Antidepressants in bipolar disorder: the case for caution

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).     

Bipolar mixed episodes and antidepressants: a cohort study of bipolar I disorder patients

Valentí M, Pacchiarotti I, Rosa AR, Bonnín CM, Popovic D, Nivoli AMA, Murru A, Grande Í, Colom F, Vieta E. Bipolar mixed episodes and antidepressants: a cohort study of bipolar I disorder patients.
Bipolar Disord 2011: 13: 145–154. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: The aim of this study was to elucidate the factors associated with the occurrence of mixed episodes, characterized by the presence of concomitant symptoms of both affective poles, during the course of illness in bipolar I disorder patients treated with an antidepressant, as well as the role of antidepressants in the course and outcome of the disorder. Method: We enrolled a sample of 144 patients followed for up to 20 years in the referral Barcelona Bipolar Disorder Program and compared subjects who had experienced at least one mixed episode during the follow‐up (n = 60) with subjects who had never experienced a mixed episode (n = 84) regarding clinical variables. Results: Nearly 40% of bipolar I disorder patients treated with antidepressants experienced at least one mixed episode during the course of their illness; no gender differences were found between two groups. Several differences regarding clinical variables were found between the two groups, but after performing logistic regression analysis, only suicide attempts (p < 0.001), the use of serotonin norepinephrine reuptake inhibitors (p = 0.041), switch rates (p = 0.010), and years spent ill (p = 0.022) were significantly associated with the occurrence of at least one mixed episode during follow‐up. Conclusions: The occurrence of mixed episodes is associated with a tendency to chronicity, with a poorer outcome, a higher number of depressive episodes, and greater use of antidepressants, especially serotonin norepinephrine reuptake inhibitors.     

Antidepressants for bipolar disorder——A meta-analysis of randomized,double-blind,controlled trials

OBJECTIVE： To examine the efficacy and safety of short-term and long-term use of antidepres- sants in the treatment of bipolar disorder. DATA SOURCES： A literature search of randomized, double-blind, controlled trials published until December 2012 was performed using the PubMed, ISI Web of Science, Medline and Cochrane Central Register of Controlled Trials databases. The keywords ＂bipolar disorder, bipolar I disorder, bipolar II disorder, bipolar mania, bipolar depression, cyclothymia, mixed mania and depression, rapid cycling and bipolar disorder＂, AND ＂antidepressant agent, antidepressive agents second- generation, antidepressive agents tricyclic, monoamine oxidase inhibitor, noradrenaline uptake in- hibitor, serotonin uptake inhibitor, and tricyclic antidepressant agent＂ were used. The studies that were listed in the reference list of the published papers but were not retrieved in the above-mentioned databases were supplemented. STUDY SELECTION： Studies selected were double-blind randomized controlled trials assessing the efficacy and safety of antidepressants in patients with bipolar disorder. All participants were aged 18 years or older, and were diagnosed as having primary bipolar disorder. Antidepressants or antidepressants combined with mood stabilizers were used in experimental interventions. Placebos, mood stabilizers, antipsychotics and other antide pressants were used in the control interventions. Studies that were quasi-randomized studies, or used antidepressants in combination with antipsy- chotics in the experimental group were excluded. All analyses were conducted using Review Man- ager 5.1 provided by the Cochrane Collaboration.     

Cigarette smoking is associated with suicidality in bipolar disorder

Objectives:  Cigarette smoking in individuals with bipolar disorder has been associated with suicidal behavior, although the precise relationship between the two remains unclear.
Methods:  In this prospective observational study of 116 individuals with bipolar disorder, we examined the association between smoking and suicidality as measured by Linehan's Suicide Behaviors Questionnaire (SBQ) and prospective suicide attempts over a nine-month period. Impulsivity was measured by the Barratt Impulsiveness Scale.
Results:  Smoking was associated with higher baseline SBQ scores in univariate and adjusted analyses, but was not significant after statistical adjustment for impulsivity in a regression model. A higher proportion of smokers at baseline made a suicide attempt during the follow-up period (5/31, 16.1%) compared to nonsmokers (3/85, 3.5%); p = 0.031, odds ratio = 5.25 (95% confidence interval: 1.2–23.5). Smoking at baseline also significantly predicted higher SBQ score at nine months.
Conclusions:  In this study, current cigarette smoking was a predictor of current and nine-month suicidal ideation and behavior in bipolar disorder, and it is likely that impulsivity accounts for some of this relationship.     

