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Bipolarity Presenting as Anxiety Disorders

Dr. Perugi is assistant professor in the Department of Psychiatry at the University of Pisa in Italy, and scientific director in the Institute of Behavioral Science in Carrara, Italy.

Dr. Toni is a researcher at the Institute of Behavioral Science.

Disclosure: The authors report no financial, academic, or other support of this work.

Please direct all correspondence to: Giulio Perugi, MD, Department of Psychiatry, University of Pisa, via Roma 67, 56100 Pisa, Italy; Tel: +39-050-835414; Fax: +39-050-21581; E-mail: gperugi@med.unipi.it.

Focus Points

The available epidemiological and clinical evidence strongly suggests high rates of anxiety disorder comorbidity in the domain of the bipolar spectrum.

Multiple comorbidity, symptomatologic instability, and alcohol and substance abuse appear as the most relevant clinical implications of anxious bipolar coexistence.

If antidepressants are to be used in patients with concurrent bipolar and anxiety disorders, adequate mood stabilization should first be achieved and antidepressants should then be added cautiously while patients are monitored carefully for emerging symptoms of hypomania or mania.

Abstract

A growing number of epidemiological and clinical studies have found that bipolar disorder significantly co-occurs with anxiety disorders at rates that are higher than those in the general population. Underdiagnosis of bipolar II disorders produced a relative neglect of this comorbidity in the past. The co-occurrence of anxiety disorders and bipolar disorders seems to result in something more complex than a simple add-on effect. Multiple comorbidity, symptomatologic instability, and alcohol and substance abuse appear as the most relevant clinical implications of anxious bipolar coexistence. The study of the complex relationships among these disorders requires further research and better-designed prospective observations. Controlled studies of mood stabilizers in anxiety disorders are lacking, as are studies comparing the efficacy of different mood stabilizers in bipolar patients with and without different comorbid anxiety disorders. However, several impressions emerge from the available literature. Generally, the data support the use of valproate as the mood stabilizer of choice for patients with comorbid panic disorder and possibly obsessive-compulsive disorder (OCD), especially if associated with prominent anxiety symptoms, mixed features, and/or rapid cycling. Gabapentin might also be utilized as an adjunctive agent with anxiolytic properties. Antidepressants, while proven effective in panic disorder, OCD, and social phobia, may worsen the course of bipolar disorder, especially if initiated before treatment with a mood stabilizer. Several lines of evidence suggest that atypical antipsychotics will be beneficial in the treatment of comorbid anxiety in patients with bipolar disorder—even if they have been hypothesized to exacerbate panic disorder and OCD—because of their serotonergic antagonistic properties.

Introduction

Current available evidence strongly suggests high rates of anxious comorbidity in the domain of the bipolar spectrum.1-5 These observations are relatively recent; until a few years ago, the mainstream opinion was that anxiety disorders were highly comorbid with unipolar depression.6,7 In an analysis of the Epidemiological Catchment Area database, Chen and Dilsaver3 reported that lifetime rates of obsessive-compulsive disorder (OCD) among probands with bipolar and unipolar disorder were 21% and 12.2%, respectively. In the National Comorbidity Survey,1 the reported risk of comorbid panic disorder and social phobia was higher in bipolar disorder (odds ratio [OR]: 11 versus 4.6, respectively) compared to unipolar disorder (OR: 7 versus 3.6, respectively). More recently, in subjects meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)8 criteria for hypomania, recurrent brief hypomania, and sporadic brief hypomania, Angst2 reported higher rates of comorbidity with panic disorder, social phobia, and OCD compared to population controls.

