Ghaemi SN, Hsu DJ, Soldani F, Goodwin FK.
Antidepressants in bipolar disorder: the case for caution.
Bipolar Disord. 2003 Dec;5(6):421-433.
"The 2002 American Psychiatric Association (APA) guidelines for the treatment of bipolar disorder recommended more conservative use of antidepressants. This change in comparison with previous APA guidelines has been criticized, especially from some groups in Europe. The Munich group in particular has published a critique of assumptions underlying the conservative recommendations of the recent APA treatment guidelines. In this paper, we re-examine the argument put forward by the Munich group, and we demonstrate that indeed, conceptually and empirically, there is a strong rationale for a cautious approach to antidepressant use in bipolar disorder, consistent with, and perhaps even more strongly than, the APA guidelines. This rationale is based on support for the following four propositions: (i) The risk of antidepressant induced mood-cycling is high, (ii) Antidepressants have not been shown to definitively prevent completed suicides and reduce mortality, whereas lithium has, (iii) Antidepressants have not been shown to be more effective than mood stabilizers in acute bipolar depression and have been shown to be less effective than mood stabilizers in preventing depressive relapse in bipolar disorder and (iv) Mood stabilizers, especially lithium and lamotrigine, have been shown to be effective in acute and prophylactic treatment of bipolar depressive episodes. We therefore draw three conclusions from this interpretation of the evidence: (i) There are significant risks of mania and long-term worsening of bipolar illness with antidepressants, (ii) Antidepressants should generally be reserved for severe cases of acute bipolar depression and not routinely used in mild to moderate cases and (iii) Antidepressants should be discontinued after recovery from the depressive episode, and maintained only in those who repeatedly relapse after antidepressant discontinuation (a minority we judge to represent only about 15-20% of bipolar depressed patients)." [Abstract]

Ghaemi SN, Rosenquist KJ, Ko JY, Baldassano CF, Kontos NJ, Baldessarini RJ.
Antidepressant treatment in bipolar versus unipolar depression.
Am J Psychiatry. 2004 Jan;161(1):163-5.
"OBJECTIVE: Antidepressant responses were compared in DSM-IV bipolar and unipolar depression. METHOD: The authors analyzed clinical records for outcomes of antidepressant trials for 41 patients with bipolar depression and 37 with unipolar depression, similar in age and sex distribution. RESULTS: Short-term nonresponse was more frequent in bipolar (51.3%) than unipolar (31.6%) depression. Manic switching occurred only in bipolar depression but happened less in patients taking mood stabilizers (31.6% versus 84.2%). Cycle acceleration occurred only in bipolar depression (25.6%), with new rapid cycling in 32.1%. Late response loss (tolerance) was 3.4 times as frequent, and withdrawal relapse into depression was 4.7 times less frequent, in bipolar as in unipolar depression. Mood stabilizers did not prevent cycle acceleration, rapid cycling, or response loss. Modern antidepressants, in general, did not have lower rates of negative outcomes than tricyclic antidepressants. CONCLUSIONS: The findings suggest an unfavorable cost/benefit ratio for antidepressant treatment of bipolar depression." [Abstract]

Kupersanin, Eve
Many Bipolor Patients Fail To Get Appropriate Medication
Psychiatr News 2002 37: 20-
"In addition, in just over 44 percent of patient visits during both study periods, physicians prescribed an antidepressant without a mood stabilizer, a treatment scenario that could induce mania in patients with bipolar disorder.

Blanco’s analysis did not address why, during a relatively large proportion of patient visits, there were no prescriptions for mood stabilizers. He speculated that a number of factors could have dissuaded psychiatrists from prescribing mood stabilizers to patients with bipolar disorder. Some patients, for example, may not have improved on a mood stabilizer in the past, may have suffered from side effects from a previous mood stabilizer, or were unwilling to take a mood stabilizer when it was suggested by their psychiatrist.

"I think these data call for more research on clinical decision making by psychiatrists," said Blanco, "to help us better understand the factors that inform psychiatrists’ treatment decisions."

Blanco received funding for the study through grants from NIMH and NIDA, the National Alliance for Research on Schizophrenia and Depression, and APA’s Van Amerigen Health Services Scholars Program." [Article]

Goldberg JF, Whiteside JE.
The association between substance abuse and antidepressant-induced mania in bipolar disorder: a preliminary study.
J Clin Psychiatry. 2002 Sep;63(9):791-5.
"BACKGROUND: Estimates of the prevalence and features of antidepressant-induced mania vary widely, with few data available on its potential risk factors. METHOD: Fifty-three DSM-IV bipolar patients were interviewed to retrospectively identify lifetime affective episodes, pharmacotherapy trials, and clinical outcomes, with corroboration from treating clinicians and reviews of medical, psychiatric, and pharmacy records. Particular attention was given to the possible relationship between antidepressant-induced mania and the presence of psychoactive substance abuse or dependence. RESULTS: Antidepressant-induced mania or hypomania was evident in 39.6% (21/53) of the study group. Patients who developed manic features soon after starting an antidepressant had more antidepressant trials per year than those who did not (p < .05). A history of substance abuse and/or dependence was associated with substantially increased risk for antidepressant-induced mania (odds ratio = 6.99, 95% CI = 1.57 to 32.28, p = .007). Concomitant mood stabilizers were not uniformly associated with protection against inductions of mania during antidepressant trials. CONCLUSION: Multiple antidepressant exposures among bipolar patients with histories of substance abuse and/or dependence may be associated with an elevated risk for antidepressant-induced mania." [Abstract]

Fortunati F, Mazure C, Preda A, Wahl R, Bowers M Jr.
Plasma catecholamine metabolites in antidepressant-exacerbated mania and psychosis.
J Affect Disord 2002 Apr;68(2-3):331-4
"We measured plasma free HVA and MHPG in 39 cases of psychosis or mania judged to be caused by antidepressant exacerbation of symptoms. A total of 24 of patients had been receiving selective serotonin reuptake inhibitors (SSRI's). The SSRI group showed a pattern of increased plasma HVA similar to a comparison group of patients with a psychotic/manic relapse secondary to medication non-compliance." [Abstract]