Light therapy for bipolar disorder: a case series in women

OBJECTIVES: To perform a dose-ranging safety and efficacy study of bright light therapy for depression in women with bipolar disorder (BD). METHODS: Nine women with DSM-IV BD I or II in the depressed phase were exposed to 50 lux (illuminance at the receiving surface) red light for two weeks, after which they received 7,000 lux light therapy for two-week epochs of 15, 30 and 45 min daily. The Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement and the Mania Rating Scale were used to assess mood symptoms. Four patients received morning light and five patients received midday light. RESULTS: Three of the four subjects treated with morning light developed mixed states. The fourth subject achieved a full, sustained response. To decrease the risk of inducing mixed episodes, we changed the time of light exposure to midday. Of the five women who received midday light therapy, two achieved full response and two showed early improvement but required a dose increase to sustain response. One woman remained depressed with 45 min of midday light but responded fully to a switch to morning light, 30 min daily. CONCLUSIONS: Women with bipolar illness are highly sensitive to morning bright light treatment; the induction of mixed states is a substantial risk. Initiating treatment with a brief duration (15 min) of midday light for bipolar depression is advisable.     

Initiation of stimulant and antidepressant medication and clinical presentation in juvenile bipolar I disorder

OBJECTIVES: The primary purpose of this study was to examine the extent to which the initiation of stimulant and antidepressant medication was associated with the subsequent onset of juvenile bipolar I disorder (BP I). Another aim was to investigate differences in clinical presentation between youths prescribed stimulant or antidepressant medication before and after the onset of juvenile BP I disorder. METHODS: Youths between the ages of 5 and 17 years meeting full, unmodified DSM-IV diagnostic symptom criteria for BP were included in this study. Data regarding the age of onset of BP I, psychiatric comorbidities, and current symptoms of mania and depression were obtained. Medication history was recorded as part of the assessment interview with parents and youths. RESULTS: Of the 245 youths with BP I, 65% (n = 160) were treated with stimulant medication; 32% (56/173) were treated after the onset of BP I, and 19% (32/173) were treated before the onset of BP I. Forty-six percent (113/245) were treated with antidepressant medication; 33% (67/206) were treated after the onset of BP I, and 3% (7/206) were treated before the onset of BP I. Patients who were treated with stimulants after the onset of BP I were significantly more likely to be younger (p < 0.0001). Patients who were treated with antidepressants before the onset of BP I were significantly more likely to be older and to have lower levels of mania on the Young Mania Rating Scale at assessment (p < 0.01). CONCLUSIONS: Data from this retrospective case series do not support the association between initial stimulant or antidepressant use and the onset of BP I or presenting symptoms of depression or manic symptoms.     

Antidepressants and suicidal behaviour in unipolar depression

OBJECTIVE: To compare the rates of suicidal behaviour during vs. after discontinuation of treatment with antidepressants, and to determine the comparative rates of suicidal behaviour for patients maintained on tricyclic (TCA) vs. selective serotonin reuptake inhibitor (SSRI) antidepressants. METHOD: Charts were reviewed for 521 patients with major depressive disorder and/or dysthymic disorder. Periods of active treatment or discontinuation with SSRIs or TCAs were determined. Rates of completed suicide, suicide attempts, and hospitalization for suicidality were analyzed. RESULTS: There was greater than a five-fold increase in risk for suicidal behaviour after discontinuation of antidepressant treatment (P < 0.0001). The rates of suicidal behavior during treatment with SSRIs or TCAs were similar. CONCLUSION: Suicidal behaviour in unipolar depressed patients treated with antidepressants increases substantially after medication discontinuation. This effect occurred in both patients who were maintained on SSRIs and TCAs. The findings support a possible protective effect on suicidal behaviour for both SSRIs and TCAs.     