Concerning clinical studies, a history of manic or hypomanic episodes has been observed in patients with panic disorder and agoraphobia,9 and intra-episode panic disorder was observed in patients with pure and depressive mania.10 The development of mania or hypomania in response to treatment with selective serotonin reuptake inhibitors (SSRIs) has also been widely described in OCD case series and reports.11,12 In a clinical study of 345 outpatients with OCD conducted by Perugi and colleagues,13  lifetime co-morbidity with bipolar disorder (primarily bipolar II disorder) was 16%. Finally, significant overlap between bipolar disorder and social phobia has also been reported and, conversely, patients with social phobia have been found to have high rates of bipolar disorder.5 In a subsequent collaborative study,14 major depression was the most common comorbid disorder in a large sample of patients with anxiety disorders; however, bipolar II disorder was widely associated with social phobia (21.1%), OCD (17.7%), and panic disorder (5%). Similar lifetime prevalence rates have been reported by McElroy and colleagues15 in a large multinational sample (N=288) of bipolar I and bipolar II patients. A high rate of subthreshold anxiety and comorbid anxiety disorders has also been reported by Feske and colleagues16 in 124 bipolar I patients studied in a randomized trial for maintenance therapy.

The relative neglect in clinical and epidemiological research of studies on the comorbidity between bipolar spectrum disorders and anxiety disorders is especially due to the underdiagnosis of bipolar II disorders (often misdiagnosed as unipolar or personality disorders) in patients with anxiety disorders. It has been recently documented that current official diagnostic systems grossly underestimate bipolar II and related disorders17; similar data have emerged from a Memphis study,18 an Italian study,19 and a French national study.20

Dunner and Tay17 reported that clinicians specifically trained in bipolar II disorders outperformed routine interviewers in such structured interviews as the Schedule for Affective Disorders and Schizophrenia and the Structured Clinical Interview for the DSM. This methodological point supports earlier recommendations based on research in Memphis21 that the diagnosis of hypomania among cyclothymic bipolar II subjects should be based on repeated expert interviews. Although this point goes against the literature on structured interviewing, it suggests that the proper identification of bipolar II requires a more sophisticated approach in diagnosis. Therefore, it is likely that bipolar comorbidity, which is very common in clinical samples,14 is not so easily detected in epidemiological studies utilizing structured interviews based on the diagnostic rules of the DSM-IV and the International Statistical Classification of Diseases and Related Health Problems.22

The Complexity of Anxious Bipolar Comorbidity

The co-occurrence of bipolar and anxiety disorders seems to result in something more complex than a simple add-on effect. Multiple comorbidity and consequent symptomatological instability appear to be the most relevant consequences of co-occurring anxiety and bipolar disorders. Because of this, many patients receive diagnoses of borderline, narcissistic, histrionic personality disorders, which in some cases prevent them from receiving adequate pharmacologic treatment. Increased risk of mixed states, suicidal behavior, and alcohol and drug abuse are other important prognostic implications.23

Different temporal relationships seem to characterize the occurrence of hypomania in individual anxiety disorder subtypes. In a recent retrospective preliminary report, Perugi and colleagues24 explored the temporal relationship of (hypo)mania with anxiety states in patients with panic disorder (n=21), OCD (n=23), and social phobia (n=19) as a principal diagnosis and comorbid bipolar I disorder (n=8, 12.7%) and (atypical) bipolar II disorder (n=55, 87.3%). In almost all cases, social phobia preceded the onset of bipolar disorder and showed complete remission during (hypo)mania. The only patient who reported the persistence of some performance anxiety suffered from a circumscribed form of social phobia, characterized by fear and avoidance of writing in public.

By contrast, panic disorder and OCD symptomatology, even when preceding hypomanic episodes, often persisted during such episodes in >40% of cases. Interestingly, panic disorder turned out to be the only anxiety disorder that began during (hypo)mania in a significant proportion of cases (28.6%). This observation is consistent with previous reports of a high frequency of intra-episode panic disorder during mania and mixed mania.10

These finding are consistent with the hypothesis that, at least in some patients, social phobia, and to some extent OCD, seem to lie on a broad affective continuum of inhibitory restraint versus disinhibited hypomania. By contrast, panic disorder in the context of a (hypo)manic episode might be interpreted as a dysphoric or mixed evolution of the symptomatology. In order to confirm these observations, further investigations should focus on the prospective assessment of patients with concomitant bipolar disorder, panic disorder, and OCD. Indeed, retrospective methodology utilized in most clinical studies makes it difficult to ascertain the extent to which antidepressants, the most common treatment for severe anxiety disorders, could explain the anxiety and bipolar comorbidity.