Manning JS, Haykal RF, Akiskal HS.
The role of bipolarity in depression in the family practice setting.
Psychiatr Clin North Am 1999 Sep;22(3):689-703, x
"The literature suggests that bipolar spectrum disorders are more prevalent than previously thought but still poorly recognized. In the primary care setting, this poor recognition is largely the result of an insensitive, cross-sectional approach and clinicians' lack of familiarity with the phenomenology of bipolar II. Failure to recognize the role of bipolarity in depressive illness is more often a cause of the poor outcome of this illness in this setting than under dosing with antidepressants. Hypomania is easily missed in clinical evaluations and, as currently defined by DSM-IV, may not represent the most diagnostic marker for all variants of bipolar illness: Mood lability and energetic activity, temperamental traits embodied in the construct of cyclothymia, have emerged as more specific. Given emerging data that as much as one third of depressions in both psychiatric and primary care settings belong to the soft bipolar spectrum, practitioner education on the necessity to consider course, temperament, and family history in the approach to depression may improve the identification of bipolar spectrum disorders and limit unproductive or potentially harmful antidepressants use unprotected with mood stabilizers." [Abstract]

Blanco, Carlos, Laje, Gonzalo, Olfson, Mark, Marcus, Steven C., Pincus, Harold Alan
Trends in the Treatment of Bipolar Disorder by Outpatient Psychiatrists
Am J Psychiatry 2002 159: 1005-1010
"In addition, bupropion, which is generally preferred over other antidepressants in this population because of its lower manicogenic properties (24–27), accounted for only about 8% of the prescriptions made during these visits and showed no increase in use over the years. All these findings raise questions about the appropriateness of antidepressant use in outpatient psychiatric practice and suggest that this may be an area to target for quality-improvement initiatives." [Full Text]

Goren JL, Levin GM.
Mania with bupropion: a dose-related phenomenon?
Ann Pharmacother 2000 May;34(5):619-21
"OBJECTIVE: To report a case in which bipolar depression was resistant to usual therapies, requiring dosages of bupropion >450 mg/d and to review the literature on mania associated with bupropion and propose a potential theory of a dose-related threshold associated with bupropion and mania. CASE SUMMARY: A 44-year-old white man with a 25-year history of bipolar affective disorder presented with depression resistant to usual therapies. Bupropion therapy was initiated and the dosage was titrated to 600 mg/d. After exceeding the maximum recommended daily dose (450 mg/d), he experienced a manic episode attributed to high-dose bupropion. DISCUSSION: Due to increased risk of seizures, current prescribing guidelines state that the total daily dose of bupropion is not to exceed 450 mg/d. Since bupropion is the agent least likely to cause a manic switch in bipolar disorder, this agent seemed a logical choice to treat the patient's depression. Due to a lack of response, the bupropion dosage was titrated to a maximum of 600 mg/d. Since the patient did not switch into mania until the dosage exceeded 450 mg/d, we speculate that this adverse reaction is a dose-related phenomenon. Scientific literature supports this theory. CONCLUSIONS: A switch into mania is a potential risk associated with antidepressant drug use in bipolar affective disorder. Bupropion is believed to be associated with a decreased risk compared with other antidepressant therapies. However, our case report as well as others support the theory that this decreased risk may be due to dosages not exceeding the recommended daily dose (450 mg/d). Doses of bupropion >450 mg/d should be used with caution in depressed patients with bipolar affective disorder." [Abstract]

El-Mallakh RS, Karippot A.
Use of antidepressants to treat depression in bipolar disorder.
Psychiatr Serv 2002 May;53(5):580-4
"For decades, clinicians and researchers did not distinguish between bipolar and unipolar depression. The safety and efficacy of antidepressants for the treatment of unipolar depression were studied, and the data were applied to the treatment of bipolar depression without validation. As evidence has accumulated that antidepressants may adversely affect the course of bipolar illness, more research has been focused on that problem. Current evidence suggests that although antidepressants are clearly effective in the acute treatment of type I and type II bipolar depression, they are also associated with a variety of adverse outcomes. They may induce a switch to mania or hypomania at a rate two or three times the spontaneous rate. Long-term use may destabilize the illness, leading to an increase in the number of both manic and depressed episodes; induce rapid cycling (at least four episodes a year); and increase the likelihood of a mixed state. Antidepressants should be used with caution in the treatment of bipolar depression." [Abstract]

Altshuler L, Suppes T, Black D, Nolen WA, Keck PE Jr, Frye MA, McElroy S, Kupka R, Grunze H, Walden J, Leverich G, Denicoff K, Luckenbaugh D, Post R.
Impact of antidepressant discontinuation after acute bipolar depression remission on rates of depressive relapse at 1-year follow-up.
Am J Psychiatry. 2003 Jul;160(7):1252-62.
"OBJECTIVE: While guidelines for treating patients with bipolar depression recommend discontinuing antidepressants within 6 months after remission, few studies have assessed the implications of this strategy on the risk for depressive relapse. This study examined the effect of antidepressant discontinuation or continuation on depressive relapse risk among bipolar subjects successfully treated for an acute depressive episode. METHOD: Eighty-four subjects with bipolar disorder who achieved remission from a depressive episode with the addition of an antidepressant to an ongoing mood stabilizer regimen were followed prospectively for 1 year. The risk of depressive relapse among 43 subjects who stopped antidepressant treatment within 6 months after remission ("discontinuation group") was compared with the risk among 41 subjects who continued taking antidepressants beyond 6 months ("continuation group"). RESULTS: A Cox proportional hazards regression analysis indicated that shorter antidepressant exposure time following successful treatment was associated with a significantly shorter time to depressive relapse. Furthermore, patients who discontinued antidepressant treatment within the first 6 months after remission experienced a significantly shorter period of euthymia before depressive relapse over the length of 1-year follow-up. One year after successful antidepressant response, 70% of the antidepressant discontinuation group experienced a depressive relapse compared with 36% of the continuation group. By the 1-year follow-up evaluation, 15 (18%) of the 84 subjects had experienced a manic relapse; only six of these subjects were taking an antidepressant at the time of manic relapse. CONCLUSIONS: The risk of depressive relapse in patients with bipolar illness was significantly associated with discontinuing antidepressants soon after remission. The risk of manic relapse was not significantly associated with continuing use of antidepressant medication and, overall, was substantially less than the risk of depressive relapse. Maintenance of antidepressant treatment in combination with a mood stabilizer may be warranted in some patients with bipolar disorder." [Abstract]

