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Olanzapine-fluoxetine combination for psychotic major depression
P.1. Affective disorders and antidepressants
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Metanalysis of olanzapine-fluoxetine use in treatment-resistant depression
S. Dube, S.W. Andersen, S. Paul, S.A. Corya, L.E. Van Campen, T.M. Sanger, L. Welge, J. Nanos, G.D. Tollefson. Eli Lilly and
Company, Indianapolis, Indiana, US.A. Background and Objective: Up to 30% of patients with major
depression are resistant to conventional antidepressant treatment (Amsterdam and Hornig-Rohan, 1996). Subsequent therapy options may include augmenting an antidepressant with an antipsychotic (Robertson and Trimble, 1982). The efficacy of olanzapinefluoxetine combination (OFC) was compared with that of olanzapine or fluoxetine monotherapy in patients with treatment-resistant depression (TRD). TRD was defined as a retrospective SSRI failure and a prospective non-SSRI failure. Methods: A metanalysis was performed on one 8-week, and one 12-week double-blind study using mixed-model, repeated measures analysis. Subjects (n=797) with nonpsychotic, unipolar treatment-resistant major depression were randomized to OFC, or olanzapine or fluoxetine monotherapy treatment groups. MADRS was the primary efficacy measure. Results: OFC patients achieved significantly greater total score improvement at Week 1 (-7.31) than olanzapine (-5.18, p=0.013) or fluoxetine (-5.26, p=0.004) patients and maintained the significant effect throughout 8 weeks of treatment (-11.60; -7.55, p<0.001; -8.73, p<0.001). OFC patients had a significantly greater endpoint response rate than olanzapine (37.3%, 21.1%) patients and significantly greater endpoint remission rates than olanzapine or fluoxetine (24.9%, 13.1%, 15.2%). Moreover, OFC showed significantly greater reductions in MADRS scores than olanzapine or fluoxetine for a subset of patients (n=253) with a history of SSRI failure in their current episode (-11.78; -7.91, p=.021; -6.40, p<.001). Conclusion: OFC showed rapid improvement in depressive symptoms by Week 1 of treatment and sustained treatment effect throughout 8 weeks of therapy. OFC demonstrated greater reductions in depressive symptoms than olanzapine or fluoxetine, as well as better response rates and remission rates. The combination represents a promising treatment for patients with TRD.
References [1] Amsterdam, J.D., Hornig-Rohan, M., 1996. Treatment algorithms in treatment-resistant depression. Psychiatr. Clin. North. Am. 19, 371386. [2] Robertson, M.M., Trimble, M.R., 1982. Major tranquillisers used as antidepressants: A review. J. Affect. Disord. 4, 173-193.
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Safety metanalysis of olanzapine-fluoxetine combination versus olanzapine
S. Corya, S.W. Andersen, S. Paul, L.E. Van Campen, T.M. Sanger, G.D. Tollefson, S. Dube. Eli Lilly and Company, Indianapolis,
Indiana, U.S.A. and Objective: Recent evidence suggests that olanzapine-fluoxetine combination (OFC) enhances antidepressant effects in difficult-to-treat depressions such as treatment-resistant depression (TRD) and psychotic depression. The safety data for OFC were evaluated for any new side effects that are not seen in olanzapine monotherapy. Methods: Metanalysis of safety data from five 8-week, doubleblind studies (n=762) was performed. OFC was compared with Background
olanzapine for treating TRD (three studies) and psychotic depression (two studies). Frequency and severity of adverse events including extrapyramidal symptoms (EPS) measured by the Simpson-Angus Scale, Barnes Akathisia Rating Scale, and Abnormal Involuntary Movement Scale, changes in vital signs, electrocardiography (ECG), and laboratory analytes were analyzed. Results: Of the adverse events occurring in >10% of OFC patients, no significant differences were seen between OFC and olanzapine patients. A significant, but small proportion of OFC patients (3.0%) had low supine diastolic blood pressure compared with olanzapine (0.7%; p=0.032) patients. Categorical changes in laboratory analytes, ECG, heart rate, and EPS measures were not significantly different between OFC and olanzapine patients. Conclusion: No significant adverse effects were seen when giving OFC compared with olanzapine monotherapy, and the OFC safety profile was consistent with those expected for component monotherapies (Beasley et al., 2000; Bhana et al., 2001). These results support the acute safety and tolerability of OFC.
