over 4 months of treatment, whereas no significant improvement in depression severity was seen with the use of risperidone or clozapine.¹⁰

It would be highly preliminary to conclude from these uncontrolled data that quetiapine had greater effects on bipolar depressive symptoms than did risperidone or clozapine. We cannot rule out the possibility that patients with different degrees of treatment resistance were enrolled and treated with the different concomitant drugs. However, patients did not differ at baseline in severity of their depression.

In this initial look at the atypicals, the severity of depressive symptoms on the IDS was much greater than that of mania, as measured by the Young Mania Rating Scale (YMRS). Thus, the precise patterns of illness being treated and the impact of these antipsychotics on depressive cyclicity and duration await closer examination. We intend to look at the relative efficacy and side-effect profiles of each of the atypical antipsychotics as used in clinical practice.

Second-generation antidepressants

Bupropion, sertraline, and venlafaxine have different mechanisms of action but appear to be of value as adjuncts to bipolar disorder treatment. When we used them as adjuncts to mood stabilizers in a prospective study, we found a 40 to 50% acute response rate and some switching into hypomania and mania (Table 1).¹¹ Many switches appeared to involve only isolated brief bursts of hypomania or recurrent brief hypomanias, but more sustained episodes of hypomania (7 days) could be more clinically problematic. Only 13% of patients treated acutely with these antidepressants had more full-blown manic symptoms (i.e., those associated with moderate or greater dysfunction on the NIMH-LCM).

During the next year, when apparent acute antidepressant responders were offered continuation treatment, 18% switched into mania. However, most patients (about 80%) dropped out because of lack of efficacy (depressive recurrences), intolerance, or for administrative reasons. The 127 patients who were randomized received 175 acute antidepressant trials. Only 9% were associated with a switch into mania with moderate dysfunction, whereas another 9% showed periods of hypomania lasting longer than 1 week.¹²

Table 2

RELAPSE INTO DEPRESSION IN BIPOLAR PATIENTS AFTER 1 YEAR WITH OR WITHOUT ADJUNCTIVE ANTIDEPRESSANT TREATMENT*

We have entered 176 patients into this double-blind, randomized comparison of bupropion, sertraline, and venlafaxine, with another 27 randomized openly. The study will attempt to examine any possible between-drug differences. Even without the blind being broken, it appears that these antidepressants are associated with a somewhat lower-than-expected rate of switching into mania with dysfunction, but a direct comparison with a placebo is not available.

In two other series, patients who remained well for 2 months on antidepressants plus mood stabilizers and then continued on their antidepressants had a much lower incidence of depressive relapses over the following year than those who discontinued their antidepressants (Table 2).^13,14 Surprisingly, continuing the antidepressant was not associated with an increased rate of switching into mania.

Prospective randomized, controlled studies are required to confirm these findings. Even so, our studies appear to challenge conventional wisdom for the first time. Stopping antidepressant treatment in bipolar patients as soon as possible for fear of inducing a manic episode may not be the optimal recommendation in the admittedly small subgroup (about 15%) of patients who have responded well to an antidepressant for at least 2 months.

Table 3

SIX STUDIES COMPLETED BY SFBN INVESTIGATORS

Second-generation anticonvulsants

Based on our patients’ substantial residual symptoms, we explored a series of newly approved anticonvulsants for potential use as mood stabilizers.

Lamotrigine Consistent with other open and double-blind, placebo-controlled studies, lamotrigine showed promise as an adjunctive treatment, with improvement in depressive symptoms and cycling.¹⁵ One such study showed acute antidepressant effects of lamotrigine monotherapy compared with a placebo at dosages of 50 or 200 mg/d.¹⁶

Another double-blind, randomized, placebo-controlled NIMH study (partially funded by the Stanley Foundation) compared lamotrigine with gabapentin and a placebo in patients for whom lithium, carbamazepine, and valproate had failed.¹⁷ Most of these treatment-refractory patients received all three agents through three 6-week randomizations. Lamotrigine was much more effective in depression and overall illness than either a placebo or gabapentin. Men with bipolar compared with unipolar illness and patients with fewer unsuccessful clinical trials and hospitalizations for depression showed the greatest response.¹⁸

In two recent industry-sponsored controlled trials of long-term prophylaxis (following a recent manic or depressive episode), lamotrigine was significantly more effective than a placebo (Bowden et al and Calabrese et al, unpublished data). Lamotrigine was more effective than lithium in preventing depressive episodes, whereas lithium was more effective than lamotrigine for manic episodes, although lamotrigine was significantly better than the placebo.

These data suggest that lamotrigine may differ from valproate, carbamazepine, and lithium in being a more effective antidepressant than antimanic agent.

Topiramate Adjunctive use of topiramate in rapid-cycling and treatment-resistant patients has been examined in open studies, but controlled studies have not yet been published. In our open-label case series observations, 19 of 30 (63%) patients taking topiramate for mania or cycling were “much” or “very much” improved after 10 weeks, whereas only 3 of 11 (27%) patients taking topiramate for acute depression were so improved.¹⁹

Table 4

STUDIES IN PROGRESS BY SFBN INVESTIGATORS

An industry-sponsored double-blind, randomized trial of topiramate in acute mania looked promising in the first 67 patients, but not as encouraging in subsequent subjects. A positive drug effect re-emerged if one eliminated patients whose manic episodes were precipitated by antidepressants.

The acute antidepressant effects of topiramate did not appear promising in our study. On the other hand, a single-blind, randomized study of topiramate versus bupropion as adjunctive therapy for breakthrough bipolar depression suggested excellent acute response (approximately 56%) to both agents.²⁰ These data leave the potential antidepressant effects of topiramate undetermined.

In patients being treated with topiramate, we found significant weight loss (average –0.7 kg at 4 weeks, –1.6 kg at 10 weeks, –4.7 kg at 6 months, and –6.2 kg at 1 year).¹⁹ Average weight loss was 4.5±6.7 kg at the final evaluation (body mass index [BMI] change of –6.3% and –5% at 1 year and last evaluation, respectively).

We and others have thus seen substantial weight loss in one-third to one-half of patients taking topiramate for bipolar disorder.²¹ This weight loss is maintained over relatively long periods, which differentiates topiramate from other weight-loss regimens. Topiramate’s ability to decrease weight—even while it is in the early stages of evaluation as a mood stabilizer—is of considerable interest, given the substantial problem of overweight in the bipolar population and the fact that many drug therapies used in the illness are associated with weight gain.

We are proceeding with a randomized open comparison of the relative weight loss and psychotropic efficacy of topiramate versus the antiobesity agent sibutramine. Sibutramine has been reported to have antidepressant properties and is FDA-approved for weight loss.

Gabapentin and tiagabine Our group and many others have reported substantial overall clinical improvement when gabapentin was used as adjunctive therapy in an open study of patients with inadequate response to previous treatments.²² As monotherapy, however, gabapentin was not more effective than a placebo¹⁷ and was less effective than lamotrigine. Similarly, gabapentin was not an effective acute antimanic agent when compared with a placebo,²³ although other double-blind, controlled studies have indicated positive effects in anxiety disorders²⁴ and social phobias.²⁵ Thus, the gabapentin literature appears to be divergent—i.e., positive studies support its adjunctive use in bipolar patients, but controlled studies suggest that it is not directly antimanic or mood-stabilizing.

Gabapentin’s effect on syndromes that are highly comorbid with bipolar illness could account for its apparent success as open adjunctive therapy. For example, in addition to its antianxiety effects, gabapentin shows positive effects in alcohol withdrawal, pain syndromes, sleep disorders (including restless leg syndrome), and obsessive-compulsive disorder. Also, combining gabapentin with other psychotropics with other mechanisms of action may have a more robust therapeutic effect than monotherapy.

Our preliminary observations with the selective GABA-reuptake inhibitor tiagabine were not promising. In an open study, only 3 of the first 17 SFBN patients with treatment-resistant affective disorders showed a partial response (moderate improvement on the Clinical Global Impressions Scale for Bipolar Illness [CGI-BP]) to adjunctive tiagabine treatment when the dosage was gradually increased. Serious side effects, including two patients with possible seizures, were noted.²⁶ Similar results were seen when tiagabine doses were rapidly increased in eight patients with acute mania; none responded, and one had a major motor seizure.²⁷

Thus, our initial observations led us to discontinue use of tiagabine and suggest any further clinical consideration of this agent for treatment-resistant affective disorders would require great care. This perspective contrasts with several previous positive case reports. It is unknown whether selected patients or those treated with lower dosages would be more responsive to this agent.

Like valproate, gabapentin and tiagabine increase brain GABA, but their apparent lack of antimanic efficacy strongly suggests that raising brain GABA alone does little to counter mania. These data further support the viewpoint already offered that all anticonvulsants are not alike and that anticonvulsants as a class are not necessarily mood stabilizers.

Zonisamide and levetiracetam Open studies of these two other anticonvulsants are near completion. Each has an interesting mechanistic profile, good tolerability, and the (potentially positive) side effect of inducing some weight loss, based on studies of neurologic patients.

Omega-3 fatty acids Based on positive reports of antidepressant effects of omega-3 fatty acids,^28-30 we recently recruited more than 120 patients with bipolar disorder for two double-blind, randomized, controlled trials. Those patients with either an acute depression or a cyclic course will receive 6 grams of omega-3 fatty acid (the eicosapentaenoate form) or a placebo for 4 months of double-blind treatment, followed by an 8-month open, active continuation phase.

If results are positive, omega-3 fatty acids would represent the much-needed addition of a well-tolerated dietary agent to the therapeutic armamentarium directed at bipolar illness.

Conclusion

The Stanley Foundation Bipolar Network has begun to evaluate the usefulness of numerous older and new compounds for patients with bipolar disorder, including second-generation antidepressants, anticonvulsants, atypical antipsychotic agents, and omega-3 fatty acids. Based on initial observations from 16 treatment studies (Table 3), we have drawn these conclusions:

• Second-generation antidepressants such as bupropion, sertraline, and venlafaxine appear to have a lower-than-expected switch rate into mania, compared with the use of the older tricyclic antidepressants.
• If the addition of a second-generation antidepressant results in good antidepressant response for 2 months and no switches into mania, one should consider continuing the antidepressant in this small minority of patients, rather than stopping it as soon as possible as previously recommended.
• Adjunctive use of lamotrigine appears to be of value, particularly for acute depression and prophylaxis, for many patients who have not responded to other treatments.
• While our group and others have reported improvement with adjunctive gabapentin in bipolar patients in uncontrolled case series, its primary antimanic or mood-stabilizing utility (as well as that of tiagabine) does not appear promising.
• Topiramate’s ability to induce substantial weight loss may emerge as clinically therapeutic for patients with problematic weight gain related to other psychotropic drugs, independent of its ultimate utility as a possible mood stabilizer.

We are preparing to analyze other open case series assessing acute and long-term treatment outcomes as well as randomized, double-blind clinical trials. Even though the funding of this unique collaborative network is ending, we look forward to more effective treatment of bipolar disorder in the future with continued development of new psychotropic agents and data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) and the VA Cooperative studies.³¹

Related resources

• National Alliance for the Mentally Ill (NAMI). www.nami.org
• National Depressive and Manic-Depressive Association (NDMDA). www.ndmda.org

Drug brand names

• Bupropion • Wellbutrin
• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Sibutramine • Meridia
• Tiagabine • Gabitril
• Topiramate • Topamax
• Valproate • Depakote
• Venlafaxine • Effexor
• Zonisamide • Zonegran

Acknowledgement

The authors are particularly indebted to the generosity of The Stanley Foundation in making funds available for this series of studies and several about to be completed.

Disclosure

Financial disclosure statements have been provided by all authors and are available upon request at [email protected].

When choosing psychopharmacologic agents for patients with bipolar disorder, the clinician lacks guidance from controlled clinical trials at virtually every therapeutic step. To help remedy this problem, we in the Stanley Foundation Bipolar Network (SFBN) evaluated compounds with potentially important therapeutic profiles. We began by documenting the demographics and illness characteristics of patients with bipolar disorder. Then we assessed some 16 treatments in naturalistic or formal studies, some of which are complete and others ongoing.

In this second installment, we report our current information about the efficacy of second-generation antidepressants, atypical antipsychotics, and anticonvulsant agents.

Mood stabilizers

As mood stabilizers, the anticonvulsants carbamazepine and valproate are well-accepted alternatives or adjuncts to lithium carbonate, which remains a mainstay treatment for acute episodes and long-term prophylaxis.¹

Valproate is approved by the FDA for treatment of acute mania but not for long-term prevention. Open studies in rapid-cycling, treatment-refractory patients demonstrate substantial improvement for both manic and depressive phases with valproate. In the most recent controlled study, valproate did not prevent manic episodes to a statistically significant degree, but it did show greater antidepressant effects than placebo or lithium.²

Carbamazepine has been widely studied in acute mania and compared with lithium for long-term prophylaxis. Most studies show nonsignificant differences between carbamazepine and lithium in preventing manic and depressive episodes, although several studies indicate less-robust antimanic effects of carbamazepine,³ particularly for patients with classic euphoric mania without psychosis, bipolar II, or associated substance abuse.⁴

In atypical patients, carbamazepine appeared to outperform lithium, suggesting clinical differences in these agents that have different mechanisms of action across neurotransmitter and peptide systems.