Post RM, Leverich GS, Nolen WA, Kupka RW, Altshuler LL, Frye MA, Suppes T, McElroy S, Keck P, Grunze H, Walden J.
A re-evaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Foundation Bipolar Network.
Bipolar Disord. 2003 Dec;5(6):396-406.
"OBJECTIVES: The risk-to-benefit ratio of the use of unimodal antidepressants (ADs) as adjuncts to mood stabilizers continues to be an area of controversy and disagreement among experts in the field. This paper reviews new data on: (1) depression in bipolar illness, (2) switch rates on ADs and (3) risks of AD discontinuation that are pertinent to the ongoing discussion and recommendations. METHODS: In the first study reviewed, 258 outpatients with bipolar illness were assessed prospectively on a daily basis using the National Institute of Mental Health-Life Chart MethodTM (NIMH-LCM) for 1 year. In the second study, 127 bipolar depressed patients were randomized to 10 weeks of sertraline, bupropion, or venlafaxine, as adjuncts to mood stabilizers; non-responders were re-randomized and responders were offered a year of continuation treatment. In the final study, Altshuler et al. retrospectively and prospectively assessed the risk of depressive relapses in patients who remained on ADs after 2 months of euthymia compared with those who discontinued ADs. RESULTS: Despite intensive naturalistic treatment, the 258 outpatients with bipolar illness followed prospectively for 1 year showed three times as many days depressed as days manic, re-emphasizing the considerable depressive morbidity that remains in bipolar disorder despite the number of treatment options available. In the study of bipolar depressed patients randomized to one of three ADs, a range of severities and durations of hypomanic to manic switches were discerned following 175 trials of AD augmentation of treatment with a mood stabilizer. Of the acute 10-week trials, 9.1% were associated with switches into hypomania or mania and another 9.1% with a week or more of hypomania alone (with no to minimal dysfunction). In 73 continuation phase AD trials, 16.4 and 19.2% were similarly associated with hypomanic to manic and hypomanic switches, respectively. In the Altshuler et al. studies, those who remained well on any AD for more than 2 months (only 15-20% of those initially treated) and who continued on ADs showed a lesser rate of relapse into depression over 1 year (35 and 36% in the first and second study, respectively) compared with those who discontinued their ADs (68 and 70% relapsing into depression). Surprisingly, this continuation of ADs was associated with no increase in the rate of switching into mania compared with those stopping ADs. CONCLUSIONS: These data reveal that depression and depressive cycling remain a substantial problem in some two-thirds of intensively treated bipolar outpatients. Acute AD augmentation was associated with a modest response rate and 18.2% switched into a hypomanic to manic episode, and 35.6% of the continuation trials showed these two types of switches. Two separate studies suggest that in the very small subgroup who remain well on ADs for at least 2 months, one should consider continuation of this AD augmentation treatment, because AD discontinuation appears associated with a substantially increased risk of depression relapse over the subsequent year with no reduced risk of switching into mania." [Abstract]

Serretti A, Artioli P, Zanardi R, Rossini D.
Clinical features of antidepressant associated manic and hypomanic switches in bipolar disorder.
Prog Neuropsychopharmacol Biol Psychiatry. 2003 Aug;27(5):751-7.
"The present study investigated possible clinical differences between bipolar patients with and without manic or hypomanic switch during antidepressant (AD) treatment. The authors undertook a retrospective assessment of 169 individuals affected by bipolar disorder type I (BP I: n=96) and II (BP II: n=73) who experienced at least one manic or hypomanic episode following depression without any interposed normothymic period ("manic switch") during AD therapy. They were compared with a sex, age (+/-5 years), and ethnicity-matched group of 247 subjects, randomly selected from our pool of bipolar subjects who have never had manic switches. Only 2 of the 169 patients had had spontaneous switches before the AD-related one. Switched subjects were marginally older (t=-2.65, df=414, P=.008) compared to not switched and less frequently delusional (chi2=13.86, P=.0002). Polarity of the onset episode was more frequently depressive in switched patients (chi2=21.93, P=.00002), which had also less previous manic episodes than not switched (t=3.44, df=332, P=.0006). Those differences were more pronounced in the BP I subsample. Switched patients were more frequently BP I (chi2=29.66; P<.00001). Maintenance with mood stabilizers appears to be a strong protective factor; in fact, of the 124 individuals undertaking a mood stabilizer therapy, 21 had a switch and 103 had no switches (chi2=41.10, P<.000001). In conclusion, some clinical variables, such as the number of manic episodes, the presence of delusions, the polarity of onset episode, and the mood-stabilizing treatment, may be involved in AD-related switches. Further studies are required to investigate the causal relationships between those factors." [Abstract]