References [1] Beasley, C.M., Koke, S.C., Nilsson, M.E., Gonzales, J.S., 2000. Adverse event and treatment discontinuationsin clinical trials of fluoxetine in major depressivedisorder: An updated meta-analysis.Clin. Ther. 22, 1319-1329. [2] Bhana, N., Foster, R.H., Olney,R., Plosker, G.L., 2001. Olanzapine:An updated review of its use in the management of schizophrenia. Drugs 61, 111-161.
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Olanzapine-fluoxetine combination for psychotic major depression
S. Dube 1 , A. Rothschild 2, S.W. Andersen 1 , T.M. Sanger 1, D.B. Clemow 1, M. Tohen1, G.D. Tollefson1. 1Eli Lilly
and Company, Indianapolis, Indiana, U.S.A.; 2University of Massachusetts Medical School, Worcester, Massachusetts, US.A. Objective: Recent evidence suggests that olanzapine-fluoxetine combination (OFC) has enhanced antidepressant qualities compared with monotherapies and is a promising treatment option for difficult-to-treat depressions such as bipolar depression, treatmentresistant depression, and psychotic depression. The present study examined efficacy and safety of a combination of olanzapine and the antidepressant fluoxetine compared to olanzapine monotherapy or placebo for treatment of major depressive disorder (MDD) with psychotic features. Methods: Two parallel, 8-week double-blind trials, with an optional 48-week open-label extension, were conducted. Subjects (n=249) with MDD with psychotic symptoms were randomized to one of three treatment groups: olanzapine-fluoxetine combination (OFC; 5-20 mg/day and 20-80 mg/day, respectively; n=48), olanzapine (5-20 mg/day; n=101) or placebo (n=100). The 24item Hamilton Depression Rating Scale (HAMD-24) was used to monitor primary efficacy. Results: Pooled data showed a significantly greater HAMD24 total score decrease at 8 weeks with OFC (-18.3) than PLA (-11.4, p<.001) and trended toward a greater decrease with OLZ (-14.4, p=.072). Eight-week endpoint response (>50% decrease in HAMD-24 total score) to OFC was significantly greater than OLZ or PLA (56%, 36% [p=.041], and 30% [p=.005], respectively). Seventy-one percent of acute OFC responders maintained response in the open-label phase. More OFC partial responders (>25% total score decrease at 2 weeks) achieved full endpoint response compared with OLZ or PLA (64%, 35%, 32%). OFC
P.1. Affective disorders and antidepressants median time to response was similar to OLZ, but faster than PLA (12, 12, 20 days). OFC's safety profile was similar to OLZ and showed no significant increases on any measure of EPS symptoms. For all patients, mean weight gain in the OFC group (2.74 kg) was similar to OLZ (3.79 kg; p=0.160). Weight gain for the OFC and OLZ groups was significantly more than observed for PLA (0.39 kg, p=0.001 and p<0.001, respectively). For males, mean weight gain for the OFC group (2.24 kg) was not significantly different from PLA (1.11 kg), while OLZ-associated weight gain (4.69 kg) was significantly greater than with OFC or PLA (p=.006, p<.001, respectively). Conclusions: OFC demonstrated significant HAMD-24-based improvement compared to OLZ monotherapy or PLA in subjects with psychotic major depression. OFC had a similar safety profile to OLZ. OFC may be a promising treatment strategy for major depression with psychotic features.