The pattern of complex relationships between these disorders certainly requires well-designed prospective observations. Nonetheless, the validity of the phenomenon of anxious bipolar comorbidity should no longer be in doubt. Investigations on differential patterns of comorbidity may provide important information in distinguishing more homogeneous clinical subtypes of affective disorders from the biological, genetic, and therapeutic point of view. Preliminary evidence supports the hypothesis that differential risk for panic disorder comorbidity is a promising tool for discerning heterogeneous genetic subtypes of bipolar disorder. MacKinnon and colleagues25 evaluated 528 members of 57 families for a genetic linkage study of bipolar disorder. Of the 57 bipolar probands, 10 had comorbid panic disorder. In their relatives, panic disorder cosegregated with bipolar disorder (in particular bipolar II disorder and cyclothymia) at a significantly higher rate than expected by chance, suggesting that comorbid panic disorder might be a specific marker for a familial subtype of bipolar disorder.

Patients with bipolar disorder and OCD seem to abuse alcohol, sedatives, stimulants, and caffeine more frequently than nonbipolar OCD patients.26 They also experience an episodic course of the anxiety disorder, a greater number of major depressive episodes, and a greater number of suicide attempts. Moreover, they have reported significantly higher rates of sexual obsessions and significantly lower rates of order rituals than nonbipolar OCD patients.26

These observations would seem to indicate that bipolar comorbidity has a strong influence on the longitudinal course and complications of OCD. In particular, long-term episodic course of OCD was related to family history for mood disorders, lifetime comorbidity for panic and bipolar II disorders, and late age of onset.26 Evidence based on a single family pedigree27 suggests a genetic linkage between OCD and bipolar disorder, while other studies indicate increased prevalence of OCD in bipolar probands and high rates of obsessional traits in the offspring of bipolar probands.28 Coryell29 reported an equal incidence (2.3%) of mania in families of probands with OCD and in families with a member with bipolar disorder. These findings are consistent with the hypothesis that, at least in some cases, episodic course of OCD is related to cyclical affective disorders. In a more theoretical vein, episodic OCD symptoms may be considered the phenotypic expression of an underlying affective genotype in a substantial minority of cases.

In regard to the relationship between social phobia and bipolar disorder, Himmelhoch5 found that 18 patients with social phobia experienced significant improvement of social anxiety after a treatment with the monoamine oxidase inhibitor (MAOI) phenelzine and the reversible inhibitor of MAO-type A (RIMA) moclobemide. Of these subjects, 14 of 32 developed a hypomanic episode along with the complete remission of social phobic symptomatology,  according to clinical judgement and structured evaluation. On the basis of this observation, the author hypothesized that social phobia might actually belong, at least in some cases, to a bipolar spectrum. It is notable that Himmelhoch5 concluded that social phobia’s special relationship with bipolar II disorder became evident only when social anxiety was “perturbed by the central actions of stimulating antidepressants.”

Protracted social anxiety, along with inhibited depression, may represent the opposite of hypomania.5 Moreover, the increased susceptibility to alcohol use in some patients with social phobia might be related more to the presence of a bipolar diathesis,30 with marked reactivity to the ethanol, than to the social-phobic symptomatology per se. This hypothesis is compatible with the observation of Himle and colleagues,31 who found that in social phobia patients without a comorbid bipolar disorder, alcohol use did not reduce social anxiety in performance situations and was not associated with better performance. The socializing and uninhibiting effect that many social phobia patients report with alcohol use might therefore be mediated by increased confidence, as part of hypomania facilitated by alcohol.

The correct identification of social phobia bipolar comorbidity has relevant clinical implications as far as other concomitant disorders, symptomatologic features, course, and complications are concerned. Severity and generalization of the social phobia symptoms, multiple comorbidities, and alcohol abuse appear to be the most relevant consequences of social phobia and bipolar coexistence. Likewise, clinicians must investigate whether bipolar disorder is a comorbid condition in patients presenting with social phobia. The suspicion of bipolar comorbidity should be even greater if patients present with multiple comorbidities or have previously been refractory to treatment.