Benazzi F.
Major depressive episodes with hypomanic symptoms are common among depressed outpatients.
Compr Psychiatry 2001 Mar-Apr;42(2):139-43
"Depressive mixed states (major depressive episodes [MDE] with some hypomanic symptoms) are not classified in DSM-IV. The aim of the present study was to determine the prevalence of depressive mixed states in depressed outpatients, and to compare bipolar II with unipolar depressive mixed states. Seventy consecutive bipolar II and unipolar depressed outpatients were interviewed using the DSM-IV Structured Clinical Interview (SCID). At least one hypomanic symptom was present in 90% of patients, and three or more in 28.5%. Symptoms of depressive mixed states included irritable mood, distractibility, racing thoughts, and increased talking. Bipolar II subjects had more concurrent hypomanic symptoms (three or more in 48.7% v 3.2%, P = 0.000). Depressive mixed states with three or more hypomanic symptoms correctly classified 70.0% of bipolar II subjects. These findings have important treatment implications, as antidepressants may worsen the symptoms of depressive mixed states, and mood stabilizers can be useful." [Abstract]

Ghaemi SN, Lenox MS, Baldessarini RJ.
Effectiveness and safety of long-term antidepressant treatment in bipolar disorder.
J Clin Psychiatry 2001 Jul;62(7):565-9
"OBJECTIVE: We sought to review research on use of antidepressants for long-term treatment of bipolar depression. METHOD: We conducted a computerized literature search of the MEDLINE, HealthStar, Current Contents, PsychInfo, and National Library of Medicine databases to identify studies involving antidepressant, anticonvulsant, or lithium use in bipolar disorder or manic-depressive illness published from 1966 through 2000. RESULTS: Only 7 blinded, controlled trials of long-term antidepressant treatment in bipolar disorders were found. The available information is not adequate to support the safety or effectiveness of long-term antidepressant treatment for bipolar depression, with or without mood-stabilizing cotherapy. CONCLUSION: Antidepressant treatment of bipolar depression is extraordinarily understudied. Controlled trials comparing specific antidepressants, particularly to compare mood-stabilizing agents given alone and combined with an antidepressant, are needed." [Abstract]

Bowden CL.
Strategies to reduce misdiagnosis of bipolar depression.
Psychiatr Serv 2001 Jan;52(1):51-5
"Research over the past decade indicates that the prevalence of bipolar disorder is similar to that of major depression. The author discusses complexities in the diagnosis of bipolar disorder, especially in distinguishing bipolar from unipolar depression. Bipolar depression is associated with more mood lability, more motor retardation, and greater time spent sleeping. Early age of onset, a high frequency of depressive episodes, a greater percentage of time ill, and a relatively acute onset or offset of symptoms are suggestive of bipolar disorder rather than major depression. Because DSM-IV criteria require a manic or hypomanic episode for a diagnosis of bipolar disorder, many patients are initially diagnosed and treated as having major depression. Treatment of bipolar disorder with antidepressants alone is not efficacious and may exacerbate hypomania, mania, or cycling. It is important that clinicians be alert to any hint of bipolarity developing in the course of antidepressant therapy, especially among patients with first-episode major depression." [Abstract]

Ghaemi SN, Ko JY, Goodwin FK.
"Cade's disease" and beyond: misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder.
Can J Psychiatry 2002 Mar;47(2):125-34
"The diagnosis and treatment of bipolar disorder (BD) has been inconsistent and frequently misunderstood in recent years. To identify the causes of this problem and suggest possible solutions, we undertook a critical review of studies concerning the nosology of BD and the effects of antidepressant agents. Both the underdiagnosis of BD and its frequent misdiagnosis as unipolar major depressive disorder (MDD) appear to be problems in patients with BD. Underdiagnosis results from clinicians' inadequate understanding of manic symptoms, from patients' impaired insight into mania, and especially from failure to involve family members or third parties in the diagnostic process. Some, but by no means all, of the underdiagnosis problem may also result from lack of agreement about the breadth of the bipolar spectrum, beyond classic type I manic-depressive illness (what Ketter has termed "Cade's Disease"). To alleviate confusion about the less classic varieties of bipolar illness, we propose a heuristic definition, "bipolar spectrum disorder." This diagnosis would give greater weight to family history and antidepressant-induced manic symptoms and would apply to non-type I or II bipolar illness, in which depressive symptom, course, and treatment response characteristics are more typical of bipolar than unipolar illness. The role of antidepressants is also controversial. Our review of the evidence leads us to conclude that there should be less emphasis on using antidepressants to treat persons with this illness." [Abstract]

Mundo E, Walker M, Cate T, Macciardi F, Kennedy JL.
The role of serotonin transporter protein gene in antidepressant-induced mania in bipolar disorder: preliminary findings.
Arch Gen Psychiatry 2001 Jun;58(6):539-44
"BACKGROUND: The occurrence of mania during antidepressant treatment is a key issue in the clinical management of bipolar disorder (BP). The serotonin transporter (5-HTT) is the selective site of action of most proserotonergic compounds used to treat bipolar depression. The 5-HTT gene (SLC6A4) has 2 known polymorphisms. The aim of this study was to investigate the role of the SLC6A4 variants in the pathogenesis of antidepressant-induced mania in BP. METHODS: Twenty-seven patients with a DSM-IV diagnosis of BP I or II, with at least 1 manic or hypomanic episode induced by treatment with proserotonergic antidepressants (IM+ group), were compared with 29 unrelated, matched patients with a diagnosis of BP I or II, who had been exposed to proserotonergic antidepressants without development of manic or hypomanic symptoms (IM- group). The 2 known polymorphisms of the SLC6A4 were genotyped, and allelic and genotypic association analyses were performed. RESULTS: With respect to the polymorphism in the promoter region (5HTTLPR), IM+ patients had an excess of the short allele (n = 34 [63%]) compared with IM- patients (n = 17 [29%]) (chi(2)(1), 12.77; P <.001). The genotypic association analysis showed a higher rate of homozygosity for the short variant in the IM+ group (n = 10 [37%]) than in the IM- group (n = 2 [7%]) and a lower rate of homozygosity for the long variant in the IM+ group (n = 3 [11%]) compared with the IM- group (n = 14 [48%]) (chi(2)(2), 12.43; P =.002). No associations were found for the polymorphism involving a variable number of tandem repeats. CONCLUSION: If these results are replicated, the 5HTTLPR polymorphism may become an important predictor of abnormal response to medication in patients with BP." [Abstract]