Low response rates Most randomized controlled trials and open adjunct studies suggest that 50% or more patients respond to lithium, valproate, or carbamazepine. Outcomes may be far less positive in clinical practice, however. Despite the use of mood stabilizers and a variety of antidepressants, benzodiazepines, and neuroleptics, our patients experienced substantial residual manic and depressive symptoms and functional impairment.

Similarly, clinician ratings on the National Institute of Mental Health Life Chart Method (NIMH-LCM) indicated a high rate of breakthrough episodes during carefully monitored and aggressive psychopharmacologic treatment.⁵ Two-thirds of the first 258 bipolar outpatients that we followed and rated daily for 1 year continued to be substantially impaired. One-quarter of them were ill for more than 75% of the year, despite using an average 4.1 psychopharmacologic agents per patient, including mood stabilizers, antidepressants, antipsychotics, and other agents.

Acute and long-term combination therapy appears more effective than monotherapy, particularly for treatment-refractory rapid cyclers.³ Even so, many patients do not respond to combination therapy. For example, in a 1-year prophylaxis study, 25% or fewer patients were rated “much improved” to “very much improved” on the Clinical Global Impressions (CGI) scale with lithium or carbamazepine as the baseline mood stabilizer and with antidepressants, neuroleptics, and benzodiazepines used as needed. In the third year of combination therapy, the overall response rate, including rapid cyclers, was roughly 50%.³

A low rate of response is apparent for lithium and valproate. While treating rapidly cycling patients, Calabrese and associates found that less than one-quarter of them responded well enough to the two-drug combination that they could be enrolled in a randomized double-blind comparison of each drug in monotherapy. Of those who were eligible, almost all relapsed with either lithium or valproate monotherapy and again required combination therapy.⁶

Table 1

RATE OF SWITCHING (%) INTO MANIA IN DEPRESSED BIPOLAR PATIENTS DURING ANTIDEPRESSANT TREATMENT*

Taken together, these studies indicate that even with our most effective and most studied agents, many patients respond inadequately. On the basis of this clinical reality, we began to explore additional options that might enhance clinical effectiveness.

Atypical antipsychotics

We assessed the addition of the atypical antipsychotic olanzapine in patients with treatment-refractory bipolar disorder⁷ and saw improvement in 57% of subjects with manic, mixed, and depressive components. These data foreshadowed more recent controlled findings of olanzapine’s usefulness in depression and mania.^8,9 Our preliminary open clinical trial experience allowed for more controlled studies and subsequent approval and wider clinical use of olanzapine in bipolar illness.

Our initial assessment of other atypical antipsychotics found that quetiapine was associated with significantly fewer depressive symptoms on the Inventory of Depressive Symptomatology (IDS) when used as part of the regular treatment regimen. This improvement, which was seen in the first month, was maintained over 4 months of treatment, whereas no significant improvement in depression severity was seen with the use of risperidone or clozapine.¹⁰

It would be highly preliminary to conclude from these uncontrolled data that quetiapine had greater effects on bipolar depressive symptoms than did risperidone or clozapine. We cannot rule out the possibility that patients with different degrees of treatment resistance were enrolled and treated with the different concomitant drugs. However, patients did not differ at baseline in severity of their depression.

In this initial look at the atypicals, the severity of depressive symptoms on the IDS was much greater than that of mania, as measured by the Young Mania Rating Scale (YMRS). Thus, the precise patterns of illness being treated and the impact of these antipsychotics on depressive cyclicity and duration await closer examination. We intend to look at the relative efficacy and side-effect profiles of each of the atypical antipsychotics as used in clinical practice.

Second-generation antidepressants

Bupropion, sertraline, and venlafaxine have different mechanisms of action but appear to be of value as adjuncts to bipolar disorder treatment. When we used them as adjuncts to mood stabilizers in a prospective study, we found a 40 to 50% acute response rate and some switching into hypomania and mania (Table 1).¹¹ Many switches appeared to involve only isolated brief bursts of hypomania or recurrent brief hypomanias, but more sustained episodes of hypomania (7 days) could be more clinically problematic. Only 13% of patients treated acutely with these antidepressants had more full-blown manic symptoms (i.e., those associated with moderate or greater dysfunction on the NIMH-LCM).

During the next year, when apparent acute antidepressant responders were offered continuation treatment, 18% switched into mania. However, most patients (about 80%) dropped out because of lack of efficacy (depressive recurrences), intolerance, or for administrative reasons. The 127 patients who were randomized received 175 acute antidepressant trials. Only 9% were associated with a switch into mania with moderate dysfunction, whereas another 9% showed periods of hypomania lasting longer than 1 week.¹²

Table 2

RELAPSE INTO DEPRESSION IN BIPOLAR PATIENTS AFTER 1 YEAR WITH OR WITHOUT ADJUNCTIVE ANTIDEPRESSANT TREATMENT*

We have entered 176 patients into this double-blind, randomized comparison of bupropion, sertraline, and venlafaxine, with another 27 randomized openly. The study will attempt to examine any possible between-drug differences. Even without the blind being broken, it appears that these antidepressants are associated with a somewhat lower-than-expected rate of switching into mania with dysfunction, but a direct comparison with a placebo is not available.

In two other series, patients who remained well for 2 months on antidepressants plus mood stabilizers and then continued on their antidepressants had a much lower incidence of depressive relapses over the following year than those who discontinued their antidepressants (Table 2).^13,14 Surprisingly, continuing the antidepressant was not associated with an increased rate of switching into mania.

Prospective randomized, controlled studies are required to confirm these findings. Even so, our studies appear to challenge conventional wisdom for the first time. Stopping antidepressant treatment in bipolar patients as soon as possible for fear of inducing a manic episode may not be the optimal recommendation in the admittedly small subgroup (about 15%) of patients who have responded well to an antidepressant for at least 2 months.

Table 3

SIX STUDIES COMPLETED BY SFBN INVESTIGATORS

Second-generation anticonvulsants

Based on our patients’ substantial residual symptoms, we explored a series of newly approved anticonvulsants for potential use as mood stabilizers.

Lamotrigine Consistent with other open and double-blind, placebo-controlled studies, lamotrigine showed promise as an adjunctive treatment, with improvement in depressive symptoms and cycling.¹⁵ One such study showed acute antidepressant effects of lamotrigine monotherapy compared with a placebo at dosages of 50 or 200 mg/d.¹⁶

Another double-blind, randomized, placebo-controlled NIMH study (partially funded by the Stanley Foundation) compared lamotrigine with gabapentin and a placebo in patients for whom lithium, carbamazepine, and valproate had failed.¹⁷ Most of these treatment-refractory patients received all three agents through three 6-week randomizations. Lamotrigine was much more effective in depression and overall illness than either a placebo or gabapentin. Men with bipolar compared with unipolar illness and patients with fewer unsuccessful clinical trials and hospitalizations for depression showed the greatest response.¹⁸

In two recent industry-sponsored controlled trials of long-term prophylaxis (following a recent manic or depressive episode), lamotrigine was significantly more effective than a placebo (Bowden et al and Calabrese et al, unpublished data). Lamotrigine was more effective than lithium in preventing depressive episodes, whereas lithium was more effective than lamotrigine for manic episodes, although lamotrigine was significantly better than the placebo.

These data suggest that lamotrigine may differ from valproate, carbamazepine, and lithium in being a more effective antidepressant than antimanic agent.

Topiramate Adjunctive use of topiramate in rapid-cycling and treatment-resistant patients has been examined in open studies, but controlled studies have not yet been published. In our open-label case series observations, 19 of 30 (63%) patients taking topiramate for mania or cycling were “much” or “very much” improved after 10 weeks, whereas only 3 of 11 (27%) patients taking topiramate for acute depression were so improved.¹⁹

Table 4

STUDIES IN PROGRESS BY SFBN INVESTIGATORS

An industry-sponsored double-blind, randomized trial of topiramate in acute mania looked promising in the first 67 patients, but not as encouraging in subsequent subjects. A positive drug effect re-emerged if one eliminated patients whose manic episodes were precipitated by antidepressants.

The acute antidepressant effects of topiramate did not appear promising in our study. On the other hand, a single-blind, randomized study of topiramate versus bupropion as adjunctive therapy for breakthrough bipolar depression suggested excellent acute response (approximately 56%) to both agents.²⁰ These data leave the potential antidepressant effects of topiramate undetermined.

In patients being treated with topiramate, we found significant weight loss (average –0.7 kg at 4 weeks, –1.6 kg at 10 weeks, –4.7 kg at 6 months, and –6.2 kg at 1 year).¹⁹ Average weight loss was 4.5±6.7 kg at the final evaluation (body mass index [BMI] change of –6.3% and –5% at 1 year and last evaluation, respectively).

We and others have thus seen substantial weight loss in one-third to one-half of patients taking topiramate for bipolar disorder.²¹ This weight loss is maintained over relatively long periods, which differentiates topiramate from other weight-loss regimens. Topiramate’s ability to decrease weight—even while it is in the early stages of evaluation as a mood stabilizer—is of considerable interest, given the substantial problem of overweight in the bipolar population and the fact that many drug therapies used in the illness are associated with weight gain.

We are proceeding with a randomized open comparison of the relative weight loss and psychotropic efficacy of topiramate versus the antiobesity agent sibutramine. Sibutramine has been reported to have antidepressant properties and is FDA-approved for weight loss.

Gabapentin and tiagabine Our group and many others have reported substantial overall clinical improvement when gabapentin was used as adjunctive therapy in an open study of patients with inadequate response to previous treatments.²² As monotherapy, however, gabapentin was not more effective than a placebo¹⁷ and was less effective than lamotrigine. Similarly, gabapentin was not an effective acute antimanic agent when compared with a placebo,²³ although other double-blind, controlled studies have indicated positive effects in anxiety disorders²⁴ and social phobias.²⁵ Thus, the gabapentin literature appears to be divergent—i.e., positive studies support its adjunctive use in bipolar patients, but controlled studies suggest that it is not directly antimanic or mood-stabilizing.

Gabapentin’s effect on syndromes that are highly comorbid with bipolar illness could account for its apparent success as open adjunctive therapy. For example, in addition to its antianxiety effects, gabapentin shows positive effects in alcohol withdrawal, pain syndromes, sleep disorders (including restless leg syndrome), and obsessive-compulsive disorder. Also, combining gabapentin with other psychotropics with other mechanisms of action may have a more robust therapeutic effect than monotherapy.

Our preliminary observations with the selective GABA-reuptake inhibitor tiagabine were not promising. In an open study, only 3 of the first 17 SFBN patients with treatment-resistant affective disorders showed a partial response (moderate improvement on the Clinical Global Impressions Scale for Bipolar Illness [CGI-BP]) to adjunctive tiagabine treatment when the dosage was gradually increased. Serious side effects, including two patients with possible seizures, were noted.²⁶ Similar results were seen when tiagabine doses were rapidly increased in eight patients with acute mania; none responded, and one had a major motor seizure.²⁷

Thus, our initial observations led us to discontinue use of tiagabine and suggest any further clinical consideration of this agent for treatment-resistant affective disorders would require great care. This perspective contrasts with several previous positive case reports. It is unknown whether selected patients or those treated with lower dosages would be more responsive to this agent.

Like valproate, gabapentin and tiagabine increase brain GABA, but their apparent lack of antimanic efficacy strongly suggests that raising brain GABA alone does little to counter mania. These data further support the viewpoint already offered that all anticonvulsants are not alike and that anticonvulsants as a class are not necessarily mood stabilizers.

Zonisamide and levetiracetam Open studies of these two other anticonvulsants are near completion. Each has an interesting mechanistic profile, good tolerability, and the (potentially positive) side effect of inducing some weight loss, based on studies of neurologic patients.

Omega-3 fatty acids Based on positive reports of antidepressant effects of omega-3 fatty acids,^28-30 we recently recruited more than 120 patients with bipolar disorder for two double-blind, randomized, controlled trials. Those patients with either an acute depression or a cyclic course will receive 6 grams of omega-3 fatty acid (the eicosapentaenoate form) or a placebo for 4 months of double-blind treatment, followed by an 8-month open, active continuation phase.

If results are positive, omega-3 fatty acids would represent the much-needed addition of a well-tolerated dietary agent to the therapeutic armamentarium directed at bipolar illness.

Conclusion

The Stanley Foundation Bipolar Network has begun to evaluate the usefulness of numerous older and new compounds for patients with bipolar disorder, including second-generation antidepressants, anticonvulsants, atypical antipsychotic agents, and omega-3 fatty acids. Based on initial observations from 16 treatment studies (Table 3), we have drawn these conclusions:

• Second-generation antidepressants such as bupropion, sertraline, and venlafaxine appear to have a lower-than-expected switch rate into mania, compared with the use of the older tricyclic antidepressants.
• If the addition of a second-generation antidepressant results in good antidepressant response for 2 months and no switches into mania, one should consider continuing the antidepressant in this small minority of patients, rather than stopping it as soon as possible as previously recommended.
• Adjunctive use of lamotrigine appears to be of value, particularly for acute depression and prophylaxis, for many patients who have not responded to other treatments.
• While our group and others have reported improvement with adjunctive gabapentin in bipolar patients in uncontrolled case series, its primary antimanic or mood-stabilizing utility (as well as that of tiagabine) does not appear promising.
• Topiramate’s ability to induce substantial weight loss may emerge as clinically therapeutic for patients with problematic weight gain related to other psychotropic drugs, independent of its ultimate utility as a possible mood stabilizer.