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$181
Impact of racing thoughts on depression
E Benazzi. University of Bologna, Department of Psychology,
Cervia RA, Italy
Background: Depression with racing thoughts is under-studied, but the presence of racing thoughts during depression may have important effects on treatment of depression. Study aim was to define the clinical and family history correlates of depression with racing thoughts. Methods: Consecutive 336 unipolar (n=130) and bipolar II (n=206) major depressive episode (MDE) psychoactive drugfree outpatients were interviewed with the Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version,when presenting for treatment of MDE in an outpatient psychiatry private center. This study setting is more representative of mood disorder patients in Italy, where it is the first or the second (after family doctors) line of treatment of mood disorders, and where psychiatric national health centers and university centers usually treat the most severe mood patients. The presence of racing Safety metanalysis of olanzapine-fluoxetine thoughts/crowded thoughts during the MDE was systematically combination versus fluoxetine assessed with structured questions. History of hypomania was systematically assessed. Often, family members or close friends S. Corya, S.W. Andersen, S. Paul, A. Deldar, T.M. Sanger, G.D. Tollefson, S. Dube. Eli Lilly and Company, Indianapolis, supplemented the clinical information during the interview. Depression with racing thoughts was compared with depression lndiana, U.S.A. without racing thoughts. Statistics: Means were compared with t test, proportions with Background and Objective. Recent evidence suggests that olanzapine-fluoxetine combination (OFC) enhances antidepressant the two-sample test of proportion. Logistic regression was used to effects in difficult to treat depressions, such as treatment-resistant control for confounding. STATA 7 statistical software was used. P depression (TRD). The safety data for OFC were evaluated for values were two-tailed, and probability level was P<0.01 to reduce any new side effects that are not seen in fluoxetine monotherapy. type I error related to many comparisons. Results: Depression with racing thoughts was present in 213 Methods: Metanalysis of safety data from four 6- to 8-week, double-blind studies (n=688) was performed. OFC was compared patients (63.3%). It had significantly more patients with bipolar with fluoxetine for treating TRD patients (three studies) or for II disorder, lower age and age of onset, more atypical feaameliorating sexual dysfunction reported with fluoxetine (one tures, psychomotor agitation, diminished ability to think, suicidal study). Adverse events, vital signs, electrocardiograms (ECGs), ideation, guilt, leaden paralysis, MDE symptoms, and bipolar II laboratory analytes, extrapyramidal symptoms (EPS) and sexual disorder family history than depression without racing thoughts. Logistic regression controlled for bipolar II (which was associated dysfunction (ASEX scale; n=564) were analyzed. Results: Of events occurring in >10% of OFC or fluoxetine with most of these variables) of depression with racing thoughts patients, significantly more OFC patients experienced weight gain, (dependent variable) versus the independent variables found sigsomnolence, increased appetite, and asthenia, and significantly nificantly different in the first analysis, found that depression with fewer OFC patients experienced headache, diarrhea, nausea, and racing thoughts was no more significantly associated with age of insomnia compared with fluoxetine patients. The proportion of onset, atypical features, psychomotor agitation, leaden paralysis, patients with > 10% weight gain was significantly higher for OFC and bipolar II family history, but that it was still significantly patients than fluoxetine (16.3%, 0.4%) patients. There were no associated with diminished ability to think, suicidal ideation, guilt, significant categorical changes in laboratory analytes, ECG, heart and higher number of MDE symptoms. Limitations: Single interrate, and EPS measures, or significant mean differences for ASEX viewer, non-blind, cross-sectional assessment, bipolar II diagnosis based on history. between OFC and fluoxetine patients. Conclusions: Depression with racing thoughts was found to Conclusion: No unexpected changes were seen in adverse effects commonly reported with fluoxetine monotherapy (Beasley be very common in depressed outpatients, and associated with et al., 2000), and the observed differences between OFC and suicide ideas. Possible negative effect of antidepressants on racing fluoxetine are consistent with the olanzapine component (Bhana et thoughts, and possible positive effects of mood stabilisers, stress al., 2001). These results support the acute safety and tolerability the importance of its identification by the clinician. Its link with bipolar II disorder further stresses its clinical importance. of OFC.
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References [i] Beasley, C.M., Koke, S.C., Nilsson, M.E., Gonzales, J.S., 2000. Adverse event and treatment discontinuationsin clinical trials of fluoxetine in major depressive disorder: An updated meta-analysis.Clin. Ther. 22, 1319-1329. [2] Bhana, N., Foster, R.H., Olney,R., Plosker, G.L., 2001. Olanzapine:An updated review of its use in the management of schizophrenia. Drugs 61, 111-161.
References [1] Benazzi, E, Akiskal, H.S.,2001. Delineating bipolar II mixed states in the Ravenna-San Diego collaborativestudy: the relative prevalenceand diagnostic significance of hypomanic features during major depressive episodes. J. Affect. Disord. 67,115-22. [2] Benazzi, E, 2001. Sensitivity and specificityof clinical markers for the diagnosis of bipolar II disorder. Compr. Psychiatry.42,461-5. [3] Benazzi, F.,2001. High prevalence of bipolar spectrum disorders. J. Clin. Psychiatry. 62,735~6.