Goldberg JF, Truman CJ.
Antidepressant-induced mania: an overview of current controversies.
Bipolar Disord. 2003 Dec;5(6):407-20.
"OBJECTIVE: The prevalence, characteristics, and possible risk factors associated with antidepressant-induced mania remain poorly described. The present review sought to identify published rates of antidepressant-induced mania and describe risk factors for its emergence. METHODS: A MedLine search was conducted of journals that focused on mania or hypomania associated with recent antidepressant use. Data from published reports were augmented with relevant findings from recent clinical trials presented at scientific conferences. RESULTS: Antidepressant-induced manias have been reported with all major antidepressant classes in a subgroup of about 20-40% of bipolar patients. Lithium may confer better protection against this outcome when compared with other standard mood stabilizers, although switch rates have been reported with comparable frequencies on or off mood stabilizers. Evidence across studies most consistently supports an elevated risk in patients with (i) previous antidepressant-induced manias, (ii) a bipolar family history, and (iii) exposure to multiple antidepressant trials. CONCLUSION: About one-quarter to one-third of bipolar patients may be inherently susceptible to antidepressant-induced manias. Bipolar patients with a strong genetic loading for bipolar illness whose initial illness begins in adolescence or young adulthood may be especially at risk. Further efforts are needed to better identify high-vulnerability subgroups and differentiate illness-specific from medication-specific factors in mood destabilization." [Abstract]

Akiskal HS, Hantouche EG, Allilaire JF, Sechter D, Bourgeois ML, Azorin JM, Chatenet-Duchene L, Lancrenon S.
Validating antidepressant-associated hypomania (bipolar III): a systematic comparison with spontaneous hypomania (bipolar II).
J Affect Disord. 2003 Jan;73(1-2):65-74.
"BACKGROUND: According to DSM-IV and ICD-10, hypomania which occurs solely during antidepressant treatment does not belong to the category of bipolar II (BP-II). METHODS: As part of the EPIDEP National Multisite French Study of 493 consecutive DSM-IV major depressive patients evaluated in at least two semi-structured interviews 1 month apart, 144 (29.2%) fulfilled the criteria for bipolar II with spontaneous hypomania (BP-II Sp), and 52 (10.5%) had hypomania associated solely with antidepressants (BP-H AA). RESULTS: BP-II Sp group had earlier age at onset, more hypomanic episodes, and higher ratings on cyclothymic and hyperthymic temperaments, and abused alcohol more often. The two groups were indistinguishable on the hypomania checklist score (12.2+/-4.0 vs. 11.4+/-4.4, respectively, P=0.25) and on rates of familial bipolarity (14.1% vs. 11.8%, respectively, P=0.68). But BP-H AA had significantly more family history of suicide, had higher ratings on depressive temperament, with greater chronicity of depression, were more likely to be admitted to the hospital for suicidal depressions, and were more likely to have psychotic features; finally, clinicians were more likely to treat them with ECT, lithium and mood stabilizing anticonvulsants. LIMITATION: Naturalistic study, where treatment was uncontrolled. CONCLUSION: BP-H AA emerges as a disorder with depressive temperamental instability, manifesting hypomania later in life (and, by definition, during pharmacotherapy only). By the standards of clinicians who have taken care of these patients for long periods of time, BP-H AA appears as no less bipolar than those with prototypical BP-II. We submit that familial bipolarity ('genotypic' bipolarity) strongly favors their inclusion within the realm of bipolar II spectrum, as a prognostically less favorable depression-prone phenotype of this disorder, and which is susceptible to destabilization under antidepressant treatment. These considerations argue for revisions of DSM-IV and ICD-10 conventions. BP-HAA may represent a genetically less penetrant expression of BP-II; phenotypically; it might provisionally be categorized as bipolar III." [Abstract]

Ghaemi SN, Boiman EE, Goodwin FK.
Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study.
J Clin Psychiatry 2000 Oct;61(10):804-8; quiz 809
"OBJECTIVES: To determine if bipolar disorder is accurately diagnosed in clinical practice and to assess the effects of antidepressants on the course of bipolar illness. METHOD: Charts of outpatients with affective disorder diagnoses seen in an outpatient clinic during 1 year (N = 85 with bipolar or unipolar disorders) were reviewed. Past diagnostic and treatment information was obtained by patient report and systematic psychiatric history. Bipolar diagnosis was based on DSM-IV criteria using a SCID-based interview. RESULTS: Bipolar disorder was found to be misdiagnosed as unipolar depression in 37% of patients who first see a mental health professional after their first manic/hypomanic episode. Antidepressants were used earlier and more frequently than mood stabilizers, and 23% of this unselected sample experienced a new or worsening rapid-cycling course attributable to antidepressant use. CONCLUSION: These results suggest that bipolar disorder tends be misdiagnosed as unipolar major depressive disorder and that antidepressants seem to be associated with a worsened course of bipolar illness. However, this naturalistic trial was uncontrolled, and more controlled research is required to confirm or refute these findings." [Abstract]