Treatment Issues

The lack of information about connections between anxiety and bipolar disorder may have a negative impact on treatment choice and management. Most of the controlled trials on bipolar disorder excluded patients with comorbid anxiety disorders and vice versa; as a consequence, the empirical basis for treating patients with bipolar and anxious comorbidity are almost exclusively founded on anecdotal reports and open clinical experiences.

Some useful suggestions can be derived from clinical experiences with mood stabilizers and anti-anxiety agents. Bipolar patients with high anxiety ratings are less likely to respond to lithium.32 Overall, lithium has not been studied in anxiety disorders. Controlled data suggest that valproate may be more effective than lithium in mania associated with depressive features, even when the depressive features are mild.33 Since anxiety symptoms are often seen in mixed states and may even be related to depression in mania, future studies should evaluate anxious features as possible predictors of response of mania to valproate (and other antimanic agents). Regarding anxiety disorders, valproate has been successfully used in the treatment of panic disorder.34 In addition, in an open-label study, Calabrese and Delucchi35 noted that rapid-cycling bipolar disorder patients with comorbid panic attacks described reduction of their panic symptoms with valproate treatment. Additionally, one open-label study36 and one case report37 have suggested that valproate may be helpful in the treatment of some patients with OCD, especially those with associated bipolar or epileptiform features.

Uhde and colleagues38 did not find carbamazepine to be an efficacious treatment for panic disorder in a double-blind, placebo-controlled study of 14 patients. In OCD, Koopowitz and Berk39 reported beneficial results with the use of carbamazepine in two patients, while Joffe and Swinson40 found carbamazepine to be ineffective in an open-label study.

Gabapentin has shown preliminary evidence of efficacy in the treatment of both anxiety41-43 and bipolar disorders.44,45 A relevant number of case reports and open studies exists that indicate that gabapentin may have an important role in the treatment of mood disorders. However, available controlled studies tend to contradict these findings.44,45 In anxiety disorders, gabapentin has been shown to be superior to placebo in one small controlled study on social phobia41 and in another controlled study on severe panic disorder.46 (In the patients with less severe panic disorder, there was no difference between gabapentin and placebo).46 There is also an open-label report on the successful treatment with gabapentin of four patients with panic disorder  and generalized anxiety disorder (GAD) who had been refractory to standard anxiolytics.42 In a recent study, Perugi and colleagues43  evaluated the predictors of response to gabapentin as adjunctive treatment in 43 patients with Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised,47 bipolar disorder, who were resistant to standard mood stabilizers. Gabapentin was administered as an adjunctive treatment for an 8-week period in combination with other mood stabilizers, benzodiazepines, antidepressants, and neuroleptics. Eighteen of 43 (41.9%) patients who began treatment were considered responders; in particular, gabapentin showed antidepressant and anxiolytic properties. Comorbid panic disorder and alcohol abuse (and to a lesser extent social phobia) were the best predictors of response. This finding might have relevant clinical implications concerning the treatment of anxious-bipolar comorbidity, but it should be confirmed in controlled clinical trials.

Benzodiazepines are relatively safe and well-tolerated when used in combination with mood stabilizers. However, long-term benzodiazepine use may be problematic in most patients, due to development of tolerance, physical dependence, and withdrawal phenomena. Antidepressants are often used in the treatment of anxiety disorders and bipolar depression. However, these compounds may worsen the course of the mood disorder by precipitating mania, mixed states, or rapid cycling. Antidepressant-induced (hypo)manic symptoms have been reported in the course of treatment of virtually all anxiety disorders, including OCD, panic disorder, and social phobia.5,48,49 In bipolar disorder, prophylactic treatment with mood stabilizers may prevent antidepressant-induced switching,50,51 but improvement in depression may require discontinuation of the antidepressant.52 Antidepressant discontinuation may also pose problems, including recurrence of depressive or anxiety symptoms and, rarely, precipitation of hypomania.53