双相障碍与强迫症的共病

概述

在双相障碍患者中强迫症状是常见的。因为双相障碍和强迫症的共病状态会令这两种障碍的临床治疗复杂化，所以确定这些共病的患者是很重要的。我们讨论了强迫症和双相障碍的共病，介绍了可能导致这种常见共病状态的发病机制，也讨论了该领域最新的研究进展，并提出一些管理这些患者的临床原则。

中文全文

本文全文中文版从2015年10月26日起在http://dx.doi.org/10.11919/j.issn.1002-0829.215009可供免费阅览下载 Previous studies have documented high rates of comorbidity of other psychiatric conditions among individuals with bipolar disorders (BD).[1] One study estimated that obsessive-compulsive disorders (OCD) accounted for 21% of all comorbidities in BD.[2] There is continuing debate about whether (a) these are two independent conditions that can co-occur or (b) OCD is a specific subtype of BD. Regardless of the interrelationship of the two conditions, the comorbid occurrence of these two types of symptoms can cause a clinical dilemma because selective serotonin reuptake inhibitors (SSRIs)-which are quite commonly used to treat OCD-increases the risk of precipitating manic symptoms.[3,4,5,6] The OCD symptoms that occur in individuals with BD often occur during the depressive episodes or during the intervals between episodes of depressive or manic symptoms.[7,8] This timing of OCD symptoms during BD is consistent with the cyclic nature of BD and suggests shared biological mechanisms between the two disorders. In support of this hypothesis, a study using Positron Emission Tomography (PET) found that in untreated persons with BD the serotonin-transporter binding potential in the insular and dorsal cingulate cortex was higher among BD patients with pathological obsessions and compulsions than among BD patients without such symptoms.[9] Moreover, a linkage study found that compared to OCD patients without comorbid BD, patients with comorbid OCD and BD were more likely to have a family history of mood disorders but less likely to have a family history of OCD.[10] However, another study found no significant difference in the rates of a positive family history of OCD between patients with OCD alone and those with comorbid OCD and BD.[11] Further support for the hypothesized common etiology comes from a preliminary molecular genetic study which found that hyperpolarization activated cyclic nucleotide-gated channel 4 (HCN4) is a common susceptible locus for both mood disorders and OCD, but further studies with larger sample sizes are needed to replicate this finding.[12] The presence of OCD in BD complicates the clinical presentation. Compared to patients with BD without comorbid OCD, those that have comorbid BD and OCD often have a more severe form of BD, have more prolonged episodes, are less adherent to medication, and are less responsive to medication. Recent studies about comorbid BD and OCD have reported the following: (a) Temporal relationship. Some studies suggest that OCD is an antecedent of BD,[10] but others report concurrent onset of OCD and BD.[13,14] (b) Course of disease. In 44% of patients with comorbid BD and OCD the episodes are cyclic.[15] The course of disease is more chronic among BD patients with OCD compared to those without comorbid OCD.[16,17] OCD is more commonly observed in patients with Type II BD, among whom the prevalence of OCD has been reported to be as high as 75%.[18] (c) Compulsive behaviors. The most commonly reported compulsions among patients with comorbid OCD and BD are compulsive sorting,[14,19,20,21] controlling or checking, [20] repeating behaviors,[13,22] excessive washing,[20] and counting.[19] Obsessive reassurance-seeking is also commonly reported in these patients.[23] In children and adolescents with BD, compulsive hoarding, impulsiveness,[24] and sorting[25] are more common. (d) Substance and alcohol abuse. A study found a higher prevalence of sedative, nicotine, alcohol, and caffeine use among individuals with comorbid OCD and BD compared to those with BD without OCD.[14] Similarly, compared to OCD patients without comorbid mood disorders, those with a comorbid mood disorder were more likely to have a substance abuse diagnosis (OR=3.18, 95%CI=1.81-5.58) or alcohol abuse diagnosis (OR=2.21, 95%CI=1.34-3.65).[11,13,26,27,28] (e) Suicidal behaviors. Compared to BD patients without OCD, a greater proportion of patients with both disorders had a lifetime history of suicidal ideation and suicide attempts.[2,11,13,29,30] The clinical management of comorbid OCD and BD requires first focusing on stabilizing the patient’s mood, which requires the combined use of multiple medications such as the use of lithium with anticonvulsants or atypical antipsychotic medications such as quetiapine;[31,32,33] adjunctive treatment with aripiprazole may be effective for the comorbid OCD symptoms.[4] In the case of OCD comorbid with type II BD, after full treatment of the mood symptoms with mood stabilizers the clinician can, while monitoring for potential drug interactions, cautiously try adjunctive treatment with antidepressants that are effective for both depressive symptoms and OCD symptoms and that have a low risk of inducing a full manic episode, including the selective serotonin reuptake inhibitors (SSRIs): fluoxetine, fluvoxamine, paroxetine, and sertraline.[32,35] In summary, BD comorbid with OCD may be etiologically distinct from either of the disorders. Clinicians should pay attention to its complex clinical manifestations and carefully consider the treatment principles outlined above.     