We are preparing to analyze other open case series assessing acute and long-term treatment outcomes as well as randomized, double-blind clinical trials. Even though the funding of this unique collaborative network is ending, we look forward to more effective treatment of bipolar disorder in the future with continued development of new psychotropic agents and data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) and the VA Cooperative studies.³¹

Related resources

• National Alliance for the Mentally Ill (NAMI). www.nami.org
• National Depressive and Manic-Depressive Association (NDMDA). www.ndmda.org

Drug brand names

• Bupropion • Wellbutrin
• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Sibutramine • Meridia
• Tiagabine • Gabitril
• Topiramate • Topamax
• Valproate • Depakote
• Venlafaxine • Effexor
• Zonisamide • Zonegran

Acknowledgement

The authors are particularly indebted to the generosity of The Stanley Foundation in making funds available for this series of studies and several about to be completed.

Disclosure

Financial disclosure statements have been provided by all authors and are available upon request at [email protected].

When choosing psychopharmacologic agents for patients with bipolar disorder, the clinician lacks guidance from controlled clinical trials at virtually every therapeutic step. To help remedy this problem, we in the Stanley Foundation Bipolar Network (SFBN) evaluated compounds with potentially important therapeutic profiles. We began by documenting the demographics and illness characteristics of patients with bipolar disorder. Then we assessed some 16 treatments in naturalistic or formal studies, some of which are complete and others ongoing.

In this second installment, we report our current information about the efficacy of second-generation antidepressants, atypical antipsychotics, and anticonvulsant agents.

Mood stabilizers

As mood stabilizers, the anticonvulsants carbamazepine and valproate are well-accepted alternatives or adjuncts to lithium carbonate, which remains a mainstay treatment for acute episodes and long-term prophylaxis.¹

Valproate is approved by the FDA for treatment of acute mania but not for long-term prevention. Open studies in rapid-cycling, treatment-refractory patients demonstrate substantial improvement for both manic and depressive phases with valproate. In the most recent controlled study, valproate did not prevent manic episodes to a statistically significant degree, but it did show greater antidepressant effects than placebo or lithium.²

Carbamazepine has been widely studied in acute mania and compared with lithium for long-term prophylaxis. Most studies show nonsignificant differences between carbamazepine and lithium in preventing manic and depressive episodes, although several studies indicate less-robust antimanic effects of carbamazepine,³ particularly for patients with classic euphoric mania without psychosis, bipolar II, or associated substance abuse.⁴

In atypical patients, carbamazepine appeared to outperform lithium, suggesting clinical differences in these agents that have different mechanisms of action across neurotransmitter and peptide systems.

Low response rates Most randomized controlled trials and open adjunct studies suggest that 50% or more patients respond to lithium, valproate, or carbamazepine. Outcomes may be far less positive in clinical practice, however. Despite the use of mood stabilizers and a variety of antidepressants, benzodiazepines, and neuroleptics, our patients experienced substantial residual manic and depressive symptoms and functional impairment.

Similarly, clinician ratings on the National Institute of Mental Health Life Chart Method (NIMH-LCM) indicated a high rate of breakthrough episodes during carefully monitored and aggressive psychopharmacologic treatment.⁵ Two-thirds of the first 258 bipolar outpatients that we followed and rated daily for 1 year continued to be substantially impaired. One-quarter of them were ill for more than 75% of the year, despite using an average 4.1 psychopharmacologic agents per patient, including mood stabilizers, antidepressants, antipsychotics, and other agents.

Acute and long-term combination therapy appears more effective than monotherapy, particularly for treatment-refractory rapid cyclers.³ Even so, many patients do not respond to combination therapy. For example, in a 1-year prophylaxis study, 25% or fewer patients were rated “much improved” to “very much improved” on the Clinical Global Impressions (CGI) scale with lithium or carbamazepine as the baseline mood stabilizer and with antidepressants, neuroleptics, and benzodiazepines used as needed. In the third year of combination therapy, the overall response rate, including rapid cyclers, was roughly 50%.³

A low rate of response is apparent for lithium and valproate. While treating rapidly cycling patients, Calabrese and associates found that less than one-quarter of them responded well enough to the two-drug combination that they could be enrolled in a randomized double-blind comparison of each drug in monotherapy. Of those who were eligible, almost all relapsed with either lithium or valproate monotherapy and again required combination therapy.⁶

Table 1

RATE OF SWITCHING (%) INTO MANIA IN DEPRESSED BIPOLAR PATIENTS DURING ANTIDEPRESSANT TREATMENT*

Taken together, these studies indicate that even with our most effective and most studied agents, many patients respond inadequately. On the basis of this clinical reality, we began to explore additional options that might enhance clinical effectiveness.

Atypical antipsychotics

We assessed the addition of the atypical antipsychotic olanzapine in patients with treatment-refractory bipolar disorder⁷ and saw improvement in 57% of subjects with manic, mixed, and depressive components. These data foreshadowed more recent controlled findings of olanzapine’s usefulness in depression and mania.^8,9 Our preliminary open clinical trial experience allowed for more controlled studies and subsequent approval and wider clinical use of olanzapine in bipolar illness.

Our initial assessment of other atypical antipsychotics found that quetiapine was associated with significantly fewer depressive symptoms on the Inventory of Depressive Symptomatology (IDS) when used as part of the regular treatment regimen. This improvement, which was seen in the first month, was maintained over 4 months of treatment, whereas no significant improvement in depression severity was seen with the use of risperidone or clozapine.¹⁰

It would be highly preliminary to conclude from these uncontrolled data that quetiapine had greater effects on bipolar depressive symptoms than did risperidone or clozapine. We cannot rule out the possibility that patients with different degrees of treatment resistance were enrolled and treated with the different concomitant drugs. However, patients did not differ at baseline in severity of their depression.

In this initial look at the atypicals, the severity of depressive symptoms on the IDS was much greater than that of mania, as measured by the Young Mania Rating Scale (YMRS). Thus, the precise patterns of illness being treated and the impact of these antipsychotics on depressive cyclicity and duration await closer examination. We intend to look at the relative efficacy and side-effect profiles of each of the atypical antipsychotics as used in clinical practice.

Second-generation antidepressants

Bupropion, sertraline, and venlafaxine have different mechanisms of action but appear to be of value as adjuncts to bipolar disorder treatment. When we used them as adjuncts to mood stabilizers in a prospective study, we found a 40 to 50% acute response rate and some switching into hypomania and mania (Table 1).¹¹ Many switches appeared to involve only isolated brief bursts of hypomania or recurrent brief hypomanias, but more sustained episodes of hypomania (7 days) could be more clinically problematic. Only 13% of patients treated acutely with these antidepressants had more full-blown manic symptoms (i.e., those associated with moderate or greater dysfunction on the NIMH-LCM).

During the next year, when apparent acute antidepressant responders were offered continuation treatment, 18% switched into mania. However, most patients (about 80%) dropped out because of lack of efficacy (depressive recurrences), intolerance, or for administrative reasons. The 127 patients who were randomized received 175 acute antidepressant trials. Only 9% were associated with a switch into mania with moderate dysfunction, whereas another 9% showed periods of hypomania lasting longer than 1 week.¹²

Table 2

RELAPSE INTO DEPRESSION IN BIPOLAR PATIENTS AFTER 1 YEAR WITH OR WITHOUT ADJUNCTIVE ANTIDEPRESSANT TREATMENT*

We have entered 176 patients into this double-blind, randomized comparison of bupropion, sertraline, and venlafaxine, with another 27 randomized openly. The study will attempt to examine any possible between-drug differences. Even without the blind being broken, it appears that these antidepressants are associated with a somewhat lower-than-expected rate of switching into mania with dysfunction, but a direct comparison with a placebo is not available.

In two other series, patients who remained well for 2 months on antidepressants plus mood stabilizers and then continued on their antidepressants had a much lower incidence of depressive relapses over the following year than those who discontinued their antidepressants (Table 2).^13,14 Surprisingly, continuing the antidepressant was not associated with an increased rate of switching into mania.

Prospective randomized, controlled studies are required to confirm these findings. Even so, our studies appear to challenge conventional wisdom for the first time. Stopping antidepressant treatment in bipolar patients as soon as possible for fear of inducing a manic episode may not be the optimal recommendation in the admittedly small subgroup (about 15%) of patients who have responded well to an antidepressant for at least 2 months.

Table 3

SIX STUDIES COMPLETED BY SFBN INVESTIGATORS

Second-generation anticonvulsants

Based on our patients’ substantial residual symptoms, we explored a series of newly approved anticonvulsants for potential use as mood stabilizers.

Lamotrigine Consistent with other open and double-blind, placebo-controlled studies, lamotrigine showed promise as an adjunctive treatment, with improvement in depressive symptoms and cycling.¹⁵ One such study showed acute antidepressant effects of lamotrigine monotherapy compared with a placebo at dosages of 50 or 200 mg/d.¹⁶

Another double-blind, randomized, placebo-controlled NIMH study (partially funded by the Stanley Foundation) compared lamotrigine with gabapentin and a placebo in patients for whom lithium, carbamazepine, and valproate had failed.¹⁷ Most of these treatment-refractory patients received all three agents through three 6-week randomizations. Lamotrigine was much more effective in depression and overall illness than either a placebo or gabapentin. Men with bipolar compared with unipolar illness and patients with fewer unsuccessful clinical trials and hospitalizations for depression showed the greatest response.¹⁸

In two recent industry-sponsored controlled trials of long-term prophylaxis (following a recent manic or depressive episode), lamotrigine was significantly more effective than a placebo (Bowden et al and Calabrese et al, unpublished data). Lamotrigine was more effective than lithium in preventing depressive episodes, whereas lithium was more effective than lamotrigine for manic episodes, although lamotrigine was significantly better than the placebo.

These data suggest that lamotrigine may differ from valproate, carbamazepine, and lithium in being a more effective antidepressant than antimanic agent.

Topiramate Adjunctive use of topiramate in rapid-cycling and treatment-resistant patients has been examined in open studies, but controlled studies have not yet been published. In our open-label case series observations, 19 of 30 (63%) patients taking topiramate for mania or cycling were “much” or “very much” improved after 10 weeks, whereas only 3 of 11 (27%) patients taking topiramate for acute depression were so improved.¹⁹

Table 4

STUDIES IN PROGRESS BY SFBN INVESTIGATORS

An industry-sponsored double-blind, randomized trial of topiramate in acute mania looked promising in the first 67 patients, but not as encouraging in subsequent subjects. A positive drug effect re-emerged if one eliminated patients whose manic episodes were precipitated by antidepressants.

The acute antidepressant effects of topiramate did not appear promising in our study. On the other hand, a single-blind, randomized study of topiramate versus bupropion as adjunctive therapy for breakthrough bipolar depression suggested excellent acute response (approximately 56%) to both agents.²⁰ These data leave the potential antidepressant effects of topiramate undetermined.

In patients being treated with topiramate, we found significant weight loss (average –0.7 kg at 4 weeks, –1.6 kg at 10 weeks, –4.7 kg at 6 months, and –6.2 kg at 1 year).¹⁹ Average weight loss was 4.5±6.7 kg at the final evaluation (body mass index [BMI] change of –6.3% and –5% at 1 year and last evaluation, respectively).

We and others have thus seen substantial weight loss in one-third to one-half of patients taking topiramate for bipolar disorder.²¹ This weight loss is maintained over relatively long periods, which differentiates topiramate from other weight-loss regimens. Topiramate’s ability to decrease weight—even while it is in the early stages of evaluation as a mood stabilizer—is of considerable interest, given the substantial problem of overweight in the bipolar population and the fact that many drug therapies used in the illness are associated with weight gain.

We are proceeding with a randomized open comparison of the relative weight loss and psychotropic efficacy of topiramate versus the antiobesity agent sibutramine. Sibutramine has been reported to have antidepressant properties and is FDA-approved for weight loss.

Gabapentin and tiagabine Our group and many others have reported substantial overall clinical improvement when gabapentin was used as adjunctive therapy in an open study of patients with inadequate response to previous treatments.²² As monotherapy, however, gabapentin was not more effective than a placebo¹⁷ and was less effective than lamotrigine. Similarly, gabapentin was not an effective acute antimanic agent when compared with a placebo,²³ although other double-blind, controlled studies have indicated positive effects in anxiety disorders²⁴ and social phobias.²⁵ Thus, the gabapentin literature appears to be divergent—i.e., positive studies support its adjunctive use in bipolar patients, but controlled studies suggest that it is not directly antimanic or mood-stabilizing.

Gabapentin’s effect on syndromes that are highly comorbid with bipolar illness could account for its apparent success as open adjunctive therapy. For example, in addition to its antianxiety effects, gabapentin shows positive effects in alcohol withdrawal, pain syndromes, sleep disorders (including restless leg syndrome), and obsessive-compulsive disorder. Also, combining gabapentin with other psychotropics with other mechanisms of action may have a more robust therapeutic effect than monotherapy.