Finally, atypical antipsychotics hold promise as mood-stabilizing agents; several lines of evidence suggest that they will also be beneficial in the treatment of comorbid anxiety in patients with bipolar disorder.54 In particular, case reports, open-label trials, and double-blind trials have shown that risperidone, olanzapine, and quetiapine may be efficacious in posttraumatic stress disorder, OCD, and GAD.54 However, these data need to be confirmed, considering that in other observations atypical antipsychotics have been hypothesized to exacerbate panic disorder and OCD because of their serotoninergic antagonistic properties.55,56

When treating comorbid bipolar and anxiety disorders, it is imperative to begin treatment with a mood stabilizer. Initiating an antidepressant before adequate mood stabilization has been achieved could worsen the anxiety symptoms by exacerbating the bipolar disorder.

In the treatment of comorbid bipolar disorder and panic disorder, utilizing mood stabilizers that have been shown to possess some antipanic efficacy, such as gabapentin in combination with other mood stabilizers or valproate, appears reasonable. These drugs can be effective on anxious symptomatology because of their gabaergic properties. Along these lines, other new antiepileptic drugs (eg, tiagabine) could be evaluated in the future. In patients with persistent and disabling panic disorder, the combination with clonazepam for a short term (eg, <2 months) or small dosages of SSRIs or tricyclic antidepressants (eg, paroxetine or trimipramine) may be considered.

Less information is available for comorbid bipolar disorder and social phobia. A small positive study41 on gabapentin in social phobia seems to indicate the possible efficacy of this drug for both mood and anxiety disorders. The combination of mood stabilizers, such as lithium, valproate, and carbamazepine with SSRIs, RIMAs, or MAOIs, might reduce the number of switches in these patients. However, there is almost no information on long-term outcome of patients with comorbid bipolar disorder and social phobia treated with drug combinations.

Patients with bipolar disorder and OCD are among the most difficult to treat. No mood stabilizers have been shown to exert any anti-OCD activity, and the effective anti-OCD pharmachologic treatments (eg, high doses of clomipramine or SSRIs) have high potential for inducing (hypo)manic switches and increasing cyclicity in bipolar disorder patients. Combination of different mood stabilizers (eg, lithium plus antiepileptics) is often necessary, and in some cases, combination with antidepressants that are less likely to induce rapid-cycling (ie, MAOIs) can be utilized. However, while the risk of cycling may be limited with MAOIs compared to other antidepressants, it must be taken into account that substance abuse and impulsivity are common in bipolar disorder, thus increasing the risk of potentially fatal outcomes for patients on MAOIs who do not follow the strict rules about concomitant medications and diet.

In certain cases, combination with atypical antipsychotics (eg, clozapine, risperidone, olanzapine) may be considered. Even if atypical antipsychotics have sometimes been reported to exacerbate OCD symptomatology,55,56 these drugs can also display a mood-stabilizing, anti-aggressive activity which facilitates effective treatment of OCD symptoms.

Finally, many of these patients present with residual OCD symptomatology and very severe manic or mixed episodes (with aggressive, hostile moods) that may require hospitalization.

Conclusion

The comorbidity between bipolar and anxiety disorders is a substantial clinical issue affecting a large number of patients. The frequent coexistence of anxiety and bipolar disorders has been also reported in epidemiological samples and primary care settings, indicating that clinical referral bias is unlikely to be the main explanation for this phenomenon. Accurate diagnosis is a central concern; in patients presenting with bipolar disorder, the clinician must screen for all anxiety disorders. Likewise, clinicians must investigate whether bipolar disorder is a comorbid condition in patients presenting with anxiety disorders. The suspicion of bipolar comorbidity should be even greater if patients present with multiple anxiety disorders or have previously been refractory to treatment.