Differences in outcome of DSM-IV bipolar I and II disorders

Objectives:  To investigate whether the course of bipolar disorder (BD) type II is more depressive than that of BD I, and, if so, to explore the underlying factors that cause this difference.
Methods:  In a prospective, naturalistic study of 191 secondary care psychiatric in- and outpatients diagnosed in an acute phase of BD I or II, 160 patients (85.1%) were followed for 18 months. Using a life chart, the exact timing of symptom states in follow-up was examined. Differences between BD I (n = 75) and II (n = 85) in duration of index phase and episode, time to full remission and recurrence, and time in any mood episode were investigated.
Results:  Patients with BD II spent a higher proportion of time ill (47.5% versus 37.7%; p = 0.02) and in depressive symptom states (58.0% versus 41.7%; p = 0.003) than BD I patients. This was a result of the higher proportion (61.7% versus 48.6%; p = 0.03) and mean number (1.69 versus 1.11; p = 0.006) of depressive illness phases in BD II, rather than of differences in the duration of depressive phases. Type of index phase strongly predicted the outcome. In linear regression models, both BD II and type of index phase predicted more time spent in depressive symptom states.
Conclusions:  In medium-term follow-up, BD II patients spend about 40% more time in depressive symptom states than BD I patients because a higher proportion of BD II patients have depressive phases and the frequency of these is higher. Differences in type of index phase may markedly confound differences in outcome between BD I and II.     

Perspectives on lithium treatment of bipolar disorder: action, efficacy, effect on suicidal behavior

Objective: To review studies of (A) whether lithium has a prophylactic action in bipolar disorder, (B) the efficacy of prophylactic lithium treatment in comparison with the efficacy of treatment with anticonvulsant drugs, and (C) the effect of lithium treatment on suicidal behavior.
Methods: Analysis of all relevant publications.
Results: (A) The claim that a prophylactic action of lithium has never been satisfactorily demonstrated is based on wrong assumptions, biased selection of references, and unjustified generalizations. (B) In typical bipolar disorder lithium is significantly more efficacious than carbamazepine; in atypical bipolar disorder there is a non-significant trend for carbamazepine to be better than lithium. Valproate has not been proven prophylactically efficacious in typical bipolar disorder; in atypical bipolar disorder it may have an effect, but it has not been compared with that of lithium. (C) A significant association has been found between prophylactic lithium treatment, on the one hand, and reduced mortality and suicidal behavior, on the other. No such association has been reported for prophylactic treatment with other mood stabilizers.
Conclusion: In bipolar disorder the choice of prophylactic drug must be based on a weighing of efficacy against tolerability, interactions, ease of management, use during pregnancy and lactation, and expense. Lithium should be the preferred prophylactic drug in patients with typical bipolar disorder and in patients who are at high risk of committing suicide, that is, patients with severe depressions or depressions combined with persistent suicidal ideas or with suicide attempts in the past.     