Our preliminary observations with the selective GABA-reuptake inhibitor tiagabine were not promising. In an open study, only 3 of the first 17 SFBN patients with treatment-resistant affective disorders showed a partial response (moderate improvement on the Clinical Global Impressions Scale for Bipolar Illness [CGI-BP]) to adjunctive tiagabine treatment when the dosage was gradually increased. Serious side effects, including two patients with possible seizures, were noted.²⁶ Similar results were seen when tiagabine doses were rapidly increased in eight patients with acute mania; none responded, and one had a major motor seizure.²⁷

Thus, our initial observations led us to discontinue use of tiagabine and suggest any further clinical consideration of this agent for treatment-resistant affective disorders would require great care. This perspective contrasts with several previous positive case reports. It is unknown whether selected patients or those treated with lower dosages would be more responsive to this agent.

Like valproate, gabapentin and tiagabine increase brain GABA, but their apparent lack of antimanic efficacy strongly suggests that raising brain GABA alone does little to counter mania. These data further support the viewpoint already offered that all anticonvulsants are not alike and that anticonvulsants as a class are not necessarily mood stabilizers.

Zonisamide and levetiracetam Open studies of these two other anticonvulsants are near completion. Each has an interesting mechanistic profile, good tolerability, and the (potentially positive) side effect of inducing some weight loss, based on studies of neurologic patients.

Omega-3 fatty acids Based on positive reports of antidepressant effects of omega-3 fatty acids,^28-30 we recently recruited more than 120 patients with bipolar disorder for two double-blind, randomized, controlled trials. Those patients with either an acute depression or a cyclic course will receive 6 grams of omega-3 fatty acid (the eicosapentaenoate form) or a placebo for 4 months of double-blind treatment, followed by an 8-month open, active continuation phase.

If results are positive, omega-3 fatty acids would represent the much-needed addition of a well-tolerated dietary agent to the therapeutic armamentarium directed at bipolar illness.

Conclusion

The Stanley Foundation Bipolar Network has begun to evaluate the usefulness of numerous older and new compounds for patients with bipolar disorder, including second-generation antidepressants, anticonvulsants, atypical antipsychotic agents, and omega-3 fatty acids. Based on initial observations from 16 treatment studies (Table 3), we have drawn these conclusions:

• Second-generation antidepressants such as bupropion, sertraline, and venlafaxine appear to have a lower-than-expected switch rate into mania, compared with the use of the older tricyclic antidepressants.
• If the addition of a second-generation antidepressant results in good antidepressant response for 2 months and no switches into mania, one should consider continuing the antidepressant in this small minority of patients, rather than stopping it as soon as possible as previously recommended.
• Adjunctive use of lamotrigine appears to be of value, particularly for acute depression and prophylaxis, for many patients who have not responded to other treatments.
• While our group and others have reported improvement with adjunctive gabapentin in bipolar patients in uncontrolled case series, its primary antimanic or mood-stabilizing utility (as well as that of tiagabine) does not appear promising.
• Topiramate’s ability to induce substantial weight loss may emerge as clinically therapeutic for patients with problematic weight gain related to other psychotropic drugs, independent of its ultimate utility as a possible mood stabilizer.

We are preparing to analyze other open case series assessing acute and long-term treatment outcomes as well as randomized, double-blind clinical trials. Even though the funding of this unique collaborative network is ending, we look forward to more effective treatment of bipolar disorder in the future with continued development of new psychotropic agents and data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) and the VA Cooperative studies.³¹

Related resources

• National Alliance for the Mentally Ill (NAMI). www.nami.org
• National Depressive and Manic-Depressive Association (NDMDA). www.ndmda.org

Drug brand names

• Bupropion • Wellbutrin
• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Sibutramine • Meridia
• Tiagabine • Gabitril
• Topiramate • Topamax
• Valproate • Depakote
• Venlafaxine • Effexor
• Zonisamide • Zonegran

Acknowledgement

The authors are particularly indebted to the generosity of The Stanley Foundation in making funds available for this series of studies and several about to be completed.

Disclosure

Financial disclosure statements have been provided by all authors and are available upon request at [email protected].

When choosing psychopharmacologic agents for patients with bipolar disorder, the clinician lacks guidance from controlled clinical trials at virtually every therapeutic step. To help remedy this problem, we in the Stanley Foundation Bipolar Network (SFBN) evaluated compounds with potentially important therapeutic profiles. We began by documenting the demographics and illness characteristics of patients with bipolar disorder. Then we assessed some 16 treatments in naturalistic or formal studies, some of which are complete and others ongoing.

In this second installment, we report our current information about the efficacy of second-generation antidepressants, atypical antipsychotics, and anticonvulsant agents.

Mood stabilizers

As mood stabilizers, the anticonvulsants carbamazepine and valproate are well-accepted alternatives or adjuncts to lithium carbonate, which remains a mainstay treatment for acute episodes and long-term prophylaxis.¹

Valproate is approved by the FDA for treatment of acute mania but not for long-term prevention. Open studies in rapid-cycling, treatment-refractory patients demonstrate substantial improvement for both manic and depressive phases with valproate. In the most recent controlled study, valproate did not prevent manic episodes to a statistically significant degree, but it did show greater antidepressant effects than placebo or lithium.²

Carbamazepine has been widely studied in acute mania and compared with lithium for long-term prophylaxis. Most studies show nonsignificant differences between carbamazepine and lithium in preventing manic and depressive episodes, although several studies indicate less-robust antimanic effects of carbamazepine,³ particularly for patients with classic euphoric mania without psychosis, bipolar II, or associated substance abuse.⁴

In atypical patients, carbamazepine appeared to outperform lithium, suggesting clinical differences in these agents that have different mechanisms of action across neurotransmitter and peptide systems.

Low response rates Most randomized controlled trials and open adjunct studies suggest that 50% or more patients respond to lithium, valproate, or carbamazepine. Outcomes may be far less positive in clinical practice, however. Despite the use of mood stabilizers and a variety of antidepressants, benzodiazepines, and neuroleptics, our patients experienced substantial residual manic and depressive symptoms and functional impairment.

Similarly, clinician ratings on the National Institute of Mental Health Life Chart Method (NIMH-LCM) indicated a high rate of breakthrough episodes during carefully monitored and aggressive psychopharmacologic treatment.⁵ Two-thirds of the first 258 bipolar outpatients that we followed and rated daily for 1 year continued to be substantially impaired. One-quarter of them were ill for more than 75% of the year, despite using an average 4.1 psychopharmacologic agents per patient, including mood stabilizers, antidepressants, antipsychotics, and other agents.

Acute and long-term combination therapy appears more effective than monotherapy, particularly for treatment-refractory rapid cyclers.³ Even so, many patients do not respond to combination therapy. For example, in a 1-year prophylaxis study, 25% or fewer patients were rated “much improved” to “very much improved” on the Clinical Global Impressions (CGI) scale with lithium or carbamazepine as the baseline mood stabilizer and with antidepressants, neuroleptics, and benzodiazepines used as needed. In the third year of combination therapy, the overall response rate, including rapid cyclers, was roughly 50%.³

A low rate of response is apparent for lithium and valproate. While treating rapidly cycling patients, Calabrese and associates found that less than one-quarter of them responded well enough to the two-drug combination that they could be enrolled in a randomized double-blind comparison of each drug in monotherapy. Of those who were eligible, almost all relapsed with either lithium or valproate monotherapy and again required combination therapy.⁶

Table 1

RATE OF SWITCHING (%) INTO MANIA IN DEPRESSED BIPOLAR PATIENTS DURING ANTIDEPRESSANT TREATMENT*

Taken together, these studies indicate that even with our most effective and most studied agents, many patients respond inadequately. On the basis of this clinical reality, we began to explore additional options that might enhance clinical effectiveness.

Atypical antipsychotics

We assessed the addition of the atypical antipsychotic olanzapine in patients with treatment-refractory bipolar disorder⁷ and saw improvement in 57% of subjects with manic, mixed, and depressive components. These data foreshadowed more recent controlled findings of olanzapine’s usefulness in depression and mania.^8,9 Our preliminary open clinical trial experience allowed for more controlled studies and subsequent approval and wider clinical use of olanzapine in bipolar illness.

Our initial assessment of other atypical antipsychotics found that quetiapine was associated with significantly fewer depressive symptoms on the Inventory of Depressive Symptomatology (IDS) when used as part of the regular treatment regimen. This improvement, which was seen in the first month, was maintained over 4 months of treatment, whereas no significant improvement in depression severity was seen with the use of risperidone or clozapine.¹⁰

It would be highly preliminary to conclude from these uncontrolled data that quetiapine had greater effects on bipolar depressive symptoms than did risperidone or clozapine. We cannot rule out the possibility that patients with different degrees of treatment resistance were enrolled and treated with the different concomitant drugs. However, patients did not differ at baseline in severity of their depression.

In this initial look at the atypicals, the severity of depressive symptoms on the IDS was much greater than that of mania, as measured by the Young Mania Rating Scale (YMRS). Thus, the precise patterns of illness being treated and the impact of these antipsychotics on depressive cyclicity and duration await closer examination. We intend to look at the relative efficacy and side-effect profiles of each of the atypical antipsychotics as used in clinical practice.

Second-generation antidepressants

Bupropion, sertraline, and venlafaxine have different mechanisms of action but appear to be of value as adjuncts to bipolar disorder treatment. When we used them as adjuncts to mood stabilizers in a prospective study, we found a 40 to 50% acute response rate and some switching into hypomania and mania (Table 1).¹¹ Many switches appeared to involve only isolated brief bursts of hypomania or recurrent brief hypomanias, but more sustained episodes of hypomania (7 days) could be more clinically problematic. Only 13% of patients treated acutely with these antidepressants had more full-blown manic symptoms (i.e., those associated with moderate or greater dysfunction on the NIMH-LCM).

During the next year, when apparent acute antidepressant responders were offered continuation treatment, 18% switched into mania. However, most patients (about 80%) dropped out because of lack of efficacy (depressive recurrences), intolerance, or for administrative reasons. The 127 patients who were randomized received 175 acute antidepressant trials. Only 9% were associated with a switch into mania with moderate dysfunction, whereas another 9% showed periods of hypomania lasting longer than 1 week.¹²

Table 2

RELAPSE INTO DEPRESSION IN BIPOLAR PATIENTS AFTER 1 YEAR WITH OR WITHOUT ADJUNCTIVE ANTIDEPRESSANT TREATMENT*

We have entered 176 patients into this double-blind, randomized comparison of bupropion, sertraline, and venlafaxine, with another 27 randomized openly. The study will attempt to examine any possible between-drug differences. Even without the blind being broken, it appears that these antidepressants are associated with a somewhat lower-than-expected rate of switching into mania with dysfunction, but a direct comparison with a placebo is not available.

In two other series, patients who remained well for 2 months on antidepressants plus mood stabilizers and then continued on their antidepressants had a much lower incidence of depressive relapses over the following year than those who discontinued their antidepressants (Table 2).^13,14 Surprisingly, continuing the antidepressant was not associated with an increased rate of switching into mania.

Prospective randomized, controlled studies are required to confirm these findings. Even so, our studies appear to challenge conventional wisdom for the first time. Stopping antidepressant treatment in bipolar patients as soon as possible for fear of inducing a manic episode may not be the optimal recommendation in the admittedly small subgroup (about 15%) of patients who have responded well to an antidepressant for at least 2 months.

Table 3

SIX STUDIES COMPLETED BY SFBN INVESTIGATORS

Second-generation anticonvulsants

Based on our patients’ substantial residual symptoms, we explored a series of newly approved anticonvulsants for potential use as mood stabilizers.

Lamotrigine Consistent with other open and double-blind, placebo-controlled studies, lamotrigine showed promise as an adjunctive treatment, with improvement in depressive symptoms and cycling.¹⁵ One such study showed acute antidepressant effects of lamotrigine monotherapy compared with a placebo at dosages of 50 or 200 mg/d.¹⁶

Another double-blind, randomized, placebo-controlled NIMH study (partially funded by the Stanley Foundation) compared lamotrigine with gabapentin and a placebo in patients for whom lithium, carbamazepine, and valproate had failed.¹⁷ Most of these treatment-refractory patients received all three agents through three 6-week randomizations. Lamotrigine was much more effective in depression and overall illness than either a placebo or gabapentin. Men with bipolar compared with unipolar illness and patients with fewer unsuccessful clinical trials and hospitalizations for depression showed the greatest response.¹⁸

In two recent industry-sponsored controlled trials of long-term prophylaxis (following a recent manic or depressive episode), lamotrigine was significantly more effective than a placebo (Bowden et al and Calabrese et al, unpublished data). Lamotrigine was more effective than lithium in preventing depressive episodes, whereas lithium was more effective than lamotrigine for manic episodes, although lamotrigine was significantly better than the placebo.

These data suggest that lamotrigine may differ from valproate, carbamazepine, and lithium in being a more effective antidepressant than antimanic agent.

Topiramate Adjunctive use of topiramate in rapid-cycling and treatment-resistant patients has been examined in open studies, but controlled studies have not yet been published. In our open-label case series observations, 19 of 30 (63%) patients taking topiramate for mania or cycling were “much” or “very much” improved after 10 weeks, whereas only 3 of 11 (27%) patients taking topiramate for acute depression were so improved.¹⁹

Table 4

STUDIES IN PROGRESS BY SFBN INVESTIGATORS

An industry-sponsored double-blind, randomized trial of topiramate in acute mania looked promising in the first 67 patients, but not as encouraging in subsequent subjects. A positive drug effect re-emerged if one eliminated patients whose manic episodes were precipitated by antidepressants.