S180
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Metanalysis of olanzapine-fluoxetine use in treatment-resistant depression
S. Dube, S.W. Andersen, S. Paul, S.A. Corya, L.E. Van Campen, T.M. Sanger, L. Welge, J. Nanos, G.D. Tollefson. Eli Lilly and
Company, Indianapolis, Indiana, US.A. Background and Objective: Up to 30% of patients with major
depression are resistant to conventional antidepressant treatment (Amsterdam and Hornig-Rohan, 1996). Subsequent therapy options may include augmenting an antidepressant with an antipsychotic (Robertson and Trimble, 1982). The efficacy of olanzapinefluoxetine combination (OFC) was compared with that of olanzapine or fluoxetine monotherapy in patients with treatment-resistant depression (TRD). TRD was defined as a retrospective SSRI failure and a prospective non-SSRI failure. Methods: A metanalysis was performed on one 8-week, and one 12-week double-blind study using mixed-model, repeated measures analysis. Subjects (n=797) with nonpsychotic, unipolar treatment-resistant major depression were randomized to OFC, or olanzapine or fluoxetine monotherapy treatment groups. MADRS was the primary efficacy measure. Results: OFC patients achieved significantly greater total score improvement at Week 1 (-7.31) than olanzapine (-5.18, p=0.013) or fluoxetine (-5.26, p=0.004) patients and maintained the significant effect throughout 8 weeks of treatment (-11.60; -7.55, p<0.001; -8.73, p<0.001). OFC patients had a significantly greater endpoint response rate than olanzapine (37.3%, 21.1%) patients and significantly greater endpoint remission rates than olanzapine or fluoxetine (24.9%, 13.1%, 15.2%). Moreover, OFC showed significantly greater reductions in MADRS scores than olanzapine or fluoxetine for a subset of patients (n=253) with a history of SSRI failure in their current episode (-11.78; -7.91, p=.021; -6.40, p<.001). Conclusion: OFC showed rapid improvement in depressive symptoms by Week 1 of treatment and sustained treatment effect throughout 8 weeks of therapy. OFC demonstrated greater reductions in depressive symptoms than olanzapine or fluoxetine, as well as better response rates and remission rates. The combination represents a promising treatment for patients with TRD.
References [1] Amsterdam, J.D., Hornig-Rohan, M., 1996. Treatment algorithms in treatment-resistant depression. Psychiatr. Clin. North. Am. 19, 371386. [2] Robertson, M.M., Trimble, M.R., 1982. Major tranquillisers used as antidepressants: A review. J. Affect. Disord. 4, 173-193.
•
Safety metanalysis of olanzapine-fluoxetine combination versus olanzapine
S. Corya, S.W. Andersen, S. Paul, L.E. Van Campen, T.M. Sanger, G.D. Tollefson, S. Dube. Eli Lilly and Company, Indianapolis,
Indiana, U.S.A. and Objective: Recent evidence suggests that olanzapine-fluoxetine combination (OFC) enhances antidepressant effects in difficult-to-treat depressions such as treatment-resistant depression (TRD) and psychotic depression. The safety data for OFC were evaluated for any new side effects that are not seen in olanzapine monotherapy. Methods: Metanalysis of safety data from five 8-week, doubleblind studies (n=762) was performed. OFC was compared with Background
olanzapine for treating TRD (three studies) and psychotic depression (two studies). Frequency and severity of adverse events including extrapyramidal symptoms (EPS) measured by the Simpson-Angus Scale, Barnes Akathisia Rating Scale, and Abnormal Involuntary Movement Scale, changes in vital signs, electrocardiography (ECG), and laboratory analytes were analyzed. Results: Of the adverse events occurring in >10% of OFC patients, no significant differences were seen between OFC and olanzapine patients. A significant, but small proportion of OFC patients (3.0%) had low supine diastolic blood pressure compared with olanzapine (0.7%; p=0.032) patients. Categorical changes in laboratory analytes, ECG, heart rate, and EPS measures were not significantly different between OFC and olanzapine patients. Conclusion: No significant adverse effects were seen when giving OFC compared with olanzapine monotherapy, and the OFC safety profile was consistent with those expected for component monotherapies (Beasley et al., 2000; Bhana et al., 2001). These results support the acute safety and tolerability of OFC.