Clinical predictors of suicidal acts after major depression in bipolar disorder: a prospective study

Objective:  This study determined the clinical predictors of suicidal behavior during a 2-year follow-up of patients with bipolar disorder presenting with a major depressive episode (MDE).
Method:  Sixty four patients with DSM-III-R bipolar disorder were assessed at presentation for treatment of an MDE. Correlates of past suicidal behavior were determined by comparing patients with and without a history of suicide attempts using a t -test, Wilcoxon test or chi-squared test of independence on individual explanatory variables. Putative predictors of attempts during the follow-up period were tested separately using Cox proportional hazards regression analysis.
Results:  Twelve of 64 patients had at least one suicide attempt in the follow-up period, five of them attempted in the first 2 months and seven around or shortly after the 1-year follow-up visit. All attempters had a history of past suicide attempts. Most predictors of future suicidal behavior were correlates of past suicidal behavior. Family history of suicide acts and comorbid borderline personality disorder predicted early attempts, while younger age, high hostility scores, number of past attempts, subjective pessimism as reflected in depression and suicidal ideation, and few reported reasons for living predicted suicidal acts during the whole period.
Conclusion:  In this data set of bipolar patients we noted an intriguing picture of two clusters of suicide attempts. Hostility was the strongest risk factor. These findings may have implications in both the identification of at-risk patients and the timing of clinical interventions including aggressive pharmacotherapeutic prophylaxis to prevent relapse or recurrence of depressive symptomatology.     

Neuropsychological functions in patients with bipolar I and bipolar II disorder

Objectives:  The literature reports persistent cognitive impairments in patients with bipolar disorder even after prolonged remission. However, a majority of studies have focused only on bipolar I disorder (BP-I), primarily because bipolar II disorder (BP-II) is often underdiagnosed or misdiagnosed. More attention should be paid to the differences between BP-I and BP-II, especially the aspects of neuropsychological functioning. We examined the different neuropsychological functions in BP-I and BP-II patients and compared them with those of healthy controls.
Methods:  The study included 67 patients with interepisode bipolar disorder (BP-I: n = 30; BP-II: n = 37) and 22 healthy controls compared using a battery of neuropsychological tests that assessed memory, psychomotor speed, and certain aspects of frontal executive function.
Results:  The BP-I group performed poorly on verbal memory, psychomotor speed, and executive function compared to the BP-II and control groups. Both bipolar groups performed significantly less well than the control group on measures of working memory and psychomotor speed, while the BP-II group showed an intermediate level of performance in psychomotor speed compared to the BP-I and control groups. There was no difference between the groups on visual memory.
Conclusions:  BP-I was characterized by reduced performance in verbal memory, working memory, psychomotor speed, and executive function, while BP-II patients showed a reduction only in working memory and psychomotor speed. Cognitive impairment existed in both subtypes of bipolar disorder, and was greater in BP-I patients. Rehabilitation interventions should take into account potential cognitive differences between these bipolar subtypes.     

Electroconvulsive therapy: an effective therapy of medication-resistant bipolar disorder

OBJECTIVES: We report our experience with a medication-refractory patient with bipolar I disorder, who remained clinically stable under continuation electroconvulsive therapy (C-ECT). We found ECT to be effective in providing functionality for a patient when various medications had failed. METHODS AND RESULTS: A 53-year-old woman with a 31-year history of recurrent manic and depressive episodes poorly responsive to medications warranted an ECT trial. Remission was achieved after 12 treatments and C-ECT at weekly intervals was used as maintenance therapy. C-ECT was continued for 37 months and 85 treatments, and discontinued when anesthetic difficulties precluded further treatment. Three months after the last ECT, she was readmitted in a severe manic relapse. Restarting ECT caused rapid remission. There are no signs of cognitive deterioration during C-ECT. CONCLUSION: Long-term C-ECT is an effective and safe prophylactic treatment in individual treatment-resistant patients with bipolar disorder.     