The acute antidepressant effects of topiramate did not appear promising in our study. On the other hand, a single-blind, randomized study of topiramate versus bupropion as adjunctive therapy for breakthrough bipolar depression suggested excellent acute response (approximately 56%) to both agents.²⁰ These data leave the potential antidepressant effects of topiramate undetermined.

In patients being treated with topiramate, we found significant weight loss (average –0.7 kg at 4 weeks, –1.6 kg at 10 weeks, –4.7 kg at 6 months, and –6.2 kg at 1 year).¹⁹ Average weight loss was 4.5±6.7 kg at the final evaluation (body mass index [BMI] change of –6.3% and –5% at 1 year and last evaluation, respectively).

We and others have thus seen substantial weight loss in one-third to one-half of patients taking topiramate for bipolar disorder.²¹ This weight loss is maintained over relatively long periods, which differentiates topiramate from other weight-loss regimens. Topiramate’s ability to decrease weight—even while it is in the early stages of evaluation as a mood stabilizer—is of considerable interest, given the substantial problem of overweight in the bipolar population and the fact that many drug therapies used in the illness are associated with weight gain.

We are proceeding with a randomized open comparison of the relative weight loss and psychotropic efficacy of topiramate versus the antiobesity agent sibutramine. Sibutramine has been reported to have antidepressant properties and is FDA-approved for weight loss.

Gabapentin and tiagabine Our group and many others have reported substantial overall clinical improvement when gabapentin was used as adjunctive therapy in an open study of patients with inadequate response to previous treatments.²² As monotherapy, however, gabapentin was not more effective than a placebo¹⁷ and was less effective than lamotrigine. Similarly, gabapentin was not an effective acute antimanic agent when compared with a placebo,²³ although other double-blind, controlled studies have indicated positive effects in anxiety disorders²⁴ and social phobias.²⁵ Thus, the gabapentin literature appears to be divergent—i.e., positive studies support its adjunctive use in bipolar patients, but controlled studies suggest that it is not directly antimanic or mood-stabilizing.

Gabapentin’s effect on syndromes that are highly comorbid with bipolar illness could account for its apparent success as open adjunctive therapy. For example, in addition to its antianxiety effects, gabapentin shows positive effects in alcohol withdrawal, pain syndromes, sleep disorders (including restless leg syndrome), and obsessive-compulsive disorder. Also, combining gabapentin with other psychotropics with other mechanisms of action may have a more robust therapeutic effect than monotherapy.

Our preliminary observations with the selective GABA-reuptake inhibitor tiagabine were not promising. In an open study, only 3 of the first 17 SFBN patients with treatment-resistant affective disorders showed a partial response (moderate improvement on the Clinical Global Impressions Scale for Bipolar Illness [CGI-BP]) to adjunctive tiagabine treatment when the dosage was gradually increased. Serious side effects, including two patients with possible seizures, were noted.²⁶ Similar results were seen when tiagabine doses were rapidly increased in eight patients with acute mania; none responded, and one had a major motor seizure.²⁷

Thus, our initial observations led us to discontinue use of tiagabine and suggest any further clinical consideration of this agent for treatment-resistant affective disorders would require great care. This perspective contrasts with several previous positive case reports. It is unknown whether selected patients or those treated with lower dosages would be more responsive to this agent.

Like valproate, gabapentin and tiagabine increase brain GABA, but their apparent lack of antimanic efficacy strongly suggests that raising brain GABA alone does little to counter mania. These data further support the viewpoint already offered that all anticonvulsants are not alike and that anticonvulsants as a class are not necessarily mood stabilizers.

Zonisamide and levetiracetam Open studies of these two other anticonvulsants are near completion. Each has an interesting mechanistic profile, good tolerability, and the (potentially positive) side effect of inducing some weight loss, based on studies of neurologic patients.

Omega-3 fatty acids Based on positive reports of antidepressant effects of omega-3 fatty acids,^28-30 we recently recruited more than 120 patients with bipolar disorder for two double-blind, randomized, controlled trials. Those patients with either an acute depression or a cyclic course will receive 6 grams of omega-3 fatty acid (the eicosapentaenoate form) or a placebo for 4 months of double-blind treatment, followed by an 8-month open, active continuation phase.

If results are positive, omega-3 fatty acids would represent the much-needed addition of a well-tolerated dietary agent to the therapeutic armamentarium directed at bipolar illness.

Conclusion

The Stanley Foundation Bipolar Network has begun to evaluate the usefulness of numerous older and new compounds for patients with bipolar disorder, including second-generation antidepressants, anticonvulsants, atypical antipsychotic agents, and omega-3 fatty acids. Based on initial observations from 16 treatment studies (Table 3), we have drawn these conclusions:

• Second-generation antidepressants such as bupropion, sertraline, and venlafaxine appear to have a lower-than-expected switch rate into mania, compared with the use of the older tricyclic antidepressants.
• If the addition of a second-generation antidepressant results in good antidepressant response for 2 months and no switches into mania, one should consider continuing the antidepressant in this small minority of patients, rather than stopping it as soon as possible as previously recommended.
• Adjunctive use of lamotrigine appears to be of value, particularly for acute depression and prophylaxis, for many patients who have not responded to other treatments.
• While our group and others have reported improvement with adjunctive gabapentin in bipolar patients in uncontrolled case series, its primary antimanic or mood-stabilizing utility (as well as that of tiagabine) does not appear promising.
• Topiramate’s ability to induce substantial weight loss may emerge as clinically therapeutic for patients with problematic weight gain related to other psychotropic drugs, independent of its ultimate utility as a possible mood stabilizer.

We are preparing to analyze other open case series assessing acute and long-term treatment outcomes as well as randomized, double-blind clinical trials. Even though the funding of this unique collaborative network is ending, we look forward to more effective treatment of bipolar disorder in the future with continued development of new psychotropic agents and data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) and the VA Cooperative studies.³¹

Related resources

• National Alliance for the Mentally Ill (NAMI). www.nami.org
• National Depressive and Manic-Depressive Association (NDMDA). www.ndmda.org

Drug brand names

• Bupropion • Wellbutrin
• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Sibutramine • Meridia
• Tiagabine • Gabitril
• Topiramate • Topamax
• Valproate • Depakote
• Venlafaxine • Effexor
• Zonisamide • Zonegran

Acknowledgement

The authors are particularly indebted to the generosity of The Stanley Foundation in making funds available for this series of studies and several about to be completed.

Disclosure

Financial disclosure statements have been provided by all authors and are available upon request at [email protected].

When choosing psychopharmacologic agents for patients with bipolar disorder, the clinician lacks guidance from controlled clinical trials at virtually every therapeutic step. To help remedy this problem, we in the Stanley Foundation Bipolar Network (SFBN) evaluated compounds with potentially important therapeutic profiles. We began by documenting the demographics and illness characteristics of patients with bipolar disorder. Then we assessed some 16 treatments in naturalistic or formal studies, some of which are complete and others ongoing.

In this second installment, we report our current information about the efficacy of second-generation antidepressants, atypical antipsychotics, and anticonvulsant agents.

Mood stabilizers

As mood stabilizers, the anticonvulsants carbamazepine and valproate are well-accepted alternatives or adjuncts to lithium carbonate, which remains a mainstay treatment for acute episodes and long-term prophylaxis.¹

Valproate is approved by the FDA for treatment of acute mania but not for long-term prevention. Open studies in rapid-cycling, treatment-refractory patients demonstrate substantial improvement for both manic and depressive phases with valproate. In the most recent controlled study, valproate did not prevent manic episodes to a statistically significant degree, but it did show greater antidepressant effects than placebo or lithium.²

Carbamazepine has been widely studied in acute mania and compared with lithium for long-term prophylaxis. Most studies show nonsignificant differences between carbamazepine and lithium in preventing manic and depressive episodes, although several studies indicate less-robust antimanic effects of carbamazepine,³ particularly for patients with classic euphoric mania without psychosis, bipolar II, or associated substance abuse.⁴

In atypical patients, carbamazepine appeared to outperform lithium, suggesting clinical differences in these agents that have different mechanisms of action across neurotransmitter and peptide systems.

Low response rates Most randomized controlled trials and open adjunct studies suggest that 50% or more patients respond to lithium, valproate, or carbamazepine. Outcomes may be far less positive in clinical practice, however. Despite the use of mood stabilizers and a variety of antidepressants, benzodiazepines, and neuroleptics, our patients experienced substantial residual manic and depressive symptoms and functional impairment.

Similarly, clinician ratings on the National Institute of Mental Health Life Chart Method (NIMH-LCM) indicated a high rate of breakthrough episodes during carefully monitored and aggressive psychopharmacologic treatment.⁵ Two-thirds of the first 258 bipolar outpatients that we followed and rated daily for 1 year continued to be substantially impaired. One-quarter of them were ill for more than 75% of the year, despite using an average 4.1 psychopharmacologic agents per patient, including mood stabilizers, antidepressants, antipsychotics, and other agents.

Acute and long-term combination therapy appears more effective than monotherapy, particularly for treatment-refractory rapid cyclers.³ Even so, many patients do not respond to combination therapy. For example, in a 1-year prophylaxis study, 25% or fewer patients were rated “much improved” to “very much improved” on the Clinical Global Impressions (CGI) scale with lithium or carbamazepine as the baseline mood stabilizer and with antidepressants, neuroleptics, and benzodiazepines used as needed. In the third year of combination therapy, the overall response rate, including rapid cyclers, was roughly 50%.³

A low rate of response is apparent for lithium and valproate. While treating rapidly cycling patients, Calabrese and associates found that less than one-quarter of them responded well enough to the two-drug combination that they could be enrolled in a randomized double-blind comparison of each drug in monotherapy. Of those who were eligible, almost all relapsed with either lithium or valproate monotherapy and again required combination therapy.⁶

Table 1

RATE OF SWITCHING (%) INTO MANIA IN DEPRESSED BIPOLAR PATIENTS DURING ANTIDEPRESSANT TREATMENT*

Taken together, these studies indicate that even with our most effective and most studied agents, many patients respond inadequately. On the basis of this clinical reality, we began to explore additional options that might enhance clinical effectiveness.

Atypical antipsychotics

We assessed the addition of the atypical antipsychotic olanzapine in patients with treatment-refractory bipolar disorder⁷ and saw improvement in 57% of subjects with manic, mixed, and depressive components. These data foreshadowed more recent controlled findings of olanzapine’s usefulness in depression and mania.^8,9 Our preliminary open clinical trial experience allowed for more controlled studies and subsequent approval and wider clinical use of olanzapine in bipolar illness.

Our initial assessment of other atypical antipsychotics found that quetiapine was associated with significantly fewer depressive symptoms on the Inventory of Depressive Symptomatology (IDS) when used as part of the regular treatment regimen. This improvement, which was seen in the first month, was maintained over 4 months of treatment, whereas no significant improvement in depression severity was seen with the use of risperidone or clozapine.¹⁰

It would be highly preliminary to conclude from these uncontrolled data that quetiapine had greater effects on bipolar depressive symptoms than did risperidone or clozapine. We cannot rule out the possibility that patients with different degrees of treatment resistance were enrolled and treated with the different concomitant drugs. However, patients did not differ at baseline in severity of their depression.

In this initial look at the atypicals, the severity of depressive symptoms on the IDS was much greater than that of mania, as measured by the Young Mania Rating Scale (YMRS). Thus, the precise patterns of illness being treated and the impact of these antipsychotics on depressive cyclicity and duration await closer examination. We intend to look at the relative efficacy and side-effect profiles of each of the atypical antipsychotics as used in clinical practice.

Second-generation antidepressants

Bupropion, sertraline, and venlafaxine have different mechanisms of action but appear to be of value as adjuncts to bipolar disorder treatment. When we used them as adjuncts to mood stabilizers in a prospective study, we found a 40 to 50% acute response rate and some switching into hypomania and mania (Table 1).¹¹ Many switches appeared to involve only isolated brief bursts of hypomania or recurrent brief hypomanias, but more sustained episodes of hypomania (7 days) could be more clinically problematic. Only 13% of patients treated acutely with these antidepressants had more full-blown manic symptoms (i.e., those associated with moderate or greater dysfunction on the NIMH-LCM).

During the next year, when apparent acute antidepressant responders were offered continuation treatment, 18% switched into mania. However, most patients (about 80%) dropped out because of lack of efficacy (depressive recurrences), intolerance, or for administrative reasons. The 127 patients who were randomized received 175 acute antidepressant trials. Only 9% were associated with a switch into mania with moderate dysfunction, whereas another 9% showed periods of hypomania lasting longer than 1 week.¹²

Table 2

RELAPSE INTO DEPRESSION IN BIPOLAR PATIENTS AFTER 1 YEAR WITH OR WITHOUT ADJUNCTIVE ANTIDEPRESSANT TREATMENT*

We have entered 176 patients into this double-blind, randomized comparison of bupropion, sertraline, and venlafaxine, with another 27 randomized openly. The study will attempt to examine any possible between-drug differences. Even without the blind being broken, it appears that these antidepressants are associated with a somewhat lower-than-expected rate of switching into mania with dysfunction, but a direct comparison with a placebo is not available.

In two other series, patients who remained well for 2 months on antidepressants plus mood stabilizers and then continued on their antidepressants had a much lower incidence of depressive relapses over the following year than those who discontinued their antidepressants (Table 2).^13,14 Surprisingly, continuing the antidepressant was not associated with an increased rate of switching into mania.