References [1] Beasley, C.M., Koke, S.C., Nilsson, M.E., Gonzales, J.S., 2000. Adverse event and treatment discontinuationsin clinical trials of fluoxetine in major depressivedisorder: An updated meta-analysis.Clin. Ther. 22, 1319-1329. [2] Bhana, N., Foster, R.H., Olney,R., Plosker, G.L., 2001. Olanzapine:An updated review of its use in the management of schizophrenia. Drugs 61, 111-161.
•
Olanzapine-fluoxetine combination for psychotic major depression
S. Dube 1 , A. Rothschild 2, S.W. Andersen 1 , T.M. Sanger 1, D.B. Clemow 1, M. Tohen1, G.D. Tollefson1. 1Eli Lilly
and Company, Indianapolis, Indiana, U.S.A.; 2University of Massachusetts Medical School, Worcester, Massachusetts, US.A. Objective: Recent evidence suggests that olanzapine-fluoxetine combination (OFC) has enhanced antidepressant qualities compared with monotherapies and is a promising treatment option for difficult-to-treat depressions such as bipolar depression, treatmentresistant depression, and psychotic depression. The present study examined efficacy and safety of a combination of olanzapine and the antidepressant fluoxetine compared to olanzapine monotherapy or placebo for treatment of major depressive disorder (MDD) with psychotic features. Methods: Two parallel, 8-week double-blind trials, with an optional 48-week open-label extension, were conducted. Subjects (n=249) with MDD with psychotic symptoms were randomized to one of three treatment groups: olanzapine-fluoxetine combination (OFC; 5-20 mg/day and 20-80 mg/day, respectively; n=48), olanzapine (5-20 mg/day; n=101) or placebo (n=100). The 24item Hamilton Depression Rating Scale (HAMD-24) was used to monitor primary efficacy. Results: Pooled data showed a significantly greater HAMD24 total score decrease at 8 weeks with OFC (-18.3) than PLA (-11.4, p<.001) and trended toward a greater decrease with OLZ (-14.4, p=.072). Eight-week endpoint response (>50% decrease in HAMD-24 total score) to OFC was significantly greater than OLZ or PLA (56%, 36% [p=.041], and 30% [p=.005], respectively). Seventy-one percent of acute OFC responders maintained response in the open-label phase. More OFC partial responders (>25% total score decrease at 2 weeks) achieved full endpoint response compared with OLZ or PLA (64%, 35%, 32%). OFC
P.1. Affective disorders and antidepressants median time to response was similar to OLZ, but faster than PLA (12, 12, 20 days). OFC's safety profile was similar to OLZ and showed no significant increases on any measure of EPS symptoms. For all patients, mean weight gain in the OFC group (2.74 kg) was similar to OLZ (3.79 kg; p=0.160). Weight gain for the OFC and OLZ groups was significantly more than observed for PLA (0.39 kg, p=0.001 and p<0.001, respectively). For males, mean weight gain for the OFC group (2.24 kg) was not significantly different from PLA (1.11 kg), while OLZ-associated weight gain (4.69 kg) was significantly greater than with OFC or PLA (p=.006, p<.001, respectively). Conclusions: OFC demonstrated significant HAMD-24-based improvement compared to OLZ monotherapy or PLA in subjects with psychotic major depression. OFC had a similar safety profile to OLZ. OFC may be a promising treatment strategy for major depression with psychotic features.