Henry C, Sorbara F, Lacoste J, Gindre C, Leboyer M.
Antidepressant-induced mania in bipolar patients: identification of risk factors.
J Clin Psychiatry 2001 Apr;62(4):249-55
"BACKGROUND: Concerns about possible risks of switching to mania associated with antidepressants continue to interfere with the establishment of an optimal treatment paradigm for bipolar depression. METHOD: The response of 44 patients meeting DSM-IV criteria for bipolar disorder to naturalistic treatment was assessed for at least 6 weeks using the Montgomery-Asberg Depression Rating Scale and the Bech-Rafaelson Mania Rating Scale. Patients who experienced a manic or hypomanic switch were compared with those who did not on several variables including age, sex, diagnosis (DSM-IV bipolar I vs. bipolar II), number of previous manic episodes, type of antidepressant therapy used (electroconvulsive therapy vs. antidepressant drugs and, more particularly, selective serotonin reuptake inhibitors [SSRIs]), use and type of mood stabilizers (lithium vs. anticonvulsants), and temperament of the patient, assessed during a normothymic period using the hyperthymia component of the Semi-structured Affective Temperament Interview. RESULTS: Switches to hypomania or mania occurred in 27% of all patients (N = 12) (and in 24% of the subgroup of patients treated with SSRIs [8/33]); 16% (N = 7) experienced manic episodes, and 11% (N = 5) experienced hypomanic episodes. Sex, age, diagnosis (bipolar I vs. bipolar II), and additional treatment did not affect the risk of switching. The incidence of mood switches seemed not to differ between patients receiving an anticonvulsant and those receiving no mood stabilizer. In contrast, mood switches were less frequent in patients receiving lithium (15%, 4/26) than in patients not treated with lithium (44%, 8/18; p = .04). The number of previous manic episodes did not affect the probability of switching, whereas a high score on the hyperthymia component of the Semistructured Affective Temperament Interview was associated with a greater risk of switching (p = .008). CONCLUSION: The frequency of mood switching associated with acute antidepressant therapy may be reduced by lithium treatment. Particular attention should be paid to patients with a hyperthymic temperament, who have a greater risk of mood switches." [Abstract]

Ali S, Milev R.
Switch to mania upon discontinuation of antidepressants in patients with mood disorders: a review of the literature.
Can J Psychiatry. 2003 May;48(4):258-64.
"OBJECTIVE: To review the literature for reported cases of mania related to discontinuing antidepressant treatment, as well as for possible explanations of this phenomenon, and to present a case report. METHOD: We undertook a literature review through the PubMed index, using the key words mania, antidepressant withdrawal, and antidepressants in bipolar disorder. We reviewed 11 articles featuring 23 cases. Where available, we noted and tabulated certain parameters for both bipolar disorder (BD) and unipolar depression. We use a case example to illustrate the phenomenon of mania induced by antidepressant withdrawal. RESULTS: For patients with unipolar depression, we found 17 reported cases of mania induced by antidepressant withdrawal. Antidepressants implicated included tricyclic antidepressants (TCAs) (12/17), monoamine oxidase inhibitors (MAOIs) (2/17), trazodone (1/17), mirtazapine (1/17), and paroxetine (1/17). For patients with BD, we found 19 reported cases of mania induced by antidepressant withdrawal, including our own case example. Of these, selective serotonin reuptake inhibitors (SSRIs) (10/19), TCAs (4/19), MAOIs (2/19), and serotonin norepinephrine reuptake inhibitors (SNRIs) (2/19) were implicated. CONCLUSION: Our case report supports the observation of antidepressant withdrawal-induced mania in patients with BD. It is distinguishable from antidepressant-induced mania, physiological drug withdrawal, and mania as a natural course of the illness. Many theories have been put forward to explain this occurrence. Noradrenergic hyperactivity and "withdrawal-induced cholinergic overdrive and the cholinergic-monoaminergic system" are the 2 most investigated and supported models. The former is limited by poor clinical correlation and the latter by its applicability only to anticholinergic drugs." [Abstract]

Yildiz A, Sachs GS.
Do antidepressants induce rapid cycling? A gender-specific association.
J Clin Psychiatry. 2003 Jul;64(7):814-8.
"OBJECTIVE: To investigate the influence of antidepressant use and gender in the genesis of rapid-cycling bipolar illness. METHOD: The charts of bipolar patients treated at the Massachusetts General Hospital Bipolar Clinic (Boston, Mass.) were reviewed for gender, presence or absence of rapid cycling, and antidepressant use prior to first mania. RESULTS: Data were obtained for 129 bipolar patients (55% women), 45% of whom had experienced a rapid-cycling course. Overall, there was no significant difference in the rates of rapid cycling between the subjects who were exposed to antidepressants prior to their first manic/ hypomanic episode and those who were not. Additional analysis carried out separately by gender found a significant association between rapid cycling and antidepressant use prior to first mania/hypomania for women but not for men. A logistic regression analysis with rapid cycling as dependent variable revealed a significant interaction between antidepressant use prior to first mania/hypomania and gender. CONCLUSION: We found a gender-specific relationship between antidepressant use prior to first manic/hypomanic episode and rapid-cycling bipolar illness. When antidepressants are prescribed to depressed women who have a risk of bipolar disorder, the risk of inducing rapid cycling should be considered. Differing proportions of women and men in previous studies may account for conflicting results reported in the literature for the relationship of antidepressants and rapid cycling. However, this naturalistic trial was uncontrolled, and controlled research is required to confirm our findings." [Abstract]

Frankle WG, Perlis RH, Deckersbach T, Grandin LD, Gray SM, Sachs GS, Nierenberg AA.
Bipolar depression: relationship between episode length and antidepressant treatment.
Psychol Med. 2002 Nov;32(8):1417-23.
"BACKGROUND: The role of antidepressant medications in bipolar depression remains controversial, mainly due to a lack of research in this area. In this study the authors examined the episode length in bipolar depression and the relationship between antidepressant therapy and episode length. METHOD: A retrospective chart review of 165 subjects identified 50 (30%) with bipolar illness who experienced a major depressive episode between 1 January 1998 and 15 December 2000. Data gathered utilized a structured instrument completed by the clinician at each visit. This instrument includes modified SCID mood modules as well as continuous ratings for each associated symptom of depression and mood elevation. Survival analysis was employed to calculate the median length of the depressive episodes for the entire group. Further survival analysis compared the episode length for subjects treated with antidepressants during the depression (N = 33) with those who did not receive antidepressants (N = 17). The rate of switch into elevated mood states was compared for the two groups. RESULTS: The survival analysis for the entire sample demonstrated 25%, 50% and 75% probability of recovery at 33 (S.E. 8.7), 66 (S.E. 17.9) and 215 (S.E. 109.9) days, respectively. Comparing those who received (N = 33) and those who did not receive (N = 17) antidepressants during the episode did not reveal any difference in the length of the depressive episode. Switch rates were not significantly different between those receiving antidepressants and those not taking these medications (15.2% v. 17.6%, respectively). CONCLUSIONS: Over the past 20 years little progress has been made in reducing the length of depressive episodes in those with bipolar illness. This is despite increasing pharmacological options available for treating depression. Clinicians treating bipolar depression should discuss with their patients the likelihood that the episode will last between 2-3 months. Our results also suggest that antidepressant treatment may not reduce the length of depressive episodes, neither did it appear to contribute to affective switch in our sample." [Abstract]