Prospective randomized, controlled studies are required to confirm these findings. Even so, our studies appear to challenge conventional wisdom for the first time. Stopping antidepressant treatment in bipolar patients as soon as possible for fear of inducing a manic episode may not be the optimal recommendation in the admittedly small subgroup (about 15%) of patients who have responded well to an antidepressant for at least 2 months.

Table 3

SIX STUDIES COMPLETED BY SFBN INVESTIGATORS

Second-generation anticonvulsants

Based on our patients’ substantial residual symptoms, we explored a series of newly approved anticonvulsants for potential use as mood stabilizers.

Lamotrigine Consistent with other open and double-blind, placebo-controlled studies, lamotrigine showed promise as an adjunctive treatment, with improvement in depressive symptoms and cycling.¹⁵ One such study showed acute antidepressant effects of lamotrigine monotherapy compared with a placebo at dosages of 50 or 200 mg/d.¹⁶

Another double-blind, randomized, placebo-controlled NIMH study (partially funded by the Stanley Foundation) compared lamotrigine with gabapentin and a placebo in patients for whom lithium, carbamazepine, and valproate had failed.¹⁷ Most of these treatment-refractory patients received all three agents through three 6-week randomizations. Lamotrigine was much more effective in depression and overall illness than either a placebo or gabapentin. Men with bipolar compared with unipolar illness and patients with fewer unsuccessful clinical trials and hospitalizations for depression showed the greatest response.¹⁸

In two recent industry-sponsored controlled trials of long-term prophylaxis (following a recent manic or depressive episode), lamotrigine was significantly more effective than a placebo (Bowden et al and Calabrese et al, unpublished data). Lamotrigine was more effective than lithium in preventing depressive episodes, whereas lithium was more effective than lamotrigine for manic episodes, although lamotrigine was significantly better than the placebo.

These data suggest that lamotrigine may differ from valproate, carbamazepine, and lithium in being a more effective antidepressant than antimanic agent.

Topiramate Adjunctive use of topiramate in rapid-cycling and treatment-resistant patients has been examined in open studies, but controlled studies have not yet been published. In our open-label case series observations, 19 of 30 (63%) patients taking topiramate for mania or cycling were “much” or “very much” improved after 10 weeks, whereas only 3 of 11 (27%) patients taking topiramate for acute depression were so improved.¹⁹

Table 4

STUDIES IN PROGRESS BY SFBN INVESTIGATORS

An industry-sponsored double-blind, randomized trial of topiramate in acute mania looked promising in the first 67 patients, but not as encouraging in subsequent subjects. A positive drug effect re-emerged if one eliminated patients whose manic episodes were precipitated by antidepressants.

The acute antidepressant effects of topiramate did not appear promising in our study. On the other hand, a single-blind, randomized study of topiramate versus bupropion as adjunctive therapy for breakthrough bipolar depression suggested excellent acute response (approximately 56%) to both agents.²⁰ These data leave the potential antidepressant effects of topiramate undetermined.

In patients being treated with topiramate, we found significant weight loss (average –0.7 kg at 4 weeks, –1.6 kg at 10 weeks, –4.7 kg at 6 months, and –6.2 kg at 1 year).¹⁹ Average weight loss was 4.5±6.7 kg at the final evaluation (body mass index [BMI] change of –6.3% and –5% at 1 year and last evaluation, respectively).

We and others have thus seen substantial weight loss in one-third to one-half of patients taking topiramate for bipolar disorder.²¹ This weight loss is maintained over relatively long periods, which differentiates topiramate from other weight-loss regimens. Topiramate’s ability to decrease weight—even while it is in the early stages of evaluation as a mood stabilizer—is of considerable interest, given the substantial problem of overweight in the bipolar population and the fact that many drug therapies used in the illness are associated with weight gain.

We are proceeding with a randomized open comparison of the relative weight loss and psychotropic efficacy of topiramate versus the antiobesity agent sibutramine. Sibutramine has been reported to have antidepressant properties and is FDA-approved for weight loss.

Gabapentin and tiagabine Our group and many others have reported substantial overall clinical improvement when gabapentin was used as adjunctive therapy in an open study of patients with inadequate response to previous treatments.²² As monotherapy, however, gabapentin was not more effective than a placebo¹⁷ and was less effective than lamotrigine. Similarly, gabapentin was not an effective acute antimanic agent when compared with a placebo,²³ although other double-blind, controlled studies have indicated positive effects in anxiety disorders²⁴ and social phobias.²⁵ Thus, the gabapentin literature appears to be divergent—i.e., positive studies support its adjunctive use in bipolar patients, but controlled studies suggest that it is not directly antimanic or mood-stabilizing.

Gabapentin’s effect on syndromes that are highly comorbid with bipolar illness could account for its apparent success as open adjunctive therapy. For example, in addition to its antianxiety effects, gabapentin shows positive effects in alcohol withdrawal, pain syndromes, sleep disorders (including restless leg syndrome), and obsessive-compulsive disorder. Also, combining gabapentin with other psychotropics with other mechanisms of action may have a more robust therapeutic effect than monotherapy.

Our preliminary observations with the selective GABA-reuptake inhibitor tiagabine were not promising. In an open study, only 3 of the first 17 SFBN patients with treatment-resistant affective disorders showed a partial response (moderate improvement on the Clinical Global Impressions Scale for Bipolar Illness [CGI-BP]) to adjunctive tiagabine treatment when the dosage was gradually increased. Serious side effects, including two patients with possible seizures, were noted.²⁶ Similar results were seen when tiagabine doses were rapidly increased in eight patients with acute mania; none responded, and one had a major motor seizure.²⁷

Thus, our initial observations led us to discontinue use of tiagabine and suggest any further clinical consideration of this agent for treatment-resistant affective disorders would require great care. This perspective contrasts with several previous positive case reports. It is unknown whether selected patients or those treated with lower dosages would be more responsive to this agent.

Like valproate, gabapentin and tiagabine increase brain GABA, but their apparent lack of antimanic efficacy strongly suggests that raising brain GABA alone does little to counter mania. These data further support the viewpoint already offered that all anticonvulsants are not alike and that anticonvulsants as a class are not necessarily mood stabilizers.

Zonisamide and levetiracetam Open studies of these two other anticonvulsants are near completion. Each has an interesting mechanistic profile, good tolerability, and the (potentially positive) side effect of inducing some weight loss, based on studies of neurologic patients.

Omega-3 fatty acids Based on positive reports of antidepressant effects of omega-3 fatty acids,^28-30 we recently recruited more than 120 patients with bipolar disorder for two double-blind, randomized, controlled trials. Those patients with either an acute depression or a cyclic course will receive 6 grams of omega-3 fatty acid (the eicosapentaenoate form) or a placebo for 4 months of double-blind treatment, followed by an 8-month open, active continuation phase.

If results are positive, omega-3 fatty acids would represent the much-needed addition of a well-tolerated dietary agent to the therapeutic armamentarium directed at bipolar illness.

Conclusion

The Stanley Foundation Bipolar Network has begun to evaluate the usefulness of numerous older and new compounds for patients with bipolar disorder, including second-generation antidepressants, anticonvulsants, atypical antipsychotic agents, and omega-3 fatty acids. Based on initial observations from 16 treatment studies (Table 3), we have drawn these conclusions:

• Second-generation antidepressants such as bupropion, sertraline, and venlafaxine appear to have a lower-than-expected switch rate into mania, compared with the use of the older tricyclic antidepressants.
• If the addition of a second-generation antidepressant results in good antidepressant response for 2 months and no switches into mania, one should consider continuing the antidepressant in this small minority of patients, rather than stopping it as soon as possible as previously recommended.
• Adjunctive use of lamotrigine appears to be of value, particularly for acute depression and prophylaxis, for many patients who have not responded to other treatments.
• While our group and others have reported improvement with adjunctive gabapentin in bipolar patients in uncontrolled case series, its primary antimanic or mood-stabilizing utility (as well as that of tiagabine) does not appear promising.
• Topiramate’s ability to induce substantial weight loss may emerge as clinically therapeutic for patients with problematic weight gain related to other psychotropic drugs, independent of its ultimate utility as a possible mood stabilizer.

We are preparing to analyze other open case series assessing acute and long-term treatment outcomes as well as randomized, double-blind clinical trials. Even though the funding of this unique collaborative network is ending, we look forward to more effective treatment of bipolar disorder in the future with continued development of new psychotropic agents and data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) and the VA Cooperative studies.³¹

Related resources

• National Alliance for the Mentally Ill (NAMI). www.nami.org
• National Depressive and Manic-Depressive Association (NDMDA). www.ndmda.org

Drug brand names

• Bupropion • Wellbutrin
• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Sibutramine • Meridia
• Tiagabine • Gabitril
• Topiramate • Topamax
• Valproate • Depakote
• Venlafaxine • Effexor
• Zonisamide • Zonegran

Acknowledgement

The authors are particularly indebted to the generosity of The Stanley Foundation in making funds available for this series of studies and several about to be completed.

Disclosure

Financial disclosure statements have been provided by all authors and are available upon request at [email protected].

It is naïve to think that psychiatry is generally accepted in the treatment of problematic sexual behaviors. Although some might think that psychiatry has a “liberated” view of sexuality born of Freud’s Oedipus, the psychiatrist’s involvement in managing sexual behavior, especially within the criminal justice system, is controversial rather than “celebrated.”

Although some such as Dr. Mahorney may assert an addiction model for problem sexual behavior, that model is seriously flawed. Parallels do exist between problem sexual behavior and other addictive behaviors. Within the broad range of sexual behaviors, however, the line between “addictive” and “alternative” cannot be finely drawn. For example:

• Certain advocacy groups such as the North American Man-Boy Love Association (NAMBLA) believe in legalized pederasty and have exerted a lobby to affect rulings on freedom of expression in “virtual” child pornography over the Internet.
• Representatives of the U.S. Catholic church have publicly “mitigated” the controversy over some priests’ sexually inappropriate behavior by stating that the offenders were “not pedophiles” because their victims were over the arbitrary age of 13.

This discussion might easily encompass the controversial “cures” for homosexuality that were quashed in the late 1960s. How also might we classify the consenting masochist or the philanderer?

Finally, there is the forensic question: Do we allow “mental illness” to “excuse” one’s willful sexual behavior by giving it a label or a treatment?

Sexual offense vs. mental illness

Part of the problem with defining sexual “addiction” is that one first needs to define sexual “normalcy.” No such definition exists. Even so, adding a “sexual addiction” diagnosis to the next Diagnostic and Statistical Manual (DSM) would likely be met with indifference or active denial from the psychiatric community, based solely on its legal ramifications. Attorneys would perceive that an official DSM diagnosis could open the door to acquittal on the basis of insanity for sexually motivated crimes in certain states that retain a “product rule.” It might even exonerate individuals in restrictive states that follow the more cognitive M’Naughten standard (Box).

Box

A number of forensic mental health issues such as sexual predator classifications and sex offender civil commitment have placed professional societies at odds with one another over sexual behavior and mental illness. Mental health organizations such as the National Association of State Mental Health Program Directors and the American Psychiatric Association argue that most sex offenders do not suffer from a mental illness. Translation: “We don’t want to be responsible for handling sex offenders.”

This distinction between sexual offenses and mental illness contrasts with the laws of several states that broadly define mental illness to include mental conditions that result in dangerous and “uncontrollable” behavior. Translation: “We want to keep sex offenders controlled or away from the community.” There has been no rational support for either of these positions, only data that have been loosely contrived to justify one or the other.

Res ipsum loquitur: the thing defines itself

Many “experts” have conjectured about the nature of sex-offending behavior and the phenomenon of “sexual addiction” without subjecting their conclusions to scientific scrutiny. Agendas have abounded, and countertransference rather than objectivity has driven many perceptions within the field. Treatments have often been theory-based rather than tested. The universal problem has been that many providers have invented solutions without defining the problems. Indeed, the problems have been multifaceted.

There has been little reliable outcome data to demonstrate the success in any given treatment, although a few notable exceptions stand out. Medical interventions with hormonal compounds like medroxyprogesterone and cyproterone have reduced recidivism.¹ According to the Task Force Report on Sexually Dangerous Offenders, however, psychodynamic treatments in general have been ineffective.¹ Most of the supportable psychological treatments have emerged since 1980 and have centered on a cognitive model of relapse prevention.²

The Minnesota Sex Offender Program has been the gold standard as a cognitive-based relapse prevention model for sex offenders.³ The program was developed as an inpatient program with a structured level system and topic-specific modules. It has focused on a relapse prevention cycle that teaches strategies to recognize and avoid cognitive distortions and maladaptive coping responses that eventually lead to re-offense.

Common beliefs about the incidence of mental illness in sex offenders, aside from paraphilias, have also been challenged by careful observation. Our research at the University of Cincinnati revealed high rates of mental illness and substance abuse in a group of sex offenders released from prison to a residential treatment center. Offenders with paraphilias had even higher rates of mood, anxiety, and impulse control disorders (Table).⁴ Concurrently, Nancy Raymond and her colleagues reported similar findings with a group of residential and outpatient child molesters in Minnesota.⁵ Data from both these studies suggest that:

• Axis I conditions, especially those related to increased sexual drive or impaired impulse control (such as bipolar disorder), have some importance in treatment.
• Some relationship exists between Axis I disorders and the expression of underlying paraphilic interests.