~
$181
Impact of racing thoughts on depression
E Benazzi. University of Bologna, Department of Psychology,
Cervia RA, Italy
Background: Depression with racing thoughts is under-studied, but the presence of racing thoughts during depression may have important effects on treatment of depression. Study aim was to define the clinical and family history correlates of depression with racing thoughts. Methods: Consecutive 336 unipolar (n=130) and bipolar II (n=206) major depressive episode (MDE) psychoactive drugfree outpatients were interviewed with the Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version,when presenting for treatment of MDE in an outpatient psychiatry private center. This study setting is more representative of mood disorder patients in Italy, where it is the first or the second (after family doctors) line of treatment of mood disorders, and where psychiatric national health centers and university centers usually treat the most severe mood patients. The presence of racing Safety metanalysis of olanzapine-fluoxetine thoughts/crowded thoughts during the MDE was systematically combination versus fluoxetine assessed with structured questions. History of hypomania was systematically assessed. Often, family members or close friends S. Corya, S.W. Andersen, S. Paul, A. Deldar, T.M. Sanger, G.D. Tollefson, S. Dube. Eli Lilly and Company, Indianapolis, supplemented the clinical information during the interview. Depression with racing thoughts was compared with depression lndiana, U.S.A. without racing thoughts. Statistics: Means were compared with t test, proportions with Background and Objective. Recent evidence suggests that olanzapine-fluoxetine combination (OFC) enhances antidepressant the two-sample test of proportion. Logistic regression was used to effects in difficult to treat depressions, such as treatment-resistant control for confounding. STATA 7 statistical software was used. P depression (TRD). The safety data for OFC were evaluated for values were two-tailed, and probability level was P<0.01 to reduce any new side effects that are not seen in fluoxetine monotherapy. type I error related to many comparisons. Results: Depression with racing thoughts was present in 213 Methods: Metanalysis of safety data from four 6- to 8-week, double-blind studies (n=688) was performed. OFC was compared patients (63.3%). It had significantly more patients with bipolar with fluoxetine for treating TRD patients (three studies) or for II disorder, lower age and age of onset, more atypical feaameliorating sexual dysfunction reported with fluoxetine (one tures, psychomotor agitation, diminished ability to think, suicidal study). Adverse events, vital signs, electrocardiograms (ECGs), ideation, guilt, leaden paralysis, MDE symptoms, and bipolar II laboratory analytes, extrapyramidal symptoms (EPS) and sexual disorder family history than depression without racing thoughts. Logistic regression controlled for bipolar II (which was associated dysfunction (ASEX scale; n=564) were analyzed. Results: Of events occurring in >10% of OFC or fluoxetine with most of these variables) of depression with racing thoughts patients, significantly more OFC patients experienced weight gain, (dependent variable) versus the independent variables found sigsomnolence, increased appetite, and asthenia, and significantly nificantly different in the first analysis, found that depression with fewer OFC patients experienced headache, diarrhea, nausea, and racing thoughts was no more significantly associated with age of insomnia compared with fluoxetine patients. The proportion of onset, atypical features, psychomotor agitation, leaden paralysis, patients with > 10% weight gain was significantly higher for OFC and bipolar II family history, but that it was still significantly patients than fluoxetine (16.3%, 0.4%) patients. There were no associated with diminished ability to think, suicidal ideation, guilt, significant categorical changes in laboratory analytes, ECG, heart and higher number of MDE symptoms. Limitations: Single interrate, and EPS measures, or significant mean differences for ASEX viewer, non-blind, cross-sectional assessment, bipolar II diagnosis based on history. between OFC and fluoxetine patients. Conclusions: Depression with racing thoughts was found to Conclusion: No unexpected changes were seen in adverse effects commonly reported with fluoxetine monotherapy (Beasley be very common in depressed outpatients, and associated with et al., 2000), and the observed differences between OFC and suicide ideas. Possible negative effect of antidepressants on racing fluoxetine are consistent with the olanzapine component (Bhana et thoughts, and possible positive effects of mood stabilisers, stress al., 2001). These results support the acute safety and tolerability the importance of its identification by the clinician. Its link with bipolar II disorder further stresses its clinical importance. of OFC.
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References [i] Beasley, C.M., Koke, S.C., Nilsson, M.E., Gonzales, J.S., 2000. Adverse event and treatment discontinuationsin clinical trials of fluoxetine in major depressive disorder: An updated meta-analysis.Clin. Ther. 22, 1319-1329. [2] Bhana, N., Foster, R.H., Olney,R., Plosker, G.L., 2001. Olanzapine:An updated review of its use in the management of schizophrenia. Drugs 61, 111-161.
References [1] Benazzi, E, Akiskal, H.S.,2001. Delineating bipolar II mixed states in the Ravenna-San Diego collaborativestudy: the relative prevalenceand diagnostic significance of hypomanic features during major depressive episodes. J. Affect. Disord. 67,115-22. [2] Benazzi, E, 2001. Sensitivity and specificityof clinical markers for the diagnosis of bipolar II disorder. Compr. Psychiatry.42,461-5. [3] Benazzi, F.,2001. High prevalence of bipolar spectrum disorders. J. Clin. Psychiatry. 62,735~6.