The relative neglect in clinical and epidemiological research for the comorbidity between anxiety and bipolar spectrum disorders is due to the relative underdiagnosis of bipolar II disorders, often misdiagnosed as unipolar or personality disorders, and the lack of utilization of structured interviews for the diagnosis of anxiety disorders in bipolar patients. The correct identification of anxious and bipolar comorbidity has relevant clinical implications as far as other concomitant disorders, symptomatologic features, course, and complications are concerned. Symptomatologic instability, multiple comorbidities, and alcohol and substance abuse appear to be the most relevant consequences of the coexistence between anxiety and bipolar disorder.

There have been virtually no systematic, controlled studies of mood stabilizers in anxiety disorders, and no such studies comparing the efficacy of different mood stabilizers in bipolar patients with and without different anxiety disorder comorbidities. Therefore, no firm recommendations can be made as to which mood stabilizer would be best for which bipolar patient, based on his or her particular comorbid anxiety disorder. Nonetheless, several impressions emerge from the available literature. Generally, the data support the use of valproate as the mood stabilizer of choice for patients with comorbid panic disorder and possibly OCD, especially if associated with prominent anxiety symptoms, mixed features, and/or rapid cycling. Gabapentin is also a potential mood-stabilizing agent with anxiolytic properties (including possible efficacy in social phobia and panic disorder).

Antidepressants, while proven effective in panic disorder, OCD, and social phobia, may worsen the course of bipolar disorder, especially if initiated before treatment with a mood stabilizer. If antidepressants are to be used in patients with concurrent bipolar and anxiety disorders, adequate mood stabilization should first be achieved, and antidepressants then added cautiously while patients are monitored carefully for emerging symptoms of hypomania or mania, which may mimic or induce worsening anxiety. Atypical antipsychotics hold promise as mood-stabilizing agents. On the other hand, they have not yet been systematically studied in anxiety disorders, and have been hypothesized to exacerbate panic disorder and OCD because of their serotonergic antagonistic properties. PP

References

1. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51(1):8-19.

2. Angst J. The emerging epidemiology of hypomania and bipolar II disorder. J Affect Disord. 1998;50(2-3):143-151.

3. Chen YW, Dilsaver SC. Comorbidity for obsessive-compulsive disorder in bipolar and unipolar disorders. Psychiatry Res. 1995;59(1-2):57-64.

4. Perugi G, Toni C, Akiskal HS. Anxious-bipolar comorbidity. Diagnostic and treatment challenges. Psychiatr Clin North Am. 1999;22(3):565-583.

5. Himmelhoch JM. Social anxiety, hypomania and the bipolar spectrum: data, theory and clinical issues. J Affect Disord. 1998;50(2-3):203-213.

6. Angst J, Dobler-Mikola A. The Zurich Study. VI. A continuum from depression to anxiety disorders? Eur Arch Psychiatry Neurol Sci. 1985;235(3):179-186.

7. Stavrakaki C, Vargo B. The relationship of anxiety and depression: a review of the literature. Br J Psychiatry. 1986;149:7-16.

8. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.

9. Savino M, Perugi G, Simonini E, Soriani A, Cassano GB, Akiskal HS. Affective comorbidity in panic disorder: is there a bipolar connection? J Affect Disord. 1993;28(3):155-163.

10. Shoaib AM, Dilsaver SC. Panic disorder in subjects with pure mania and depressive mania. Anxiety. 1994-1995;1(6):302-304.

11. Rihmer Z, Barsi J, Belso N, Pestality P, Gyorgy S. Antidepressant-induced hypomania in obsessive-compulsive disorder. Int Clin Psychopharmacol. 1996;11(3):203-205.

12. Kruger S, Cooke RG, Hasey GM, Jorna T, Persad E. Comorbidity of obsessive compulsive disorder in bipolar disorder. J Affect Disord. 1995;34(2):117-120.

13. Perugi G, Akiskal HS, Pfanner C, et al. The clinical impact of bipolar and unipolar affective comorbidity on obsessive-compulsive disorder. J Affect Disord. 1997;46(1):15-23.

14. Perugi G, Akiskal HS, Ramacciotti S, et al. Depressive comorbidity of panic, social phobic, and obsessive-compulsive disorders re-examined: is there a bipolar II connection?
J Psychiatr Res. 1999;33(1):53-61.