It is clear that sexual compulsions are not homogeneous, and different characteristics exist across different populations. In our sample, for instance, pedophiles had lower rates of antisocial personality disorder but higher rates of anxiety than other offenders. Pharmacologically, Martin Kafka found that self-identified, noncriminal clients with sexual compulsions responded well to selective serotonin reuptake inhibitors (SSRIs) and stimulants,⁶ whereas patients at the University of Cincinnati program had a far less robust response to SSRI treatment.⁷ In essence, one style of intervention may not fit all patients.

Table

COMMON AXIS I DIAGNOSES IN 113 CONVICTED SEX OFFENDERS WITH AND WITHOUT PARAPHILIAS*

One other problem has plagued the forensic setting: Sex offenders lie about their sexual urges. In our program, they often appeared to “comply” with the program but concealed their sexual urges and fantasies. Sometimes they were embarrassed, ashamed, or simply in denial. We found that serial polygraph testing was essential for gauging treatment because it allowed us to objectively examine the information that the patients offered.

Frequently, I have heard people assert that an individual who seeks treatment actually wants treatment. Few sex offenders self-identify, however, and many more enter treatment as a condition of probation or parole. Thus most have an external motivation to participate. And with sex offenders, voluntary treatment is less successful than mandated treatment.¹

Summary

Ultimately, self-help, 12-step, and psychodynamic approaches have an unproven role in managing problem sexual behaviors. The most appropriate intervention is a multidisciplinary team approach with screening for Axis I disorders and paraphilias, a thorough psychological assessment, substance abuse treatment, and a cognitive relapse prevention program. Forensic patients additionally benefit from collateral data such as polygraph testing and ongoing monitoring by community corrections personnel.

It is naïve to think that psychiatry is generally accepted in the treatment of problematic sexual behaviors. Although some might think that psychiatry has a “liberated” view of sexuality born of Freud’s Oedipus, the psychiatrist’s involvement in managing sexual behavior, especially within the criminal justice system, is controversial rather than “celebrated.”

Although some such as Dr. Mahorney may assert an addiction model for problem sexual behavior, that model is seriously flawed. Parallels do exist between problem sexual behavior and other addictive behaviors. Within the broad range of sexual behaviors, however, the line between “addictive” and “alternative” cannot be finely drawn. For example:

• Certain advocacy groups such as the North American Man-Boy Love Association (NAMBLA) believe in legalized pederasty and have exerted a lobby to affect rulings on freedom of expression in “virtual” child pornography over the Internet.
• Representatives of the U.S. Catholic church have publicly “mitigated” the controversy over some priests’ sexually inappropriate behavior by stating that the offenders were “not pedophiles” because their victims were over the arbitrary age of 13.

This discussion might easily encompass the controversial “cures” for homosexuality that were quashed in the late 1960s. How also might we classify the consenting masochist or the philanderer?

Finally, there is the forensic question: Do we allow “mental illness” to “excuse” one’s willful sexual behavior by giving it a label or a treatment?

Sexual offense vs. mental illness

Part of the problem with defining sexual “addiction” is that one first needs to define sexual “normalcy.” No such definition exists. Even so, adding a “sexual addiction” diagnosis to the next Diagnostic and Statistical Manual (DSM) would likely be met with indifference or active denial from the psychiatric community, based solely on its legal ramifications. Attorneys would perceive that an official DSM diagnosis could open the door to acquittal on the basis of insanity for sexually motivated crimes in certain states that retain a “product rule.” It might even exonerate individuals in restrictive states that follow the more cognitive M’Naughten standard (Box).

Box

A number of forensic mental health issues such as sexual predator classifications and sex offender civil commitment have placed professional societies at odds with one another over sexual behavior and mental illness. Mental health organizations such as the National Association of State Mental Health Program Directors and the American Psychiatric Association argue that most sex offenders do not suffer from a mental illness. Translation: “We don’t want to be responsible for handling sex offenders.”

This distinction between sexual offenses and mental illness contrasts with the laws of several states that broadly define mental illness to include mental conditions that result in dangerous and “uncontrollable” behavior. Translation: “We want to keep sex offenders controlled or away from the community.” There has been no rational support for either of these positions, only data that have been loosely contrived to justify one or the other.

Res ipsum loquitur: the thing defines itself

Many “experts” have conjectured about the nature of sex-offending behavior and the phenomenon of “sexual addiction” without subjecting their conclusions to scientific scrutiny. Agendas have abounded, and countertransference rather than objectivity has driven many perceptions within the field. Treatments have often been theory-based rather than tested. The universal problem has been that many providers have invented solutions without defining the problems. Indeed, the problems have been multifaceted.

There has been little reliable outcome data to demonstrate the success in any given treatment, although a few notable exceptions stand out. Medical interventions with hormonal compounds like medroxyprogesterone and cyproterone have reduced recidivism.¹ According to the Task Force Report on Sexually Dangerous Offenders, however, psychodynamic treatments in general have been ineffective.¹ Most of the supportable psychological treatments have emerged since 1980 and have centered on a cognitive model of relapse prevention.²

The Minnesota Sex Offender Program has been the gold standard as a cognitive-based relapse prevention model for sex offenders.³ The program was developed as an inpatient program with a structured level system and topic-specific modules. It has focused on a relapse prevention cycle that teaches strategies to recognize and avoid cognitive distortions and maladaptive coping responses that eventually lead to re-offense.

Common beliefs about the incidence of mental illness in sex offenders, aside from paraphilias, have also been challenged by careful observation. Our research at the University of Cincinnati revealed high rates of mental illness and substance abuse in a group of sex offenders released from prison to a residential treatment center. Offenders with paraphilias had even higher rates of mood, anxiety, and impulse control disorders (Table).⁴ Concurrently, Nancy Raymond and her colleagues reported similar findings with a group of residential and outpatient child molesters in Minnesota.⁵ Data from both these studies suggest that:

• Axis I conditions, especially those related to increased sexual drive or impaired impulse control (such as bipolar disorder), have some importance in treatment.
• Some relationship exists between Axis I disorders and the expression of underlying paraphilic interests.

It is clear that sexual compulsions are not homogeneous, and different characteristics exist across different populations. In our sample, for instance, pedophiles had lower rates of antisocial personality disorder but higher rates of anxiety than other offenders. Pharmacologically, Martin Kafka found that self-identified, noncriminal clients with sexual compulsions responded well to selective serotonin reuptake inhibitors (SSRIs) and stimulants,⁶ whereas patients at the University of Cincinnati program had a far less robust response to SSRI treatment.⁷ In essence, one style of intervention may not fit all patients.

Table

COMMON AXIS I DIAGNOSES IN 113 CONVICTED SEX OFFENDERS WITH AND WITHOUT PARAPHILIAS*

One other problem has plagued the forensic setting: Sex offenders lie about their sexual urges. In our program, they often appeared to “comply” with the program but concealed their sexual urges and fantasies. Sometimes they were embarrassed, ashamed, or simply in denial. We found that serial polygraph testing was essential for gauging treatment because it allowed us to objectively examine the information that the patients offered.

Frequently, I have heard people assert that an individual who seeks treatment actually wants treatment. Few sex offenders self-identify, however, and many more enter treatment as a condition of probation or parole. Thus most have an external motivation to participate. And with sex offenders, voluntary treatment is less successful than mandated treatment.¹

Summary

Ultimately, self-help, 12-step, and psychodynamic approaches have an unproven role in managing problem sexual behaviors. The most appropriate intervention is a multidisciplinary team approach with screening for Axis I disorders and paraphilias, a thorough psychological assessment, substance abuse treatment, and a cognitive relapse prevention program. Forensic patients additionally benefit from collateral data such as polygraph testing and ongoing monitoring by community corrections personnel.

It is naïve to think that psychiatry is generally accepted in the treatment of problematic sexual behaviors. Although some might think that psychiatry has a “liberated” view of sexuality born of Freud’s Oedipus, the psychiatrist’s involvement in managing sexual behavior, especially within the criminal justice system, is controversial rather than “celebrated.”

Although some such as Dr. Mahorney may assert an addiction model for problem sexual behavior, that model is seriously flawed. Parallels do exist between problem sexual behavior and other addictive behaviors. Within the broad range of sexual behaviors, however, the line between “addictive” and “alternative” cannot be finely drawn. For example:

• Certain advocacy groups such as the North American Man-Boy Love Association (NAMBLA) believe in legalized pederasty and have exerted a lobby to affect rulings on freedom of expression in “virtual” child pornography over the Internet.
• Representatives of the U.S. Catholic church have publicly “mitigated” the controversy over some priests’ sexually inappropriate behavior by stating that the offenders were “not pedophiles” because their victims were over the arbitrary age of 13.

This discussion might easily encompass the controversial “cures” for homosexuality that were quashed in the late 1960s. How also might we classify the consenting masochist or the philanderer?

Finally, there is the forensic question: Do we allow “mental illness” to “excuse” one’s willful sexual behavior by giving it a label or a treatment?

Sexual offense vs. mental illness

Part of the problem with defining sexual “addiction” is that one first needs to define sexual “normalcy.” No such definition exists. Even so, adding a “sexual addiction” diagnosis to the next Diagnostic and Statistical Manual (DSM) would likely be met with indifference or active denial from the psychiatric community, based solely on its legal ramifications. Attorneys would perceive that an official DSM diagnosis could open the door to acquittal on the basis of insanity for sexually motivated crimes in certain states that retain a “product rule.” It might even exonerate individuals in restrictive states that follow the more cognitive M’Naughten standard (Box).

Box

A number of forensic mental health issues such as sexual predator classifications and sex offender civil commitment have placed professional societies at odds with one another over sexual behavior and mental illness. Mental health organizations such as the National Association of State Mental Health Program Directors and the American Psychiatric Association argue that most sex offenders do not suffer from a mental illness. Translation: “We don’t want to be responsible for handling sex offenders.”

This distinction between sexual offenses and mental illness contrasts with the laws of several states that broadly define mental illness to include mental conditions that result in dangerous and “uncontrollable” behavior. Translation: “We want to keep sex offenders controlled or away from the community.” There has been no rational support for either of these positions, only data that have been loosely contrived to justify one or the other.

Res ipsum loquitur: the thing defines itself

Many “experts” have conjectured about the nature of sex-offending behavior and the phenomenon of “sexual addiction” without subjecting their conclusions to scientific scrutiny. Agendas have abounded, and countertransference rather than objectivity has driven many perceptions within the field. Treatments have often been theory-based rather than tested. The universal problem has been that many providers have invented solutions without defining the problems. Indeed, the problems have been multifaceted.

There has been little reliable outcome data to demonstrate the success in any given treatment, although a few notable exceptions stand out. Medical interventions with hormonal compounds like medroxyprogesterone and cyproterone have reduced recidivism.¹ According to the Task Force Report on Sexually Dangerous Offenders, however, psychodynamic treatments in general have been ineffective.¹ Most of the supportable psychological treatments have emerged since 1980 and have centered on a cognitive model of relapse prevention.²

The Minnesota Sex Offender Program has been the gold standard as a cognitive-based relapse prevention model for sex offenders.³ The program was developed as an inpatient program with a structured level system and topic-specific modules. It has focused on a relapse prevention cycle that teaches strategies to recognize and avoid cognitive distortions and maladaptive coping responses that eventually lead to re-offense.

Common beliefs about the incidence of mental illness in sex offenders, aside from paraphilias, have also been challenged by careful observation. Our research at the University of Cincinnati revealed high rates of mental illness and substance abuse in a group of sex offenders released from prison to a residential treatment center. Offenders with paraphilias had even higher rates of mood, anxiety, and impulse control disorders (Table).⁴ Concurrently, Nancy Raymond and her colleagues reported similar findings with a group of residential and outpatient child molesters in Minnesota.⁵ Data from both these studies suggest that:

• Axis I conditions, especially those related to increased sexual drive or impaired impulse control (such as bipolar disorder), have some importance in treatment.
• Some relationship exists between Axis I disorders and the expression of underlying paraphilic interests.

It is clear that sexual compulsions are not homogeneous, and different characteristics exist across different populations. In our sample, for instance, pedophiles had lower rates of antisocial personality disorder but higher rates of anxiety than other offenders. Pharmacologically, Martin Kafka found that self-identified, noncriminal clients with sexual compulsions responded well to selective serotonin reuptake inhibitors (SSRIs) and stimulants,⁶ whereas patients at the University of Cincinnati program had a far less robust response to SSRI treatment.⁷ In essence, one style of intervention may not fit all patients.

Table

COMMON AXIS I DIAGNOSES IN 113 CONVICTED SEX OFFENDERS WITH AND WITHOUT PARAPHILIAS*

One other problem has plagued the forensic setting: Sex offenders lie about their sexual urges. In our program, they often appeared to “comply” with the program but concealed their sexual urges and fantasies. Sometimes they were embarrassed, ashamed, or simply in denial. We found that serial polygraph testing was essential for gauging treatment because it allowed us to objectively examine the information that the patients offered.