Substance abuse in bipolar disorder

Background: High rates of substance abuse have been reported in the general population, with males more often affected than females. Although high rates of substance abuse have also been reported in bipolar patients, the relationship between substance abuse and bipolar disorder has not been well characterized.

Methods: Substance abuse histories were obtained in 392 patients hospitalized for manic or mixed episodes of bipolar disorder and rates of current and lifetime abuse calculated. Analyses comparing sex, subtype (manic vs. mixed) and clinical history variables were conducted.

Results: Rates of lifetime substance abuse were high for both alcohol (48.5%) and drugs (43.9%). Nearly 60% of the cohort had a history of some lifetime substance abuse. Males had higher rates of abuse than females, but no differences in substance abuse were observed between subjects in manic and mixed bipolar states. Rates of active substance abuse were lower in older age cohorts. Subjects with a comorbid diagnosis of lifetime substance abuse had more psychiatric hospitalizations.

Conclusions: Substance abuse is a major comorbidity in bipolar patients. Although rates decrease in older age groups, substance abuse is still present at clinically important rates in the elderly. Bipolar patients with comorbid substance abuse may have a more severe course. These data underscore the significance of recognition and treatment of substance abuse in bipolar disorder patients.     

Posttraumatic stress disorder and substance use disorder in adolescent bipolar disorder

Objective: Anxiety disorders such as posttraumatic stress disorder (PTSD) and substance use disorders (SUD) are increasingly recognized as comorbid disorders in children with bipolar disorder (BPD). This study explores the relationship between BPD, PTSD, and SUD in a cohort of BPD and non‐BPD adolescents. Methods: We studied 105 adolescents with BPD and 98 non‐mood‐disordered adolescent controls. Psychiatric assessments were made using the Kiddie Schedule for Affective Disorders and Schizophrenia–Epidemiologic Version (KSADS‐E), or Structured Clinical Interview for DSM‐IV (SCID) if 18 years or older. SUD was assessed by KSADS Substance Use module for subjects under 18 years, or SCID module for SUD if age 18 or older. Results: Nine (8%) BPD subjects endorsed PTSD and nine (8%) BPD subjects endorsed subthreshold PTSD compared to one (1%) control subject endorsing full PTSD and two (2%) controls endorsing subthreshold PTSD. Within BPD subjects endorsing PTSD, seven (39%) met criteria for SUD. Significantly more SUD was reported with full PTSD than with subthreshold PTSD (χ² = 5.58, p = 0.02) or no PTSD (χ² = 6.45, p = 0.01). Within SUD, the order of onset was BPD, PTSD, and SUD in three cases, while in two cases the order was PTSD, BPD, SUD. The remaining two cases experienced coincident onset of BPD and SUD, which then led to trauma, after which they developed PTSD and worsening SUD. Conclusion: An increased rate of PTSD was found in adolescents with BPD. Subjects with both PTSD and BPD developed significantly more subsequent SUD, with BPD, PTSD, then SUD being the most common order of onset. Follow‐up studies need to be conducted to elucidate the course and causal relationship of BPD, PTSD and SUD.     

One-year outcome with antidepressant--treatment of bipolar depression

OBJECTIVE: To examine the risk of relapse into mania or depression with varying duration of antidepressant treatment in a cohort of 59 patients with bipolar disorder. METHOD: An open naturalistic evaluation using life charting methods of patients with 1 year follow-up, who responded to antidepressant treatment and who then less or more than 6 months of antidepressant treatment. RESULTS: Patients who received more than 6 months of antidepressant treatment were less likely to relapse into depression at follow-up of 1 year. There was no difference in relapse rates for mania in the different antidepressant treatment duration groups. Gender and bipolar subtype did not significantly affect relapse rates for depression or mania. CONCLUSION: Our data, taken with other studies, suggest that the duration of optimal antidepressant treatment in bipolar disorder must be further evaluated.