Goldstein TR, Frye MA, Denicoff KD, Smith-Jackson E, Leverich GS, Bryan AL, Ali SO, Post RM.
Antidepressant discontinuation-related mania: critical prospective observation and theoretical implications in bipolar disorder.
J Clin Psychiatry 1999 Aug;60(8):563-7; quiz 568-9
"BACKGROUND: Development of manic symptoms on antidepressant discontinuation has primarily been reported in unipolar patients. This case series presents preliminary evidence for a similar phenomenon in bipolar patients. METHOD: Prospectively obtained life chart ratings of 73 bipolar patients at the National Institute of Mental Health were reviewed for manic episodes that emerged during antidepressant taper or discontinuation. Medical records were utilized as a corroborative resource. Six cases of antidepressant discontinuation-related mania were identified and critically evaluated. RESULTS: All patients were taking conventional mood stabilizers. The patients were on antidepressant treatment a mean of 6.5 months prior to taper, which lasted an average of 20 days (range, 1-43 days). First manic symptoms emerged, on average, 2 weeks into the taper (range, 1-23 days). These 6 cases of antidepressant discontinuation-related mania involved 3 selective serotonin reuptake inhibitors (SSRIs), 2 tricyclic antidepressants (TCAs), and 1 serotonin-norepinephrine reuptake inhibitor. Mean length of the ensuing manic episode was 27.8 days (range, 12-49 days). Potential confounds such as antidepressant induction, phenomenological misdiagnosis of agitated depression, physiologic drug withdrawal syndrome, and course of illness were carefully evaluated and determined to be noncontributory. CONCLUSION: These 6 cases suggest a paradoxical effect whereby antidepressant discontinuation actually induces mania in spite of adequate concomitant mood-stabilizing treatment. These preliminary observations, if replicated in larger and controlled prospective studies, suggest the need for further consideration of the potential biochemical mechanisms involved so that new preventive treatment approaches can be assessed." [Abstract]

Benazzi F.
Atypical depression with hypomanic symptoms.
J Affect Disord 2001 Jul;65(2):179-83
"BACKGROUND: Depressive mixed states (major depressive episodes with some hypomanic symptoms) (DMS) are not classified in DSM-IV and are understudied. The aims of this study were to find the prevalence and clinical features of DMS in atypical depression. METHODS: A total of 87 bipolar II and unipolar depressed outpatients were interviewed within the DSM-IV Structured Clinical Interview. RESULTS: More than two hypomanic symptoms were present in 50.0% of the atypical and 20.3% of the non-atypical depression cases (P=0.006). DMS mainly included irritable mood, distractibility, racing thoughts, and increased talking. LIMITATIONS: There was a single interviewer, and it was a non-blind, cross-sectional assessment, with bipolar II reliability. CONCLUSIONS: Findings have treatment implications, as antidepressants may worsen DMS, and mood stabilizers may improve it." [Abstract]

Benazzi F.
Major depressive episodes with hypomanic symptoms are common among depressed outpatients.
Compr Psychiatry 2001 Mar-Apr;42(2):139-43
"Depressive mixed states (major depressive episodes [MDE] with some hypomanic symptoms) are not classified in DSM-IV. The aim of the present study was to determine the prevalence of depressive mixed states in depressed outpatients, and to compare bipolar II with unipolar depressive mixed states. Seventy consecutive bipolar II and unipolar depressed outpatients were interviewed using the DSM-IV Structured Clinical Interview (SCID). At least one hypomanic symptom was present in 90% of patients, and three or more in 28.5%. Symptoms of depressive mixed states included irritable mood, distractibility, racing thoughts, and increased talking. Bipolar II subjects had more concurrent hypomanic symptoms (three or more in 48.7% v 3.2%, P = 0.000). Depressive mixed states with three or more hypomanic symptoms correctly classified 70.0% of bipolar II subjects. These findings have important treatment implications, as antidepressants may worsen the symptoms of depressive mixed states, and mood stabilizers can be useful. Copyright 2001 by W.B. Saunders Company." [Abstract]

Benazzi F.
Depressive mixed states: unipolar and bipolar II.
Eur Arch Psychiatry Clin Neurosci 2000;250(5):249-53
"Depressive mixed states (DMS) (major depressive episodes with some hypomanic symptoms) are understudied, and not classified in DSM-IV. The study aim was to find prevalence of DMS among depressed outpatients, to study clinical differences between DMS and non-DMS, and relationships of DMS with unipolar and bipolar II. Ninety eight consecutive DSM-IV bipolar II and unipolar depressed outpatients were interviewed with the Structured Clinical Interview for DSM-IV. DMS was defined as an MDE with at least two concurrent hypomanic symptoms. DMS was present in 62.2% of patients [48.7% of unipolar, 71.9% of bipolar II, (p=0.022)]. DMS had significantly fewer unipolar, more bipolar II patients, lower age at onset, and more atypical features than non-DMS. Bipolar II DMS had significantly more recurrences, more atypical features, and lower age at onset (trend) than unipolar DMS. Bipolar II DMS had (trend) lower age at onset and more atypical features than bipolar II non-DMS. High DMS prevalence has important treatment implications, as antidepressants may worsen DMS, and some antidepressant-resistant depressions may be DMS responding to mood stabilizers. DMS may be distinct from non-DMS, but not from unipolar and bipolar II disorders, and this distinction may be due mainly to high bipolar II prevalence in DMS." [Abstract]