Frequently, I have heard people assert that an individual who seeks treatment actually wants treatment. Few sex offenders self-identify, however, and many more enter treatment as a condition of probation or parole. Thus most have an external motivation to participate. And with sex offenders, voluntary treatment is less successful than mandated treatment.¹

Summary

Ultimately, self-help, 12-step, and psychodynamic approaches have an unproven role in managing problem sexual behaviors. The most appropriate intervention is a multidisciplinary team approach with screening for Axis I disorders and paraphilias, a thorough psychological assessment, substance abuse treatment, and a cognitive relapse prevention program. Forensic patients additionally benefit from collateral data such as polygraph testing and ongoing monitoring by community corrections personnel.

It is naïve to think that psychiatry is generally accepted in the treatment of problematic sexual behaviors. Although some might think that psychiatry has a “liberated” view of sexuality born of Freud’s Oedipus, the psychiatrist’s involvement in managing sexual behavior, especially within the criminal justice system, is controversial rather than “celebrated.”

Although some such as Dr. Mahorney may assert an addiction model for problem sexual behavior, that model is seriously flawed. Parallels do exist between problem sexual behavior and other addictive behaviors. Within the broad range of sexual behaviors, however, the line between “addictive” and “alternative” cannot be finely drawn. For example:

• Certain advocacy groups such as the North American Man-Boy Love Association (NAMBLA) believe in legalized pederasty and have exerted a lobby to affect rulings on freedom of expression in “virtual” child pornography over the Internet.
• Representatives of the U.S. Catholic church have publicly “mitigated” the controversy over some priests’ sexually inappropriate behavior by stating that the offenders were “not pedophiles” because their victims were over the arbitrary age of 13.

This discussion might easily encompass the controversial “cures” for homosexuality that were quashed in the late 1960s. How also might we classify the consenting masochist or the philanderer?

Finally, there is the forensic question: Do we allow “mental illness” to “excuse” one’s willful sexual behavior by giving it a label or a treatment?

Sexual offense vs. mental illness

Part of the problem with defining sexual “addiction” is that one first needs to define sexual “normalcy.” No such definition exists. Even so, adding a “sexual addiction” diagnosis to the next Diagnostic and Statistical Manual (DSM) would likely be met with indifference or active denial from the psychiatric community, based solely on its legal ramifications. Attorneys would perceive that an official DSM diagnosis could open the door to acquittal on the basis of insanity for sexually motivated crimes in certain states that retain a “product rule.” It might even exonerate individuals in restrictive states that follow the more cognitive M’Naughten standard (Box).

Box

A number of forensic mental health issues such as sexual predator classifications and sex offender civil commitment have placed professional societies at odds with one another over sexual behavior and mental illness. Mental health organizations such as the National Association of State Mental Health Program Directors and the American Psychiatric Association argue that most sex offenders do not suffer from a mental illness. Translation: “We don’t want to be responsible for handling sex offenders.”

This distinction between sexual offenses and mental illness contrasts with the laws of several states that broadly define mental illness to include mental conditions that result in dangerous and “uncontrollable” behavior. Translation: “We want to keep sex offenders controlled or away from the community.” There has been no rational support for either of these positions, only data that have been loosely contrived to justify one or the other.

Res ipsum loquitur: the thing defines itself

Many “experts” have conjectured about the nature of sex-offending behavior and the phenomenon of “sexual addiction” without subjecting their conclusions to scientific scrutiny. Agendas have abounded, and countertransference rather than objectivity has driven many perceptions within the field. Treatments have often been theory-based rather than tested. The universal problem has been that many providers have invented solutions without defining the problems. Indeed, the problems have been multifaceted.

There has been little reliable outcome data to demonstrate the success in any given treatment, although a few notable exceptions stand out. Medical interventions with hormonal compounds like medroxyprogesterone and cyproterone have reduced recidivism.¹ According to the Task Force Report on Sexually Dangerous Offenders, however, psychodynamic treatments in general have been ineffective.¹ Most of the supportable psychological treatments have emerged since 1980 and have centered on a cognitive model of relapse prevention.²

The Minnesota Sex Offender Program has been the gold standard as a cognitive-based relapse prevention model for sex offenders.³ The program was developed as an inpatient program with a structured level system and topic-specific modules. It has focused on a relapse prevention cycle that teaches strategies to recognize and avoid cognitive distortions and maladaptive coping responses that eventually lead to re-offense.

Common beliefs about the incidence of mental illness in sex offenders, aside from paraphilias, have also been challenged by careful observation. Our research at the University of Cincinnati revealed high rates of mental illness and substance abuse in a group of sex offenders released from prison to a residential treatment center. Offenders with paraphilias had even higher rates of mood, anxiety, and impulse control disorders (Table).⁴ Concurrently, Nancy Raymond and her colleagues reported similar findings with a group of residential and outpatient child molesters in Minnesota.⁵ Data from both these studies suggest that:

• Axis I conditions, especially those related to increased sexual drive or impaired impulse control (such as bipolar disorder), have some importance in treatment.
• Some relationship exists between Axis I disorders and the expression of underlying paraphilic interests.

It is clear that sexual compulsions are not homogeneous, and different characteristics exist across different populations. In our sample, for instance, pedophiles had lower rates of antisocial personality disorder but higher rates of anxiety than other offenders. Pharmacologically, Martin Kafka found that self-identified, noncriminal clients with sexual compulsions responded well to selective serotonin reuptake inhibitors (SSRIs) and stimulants,⁶ whereas patients at the University of Cincinnati program had a far less robust response to SSRI treatment.⁷ In essence, one style of intervention may not fit all patients.

Table

COMMON AXIS I DIAGNOSES IN 113 CONVICTED SEX OFFENDERS WITH AND WITHOUT PARAPHILIAS*

One other problem has plagued the forensic setting: Sex offenders lie about their sexual urges. In our program, they often appeared to “comply” with the program but concealed their sexual urges and fantasies. Sometimes they were embarrassed, ashamed, or simply in denial. We found that serial polygraph testing was essential for gauging treatment because it allowed us to objectively examine the information that the patients offered.

Frequently, I have heard people assert that an individual who seeks treatment actually wants treatment. Few sex offenders self-identify, however, and many more enter treatment as a condition of probation or parole. Thus most have an external motivation to participate. And with sex offenders, voluntary treatment is less successful than mandated treatment.¹

Summary

Ultimately, self-help, 12-step, and psychodynamic approaches have an unproven role in managing problem sexual behaviors. The most appropriate intervention is a multidisciplinary team approach with screening for Axis I disorders and paraphilias, a thorough psychological assessment, substance abuse treatment, and a cognitive relapse prevention program. Forensic patients additionally benefit from collateral data such as polygraph testing and ongoing monitoring by community corrections personnel.

It is naïve to think that psychiatry is generally accepted in the treatment of problematic sexual behaviors. Although some might think that psychiatry has a “liberated” view of sexuality born of Freud’s Oedipus, the psychiatrist’s involvement in managing sexual behavior, especially within the criminal justice system, is controversial rather than “celebrated.”

Although some such as Dr. Mahorney may assert an addiction model for problem sexual behavior, that model is seriously flawed. Parallels do exist between problem sexual behavior and other addictive behaviors. Within the broad range of sexual behaviors, however, the line between “addictive” and “alternative” cannot be finely drawn. For example:

• Certain advocacy groups such as the North American Man-Boy Love Association (NAMBLA) believe in legalized pederasty and have exerted a lobby to affect rulings on freedom of expression in “virtual” child pornography over the Internet.
• Representatives of the U.S. Catholic church have publicly “mitigated” the controversy over some priests’ sexually inappropriate behavior by stating that the offenders were “not pedophiles” because their victims were over the arbitrary age of 13.

This discussion might easily encompass the controversial “cures” for homosexuality that were quashed in the late 1960s. How also might we classify the consenting masochist or the philanderer?

Finally, there is the forensic question: Do we allow “mental illness” to “excuse” one’s willful sexual behavior by giving it a label or a treatment?

Sexual offense vs. mental illness

Part of the problem with defining sexual “addiction” is that one first needs to define sexual “normalcy.” No such definition exists. Even so, adding a “sexual addiction” diagnosis to the next Diagnostic and Statistical Manual (DSM) would likely be met with indifference or active denial from the psychiatric community, based solely on its legal ramifications. Attorneys would perceive that an official DSM diagnosis could open the door to acquittal on the basis of insanity for sexually motivated crimes in certain states that retain a “product rule.” It might even exonerate individuals in restrictive states that follow the more cognitive M’Naughten standard (Box).

Box

A number of forensic mental health issues such as sexual predator classifications and sex offender civil commitment have placed professional societies at odds with one another over sexual behavior and mental illness. Mental health organizations such as the National Association of State Mental Health Program Directors and the American Psychiatric Association argue that most sex offenders do not suffer from a mental illness. Translation: “We don’t want to be responsible for handling sex offenders.”

This distinction between sexual offenses and mental illness contrasts with the laws of several states that broadly define mental illness to include mental conditions that result in dangerous and “uncontrollable” behavior. Translation: “We want to keep sex offenders controlled or away from the community.” There has been no rational support for either of these positions, only data that have been loosely contrived to justify one or the other.

Res ipsum loquitur: the thing defines itself

Many “experts” have conjectured about the nature of sex-offending behavior and the phenomenon of “sexual addiction” without subjecting their conclusions to scientific scrutiny. Agendas have abounded, and countertransference rather than objectivity has driven many perceptions within the field. Treatments have often been theory-based rather than tested. The universal problem has been that many providers have invented solutions without defining the problems. Indeed, the problems have been multifaceted.

There has been little reliable outcome data to demonstrate the success in any given treatment, although a few notable exceptions stand out. Medical interventions with hormonal compounds like medroxyprogesterone and cyproterone have reduced recidivism.¹ According to the Task Force Report on Sexually Dangerous Offenders, however, psychodynamic treatments in general have been ineffective.¹ Most of the supportable psychological treatments have emerged since 1980 and have centered on a cognitive model of relapse prevention.²

The Minnesota Sex Offender Program has been the gold standard as a cognitive-based relapse prevention model for sex offenders.³ The program was developed as an inpatient program with a structured level system and topic-specific modules. It has focused on a relapse prevention cycle that teaches strategies to recognize and avoid cognitive distortions and maladaptive coping responses that eventually lead to re-offense.

Common beliefs about the incidence of mental illness in sex offenders, aside from paraphilias, have also been challenged by careful observation. Our research at the University of Cincinnati revealed high rates of mental illness and substance abuse in a group of sex offenders released from prison to a residential treatment center. Offenders with paraphilias had even higher rates of mood, anxiety, and impulse control disorders (Table).⁴ Concurrently, Nancy Raymond and her colleagues reported similar findings with a group of residential and outpatient child molesters in Minnesota.⁵ Data from both these studies suggest that:

• Axis I conditions, especially those related to increased sexual drive or impaired impulse control (such as bipolar disorder), have some importance in treatment.
• Some relationship exists between Axis I disorders and the expression of underlying paraphilic interests.

It is clear that sexual compulsions are not homogeneous, and different characteristics exist across different populations. In our sample, for instance, pedophiles had lower rates of antisocial personality disorder but higher rates of anxiety than other offenders. Pharmacologically, Martin Kafka found that self-identified, noncriminal clients with sexual compulsions responded well to selective serotonin reuptake inhibitors (SSRIs) and stimulants,⁶ whereas patients at the University of Cincinnati program had a far less robust response to SSRI treatment.⁷ In essence, one style of intervention may not fit all patients.

Table

COMMON AXIS I DIAGNOSES IN 113 CONVICTED SEX OFFENDERS WITH AND WITHOUT PARAPHILIAS*

One other problem has plagued the forensic setting: Sex offenders lie about their sexual urges. In our program, they often appeared to “comply” with the program but concealed their sexual urges and fantasies. Sometimes they were embarrassed, ashamed, or simply in denial. We found that serial polygraph testing was essential for gauging treatment because it allowed us to objectively examine the information that the patients offered.

Frequently, I have heard people assert that an individual who seeks treatment actually wants treatment. Few sex offenders self-identify, however, and many more enter treatment as a condition of probation or parole. Thus most have an external motivation to participate. And with sex offenders, voluntary treatment is less successful than mandated treatment.¹

Summary

Ultimately, self-help, 12-step, and psychodynamic approaches have an unproven role in managing problem sexual behaviors. The most appropriate intervention is a multidisciplinary team approach with screening for Axis I disorders and paraphilias, a thorough psychological assessment, substance abuse treatment, and a cognitive relapse prevention program. Forensic patients additionally benefit from collateral data such as polygraph testing and ongoing monitoring by community corrections personnel.

It is naïve to think that psychiatry is generally accepted in the treatment of problematic sexual behaviors. Although some might think that psychiatry has a “liberated” view of sexuality born of Freud’s Oedipus, the psychiatrist’s involvement in managing sexual behavior, especially within the criminal justice system, is controversial rather than “celebrated.”

Although some such as Dr. Mahorney may assert an addiction model for problem sexual behavior, that model is seriously flawed. Parallels do exist between problem sexual behavior and other addictive behaviors. Within the broad range of sexual behaviors, however, the line between “addictive” and “alternative” cannot be finely drawn. For example:

• Certain advocacy groups such as the North American Man-Boy Love Association (NAMBLA) believe in legalized pederasty and have exerted a lobby to affect rulings on freedom of expression in “virtual” child pornography over the Internet.
• Representatives of the U.S. Catholic church have publicly “mitigated” the controversy over some priests’ sexually inappropriate behavior by stating that the offenders were “not pedophiles” because their victims were over the arbitrary age of 13.