15. McElroy SL, Altshuler LL, Suppes T, et al. Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. Am J Psychiatry. 2001;158(3):420-426.

16. Feske U, Frank E, Mallinger AG, et al. Anxiety as a correlate of response to the acute treatment of bipolar I disorder. Am J Psychiatry. 2000;157(6):956-962.

17. Dunner DL, Tay LK. Diagnostic reliability of the history of hypomania in bipolar II patients and patients with major depression. Compr Psychiatry. 1993;34(5):303-307.

18. Manning JS, Haykal RF, Connor PD, Akiskal HS. On the nature of depressive and anxious states in a family practice setting: the high prevalence of bipolar II and related disorders in a cohort followed longitudinally. Compr Psychiatry. 1997;38(2):102-108.

19. Benazzi F. Prevalence of bipolar II disorder in outpatient depression: a 203-case study in private practice. J Affect Disord. 1997;43(2):163-166.

20. Hantouche EG, Akiskal HS, Lancrenon S, et al. Systematic clinical methodology for validating bipolar-II disorder: data in mid-stream from a French national multi-site study (EPIDEP).
J Affect Disord. 1998;50(2-3):163-173.

21. Akiskal HS, Djenderedjian AM, Rosenthal RH, Khani MK. Cyclothymic disorder: validating criteria for inclusion in the bipolar affective group. Am J Psychiatry. 1977;134(11):1227-1233.

22. International Statistical Classification of Diseases and Related Health Problems. 10th rev. Geneva, Switzerland: World Health Organization; 1992.

23. Perugi G, Akiskal HS. The soft bipolar spectrum redefined: focus on the cyclothymic, anxious-sensitive, impulse-dyscontrol, and binge-eating connection in bipolar II and related conditions. Psychiatr Clin North Am. 2002;25(4):713-737.

24. Perugi G, Akiskal HS, Toni C, Simonini E, Gemignani A. The temporal relationship between anxiety disorders and (hypo)mania: a retrospective examination of 63 panic, social phobic and obsessive-compulsive patients with comorbid bipolar disorder. J Affect Disord. 2001;67(1-3):199-206.

25. MacKinnon DF, McMahon FJ, Simpson SG, McInnis MG, DePaulo JR. Panic disorder with familial bipolar disorder. Biol Psychiatry. 1997;42(2):90-95.

26. Perugi G, Akiskal HS, Gemignani A, et al. Episodic course in obsessive-compulsive disorder. Eur Arch Psychiatry Clin Neurosci. 1998;248(5):240-244.

27. Dilsaver SC, White K. Affective disorders and associated psychopathology: a family history study. J Clin Psychiatry. 1986;47(4):162-169.

28. Klein DN, Depue RA, Slater JF. Inventory identification of cyclothymia. IX. Validation in offspring of bipolar I patients. Arch Gen Psychiatry. 1986;43(5):441-445.

29. Coryell W. Obsessive-compulsive disorder and primary unipolar depression. Comparisons of background, family history, course, and mortality. J Nerv Ment Dis. 1981;169(4):220-224.

30. Perugi G, Frare F, Madaro D, Maremmani I, Akiskal HS. Alcohol abuse in social phobic patients: is there a bipolar connection? J Affect Disord. 2002;68(1):33-39.

31. Himle JA, Abelson JL, Haghightgou H, Hill EM, Nesse RM, Curtis GC. Effect of alcohol on social phobic anxiety. Am J Psychiatry. 1999;156(8):1237-1243.

32. Young LT, Cooke RG, Robb JC, Levitt AJ, Joffe RT. Anxious and non-anxious bipolar disorder. J Affect Disord. 1993;29(1):49-52.

33. Swann AC, Bowden CL, Morris D, et al. Depression during mania. Treatment response to lithium or divalproex. Arch Gen Psychiatry. 1997;54(1):37-42.

34. Lum M, Fontaine R, Elie R, et al. Divalproex sodium’s anti-panic effect in panic disorder: a placebo-controlled study. Biol Psychiatry. 1990;27:164A-165A.