Benazzi F, Rihmer Z.
Sensitivity and specificity of DSM-IV atypical features for bipolar II disorder diagnosis.
Psychiatry Res 2000 Apr 10;93(3):257-62
"The aim of the study was to find the sensitivity and the specificity of DSM-IV atypical features (mood reactivity, weight gain, appetite increase, hypersomnia, leaden paralysis, interpersonal rejection sensitivity) for the diagnosis of bipolar II disorder. Consecutive 557 unipolar (54.9%) and bipolar II (45.0%) major depressive episode (MDE) outpatients were interviewed with the Structured Clinical Interview for DSM-IV and the Global Assessment of Functioning Scale. Bipolar II was diagnosed broadly, with a minimum duration of hypomania of at least some days, instead of the 4 days required by DSM-IV. MDE with atypical features was significantly more common in bipolar II patients. For the diagnosis of bipolar II disorder, MDE with atypical features, sensitivity was 0.45, and specificity was 0. 74. Among individual atypical features, hypersomnia had the best combination of sensitivity (0.35) and specificity (0.81). Combinations of two and three features did not improve sensitivity and specificity. As the diagnosis of past hypomania may not be very reliable from a patient's interview, atypical features may be an important marker of bipolar II disorder." [Abstract]

Benazzi F.
Antidepressant-associated hypomania in outpatient depression: a 203-case study in private practice.
J Affect Disord 1997 Oct;46(1):73-7
"The incidence of hypomania/mania was studied in 203 consecutive mood disorder outpatients, presenting for treatment of depression in private practice, during a follow-up of 3 to 6 months. Of these 50.7% were unipolar, 45.3% were bipolar II, and 3.9% were bipolar I patients. Compared to unipolar patients, bipolar II patients had a threefold greater risk of switching (17.3% vs. 5.8%, a significant difference), but a lower rate than expected from previous work. In a previous analysis of the whole sample, bipolar II patients had a lower age at onset and more frequent atypical features than unipolar patients. Both unipolar and bipolar switchers had instead early age at onset and frequent atypical features, suggesting that these factors might increase the risk of switching in unipolar depression." [Abstract]

Young RC, Jain H, Kiosses DN, Meyers BS.
Antidepressant-associated mania in late life.
Int J Geriatr Psychiatry. 2003 May;18(5):421-4.
"BACKGROUND: Elderly patients can present with mania for the first time late in life, and some elders treated with antidepressants can present with mania. Clinical characteristics of antidepressant-associated mania (AAM) in late life have not been examined. OBJECTIVES: The aims of the study were to identify elders with AAM and to compare selected clinical characteristics to those of manic elders who had not been treated with an antidepressant. We hypothesized that AAM patients would have later age at presentation of bipolar disorder. METHODS: We retrospectively reviewed inpatients with manic disorder who were aged >or=60 years. The sample was selected from admissions prior to 1990. RESULTS: AAM patients (n = 11) were more often experiencing first manic episode, and they had later age at onset of first manic episode, compared to non-AAM patients (n = 46). Most of the AAM patients had been treated with tricyclic agents. CONCLUSIONS: These preliminary findings invite further investigation. Related studies may contribute to risk-benefit analyses for the use of particular antidepressants in the elderly. Also, first episode mania in late life may prove to be a useful model of vulnerability to AAM." [Abstract]

Ruiz M, Vairo C, Matusevich D, Finkelsztein C.
[High-Dose Fluoxetine- induced mania. Review and case report]
Vertex 2002 Jun;13(48):93-7
"We report the case of a 53 year old woman who attempted suicide taking one high-dose of fluoxetine, developing a manic episode 19 days later. We also make a review about antidepressant-induced mania. In patients with mood disorder, the frequency of antidepressant-induced mania switch has been estimated to be 3.7 to 33%, varying across studies that included different diagnoses and different antidepressant treatments. Among the used data basis (Medline) there are papers reporting fluoxetine-induced mania. All of them include patients receiving adequate dose and time fluoxetine treatment. We found no reports of switch occurring after one high-dose of fluoxetine. As the impact on the clinical management of antidepressant-induced manic switches is quite high, several studies have focused on the possible clinical predictors of this phenomenon. By the time, is not possible to determine whether a manic episode is due to the natural course of bipolar disorder or to the medication. Thus, the phenomenon of antidepressant-induced mania should be defined and investigated with controlled prospective studies." [Abstract]

Preda A, MacLean RW, Mazure CM, Bowers MB Jr.
Antidepressant-associated mania and psychosis resulting in psychiatric admissions.
J Clin Psychiatry 2001 Jan;62(1):30-3
"BACKGROUND: The safety and tolerability of the selective serotonin reuptake inhibitors and the newer atypical agents have led to a significant increase in antidepressant use. These changes raise concern as to the likelihood of a corresponding increase in adverse behavioral reactions attributable to these drugs. METHOD: All admissions to a university-based general hospital psychiatric unit during a 14-month period were reviewed. RESULTS: Forty-three (8.1%) of 533 patients were found to have been admitted owing to antidepressant-associated mania or psychosis. CONCLUSION: Despite the positive changes in the side effect profile of antidepressant drugs, the rate of admissions due to antidepressant-associated adverse behavioral effects remains significant." [Abstract]

Bowers MB Jr, McKay BG, Mazure CM.
Discontinuation of antidepressants in newly admitted psychotic patients.
J Neuropsychiatry Clin Neurosci. 2003 Spring;15(2):227-30.
"Antidepressants may exacerbate manic or psychotic symptoms in vulnerable individuals. The authors discontinued antidepressants in 16 consecutive cases in which patients with manic or psychotic symptoms were otherwise judged to be on a satisfactory regimen prior to admission. Thirteen of the patients improved rapidly, which suggests a possible association between antidepressant discontinuation and clinical improvement in this patient group." [Abstract]