35. Calabrese JR, Delucchi GA. Spectrum of efficacy of valproate in 55 patients with rapid-cycling bipolar disorder. Am J Psychiatry. 1990;147(4):431-434.

36. Deltito JA. Valproate pretreatment for the difficult-to-treat patient with OCD. J Clin Psychiatry. 1994;55(11):500.

37. Cora-Locatelli G, Greenberg BD, Martin JD, Murphy DL. Valproate monotherapy in an SRI-intolerant OCD patient. J Clin Psychiatry. 1998;59(2):82.

38. Uhde TW, Stein MB, Post RM. Lack of efficacy of carbamazepine in the treatment of panic disorder. Am J Psychiatry. 1988;145(9):1104-1109.

39. Koopowitz LF, Berk M. Response of obsessive compulsive disorder to carbamazepine in two patients with comorbid epilepsy. Ann Clin Psychiatry. 1997;9(3):171-173.

40. Joffe RT, Swinson RP. Carbamazepine in obsessive-compulsive disorder. Biol Psychiatry. 1987;22(9):1169-1171.

41. Pande AC, Davidson JR, Jefferson JW, Jet al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol. 1999;19(4):341-348. 

42. Pollack MH, Matthews J, Scott EL. Gabapentin as a potential treatment for anxiety disorders. Am J Psychiatry. 1998;155(7):992-993.

43. Perugi G, Toni C, Frare F, et al. Effectiveness of adjunctive gabapentin in resistant bipolar disorder: is it due to anxious-alcohol abuse comorbidity? J Clin Psychopharmacol. 2002;22(6):584-591.

44. Carta MG, Hardoy MC, Hardoy MJ, Grunze H, Carpiniello B. The clinical use of gabapentin in bipolar spectrum disorders. J Affect Disord. 2003;75(1):83-91.

45. Spina E, Perugi G. Antiepileptic drugs: indications other than epilepsy. Epileptic Disord. 2004;6(2):57-75.

46. Pande AC, Pollack MH, Crockatt J, et al. Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol. 2000;20(4):467-471.

47. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed rev. Washington, DC: American Psychiatric Association; 1987.

48. Steiner W. Fluoxetine-induced mania in a patient with obsessive-compulsive disorder. Am J Psychiatry. 1991;148(10):1403-1404.

49. Sholomskas AJ. Mania in a panic disorder patient treated with fluoxetine. Am J Psychiatry. 1990;147(8):1090-1091.

50. Jann MW, Bitar AH, Rao A. Lithium prophylaxis of tricyclic-antidepressant-induced mania in bipolar patients. Am J Psychiatry. 1982;139(5):683-684.

51. Kane JM, Quitkin FM, Rifkin A, Ramos-Lorenzi JR, Nayak DD, Howard A. Lithium carbonate and imipramine in the prophylaxis of unipolar and bipolar II illness: a prospective, placebo-controlled comparison. Arch Gen Psychiatry. 1982;39(9):1065-1069.

52. Hurowitz GI, Liebowitz MR. Antidepressant-induced rapid cycling: six case reports. J Clin Psychopharmacol. 1993;13(1):52-56.

53. Landry P, Roy L. Withdrawal hypomania associated with paroxetine. J Clin Psychopharmacol. 1997;17(1):60-61.

54. McIntyre R, Katzman M. The role of atypical antipsychotics in bipolar depression and anxiety disorders. Bipolar Disord. 2003;5(suppl 2):20-35.

55. Baker RW, Chengappa KN, Baird JW, Steingard S, Christ MA, Schooler NR. Emergence of obsessive compulsive symptoms during treatment with clozapine. J Clin Psychiatry. 1992;53(12):439-442.

56.  de Haan L, Beuk N, Hoogenboom B, Dingemans P, Linszen D. Obsessive-compulsive symptoms during treatment with olanzapine and risperidone: a prospective study of 113 patients with recent-onset schizophrenia or related disorders. J Clin Psychiatry. 2002;63(2):104-107.