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.     

Do antidepressants influence mood patterns? A naturalistic study in bipolar disorder

This prospective, longitudinal study compared the frequency and pattern of mood changes between outpatients receiving usual care for bipolar disorder who were either taking or not taking antidepressants. One hundred and eighty-two patients with bipolar disorder self-reported mood and psychiatric medications for 4 months using a computerized system (ChronoRecord) and returned 22,626 days of data. One hundred and four patients took antidepressants, 78 did not. Of the antidepressants taken, 95% were selective serotonin or norepinephrine reuptake inhibitors, or second-generation antidepressants. Of the patients taking an antidepressant, 91.3% were concurrently taking a mood stabilizer. The use of antidepressants did not influence the daily rate of switching from depression to mania or the rate of rapid cycling, independent of diagnosis of bipolar I or II. The primary difference in mood pattern was the time spent normal or depressed. Patients taking antidepressants frequently remained in a subsyndromal depression. In this naturalistic study using self-reported data, patients with bipolar disorder who were taking antidepressants--overwhelmingly not tricyclics and with a concurrent mood stabilizer--did not experience an increase in the rate of switches to mania or rapid cycling compared to those not taking antidepressants. Antidepressants had little impact on the mood patterns of bipolar patients taking mood stabilizers.     

不同类型抗抑郁剂在双相抑郁治疗中导致转相的回顾性研究

目的比较不同抗抑郁剂在双相抑郁治疗过程中转相率的差异。方法对150例接受抗抑郁剂治疗的双相抑郁患者出现躁狂、轻躁狂、快速循环情况进行调查，并比较不同抗抑郁剂之间的差异。结果150例双相抑郁中，共有41例患者在治疗过程中转相，总发生率（转相率）34％。其中使用双重作用抗抑郁剂（DAA）患者的转相率为29．2％，使用选择性5-羟色胺回吸收抑制剂〈SSRI）的患者为12.7％，DAA与SSRI联合应用者为48．7％，三组间差异有统计学意义（Χ^2=11．87，P〈0．001）。DDA与SSRI联合应用者转相率高于SSRI，差异有统计学意义（Χ^2=16．06，P〈0．001，危险比OR=6．53）；DAA转相率高于SSRI。差异有统计学意义（Χ^2=4.65，P〈0．01，OR=6．53）；DAA与SSRI联合应用者转相率高于DAA（Χ^2=3．49，P〉0.05，OR=2．31）。转相与未转相者相比，心境稳定剂的应用差异有统计学意义（7／41，52／109，Χ^2=11．72，P〈0．001）。结论不同类型抗抑郁荆在双相抑郁治疗中引起的转相率有差异，其中联合使用抗抑郁剂的转相率最高，而心境稳定剂的联合应用有助于预防转相。     

Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers

OBJECTIVE: The authors examined the comparative risks of switches in mood polarity into hypomania or mania during acute and continuation trials of adjunctive antidepressant treatment of bipolar depression. METHOD: One hundred fifty-nine patients with bipolar I disorder or bipolar II disorder participated in a total of 228 acute (10-week) randomized trials of bupropion, sertraline, or venlafaxine as an adjunct to a mood stabilizer. Patients in 87 of these trials entered continuation treatment for up to 1 year. Antidepressant response and the occurrence of subthreshold brief hypomania (emergence of brief hypomania [at least 1 but <7 days] or recurrent brief hypomania) and threshold switches (emergence of full-duration hypomania [> or =7 days] or mania) were blindly assessed by using clinician-rated daily reports of mood-associated dysfunction on the National Institute of Mental Health Life Chart Method. RESULTS: Threshold switches into full-duration hypomania and mania occurred in 11.4% and 7.9%, respectively, of the acute treatment trials and in 21.8% and 14.9%, respectively, of the continuation trials. The rate of threshold switches was higher in the 169 trials in patients with bipolar I disorder (30.8%) than the 59 trials in patients with bipolar II disorder (18.6%). The ratio of threshold switches to subthreshold brief hypomanias was higher in both the acute (ratio=3.60) and continuation trials (ratio=3.75) of venlafaxine than in the acute and continuation trials of bupropion (ratios=0.85 and 1.17, respectively) and sertraline (ratios=1.67 and 1.66, respectively). In only 37 (16.2%) of the original 228 acute antidepressant trials, or in only 23.3% of the patients, was there a sustained antidepressant response in the continuation phase in the absence of a threshold switch. CONCLUSIONS: Adjunctive treatment with antidepressants in bipolar depression was associated with substantial risks of threshold switches to full-duration hypomania or mania in both acute and long-term continuation treatment. Of the three antidepressants included in the study, venlafaxine was associated with the highest relative risk of such switching and bupropion with the lowest risk.     

Duloxetine Treatment of Stress Urinary Incontinence in Women Does Not Induce Mania or Hypomania

BACKGROUND: Mania is a rare but unwelcome side effect of treating depressed patients with antidepressants. This research sought to determine the risk of treatment-emergent mania or hypomania in women with stress urinary incontinence treated with duloxetine, a balanced dual serotonin-norepinephrine reuptake inhibitor currently under investigation for the treatment of both stress urinary incontinence and major depressive disorder. METHOD: Data were obtained from 4 double-blind, randomized, placebo-controlled studies involving 1913 women aged 22 to 83 years and 4 ongoing uncontrolled longer-term studies involving 1877 women aged 20 to 87 years. In all studies, women had the predominant symptom of stress urinary incontinence; in the active treatment arms, all women received duloxetine 80 mg/day. Women receiving antidepressants for major depressive disorder were excluded. In the placebo-controlled studies, 1 woman reported a history of bipolar disorder and 74 women reported a history of depression. In the uncontrolled longer-term studies, 1 woman reported a history of bipolar disorder and 69 reported a history of depression. RESULTS: In the placebo-controlled trials, 1 woman treated with duloxetine reported euphoria, while 1 reported mania and 1 reported euphoria when on placebo. In the uncontrolled longer-term studies, 1 woman reported mania; 1, euphoria; and 4, elevated moods. No women discontinued the study due to treatment-emergent mood elevation. CONCLUSION: These data suggest that duloxetine does not induce mania or hypomania in women with stress urinary incontinence in this population, in which few women had a history of bipolar disorder or depression and women on antidepressants were excluded.     

Switching to Hypomania and Mania: Differential Neurochemical, Neuropsychological, and Pharmacologic Triggers and Their Mechanisms

Current data suggest that monoamines, acetylcholine, amino acids, cortisol, thyroid hormones, and melatonin may be involved in the pathophysiology of bipolar disorder (BPD). Any neuropsychological or pharmacologic factor causing a disturbance in these neurochemicals may trigger manic/hypomanic switching. Antidepressants, stimulants, anticholinergics, steroids, and thyroid hormone have been reported to cause treatment-emergent mania (TEM) in BPD, but only recently have the traditional antidepressants been systematically studied. Paroxetine, 20 mg/d, monotherapy in treatment of acute, relatively “pure” bipolar I and II depression, and fluoxetine monotherapy in bipolar II depression conferred a similar risk as placebo for TEM. Paroxetine or bupropion adjunctive therapy to mood stabilizer(s) had a similar risk as placebo for treatment of TEM in real world patients with bipolar depression during continuation treatment. Venlafaxine was shown to have an increased risk of TEM compared with bupropion and sertraline. The evolving literature continues to support the role of mood stabilizers in preventing future mood episodes of BPD.     

A re-evaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Foundation Bipolar Network

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 Method^TM (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.     

Carbamazepine in bipolar-depressed disorder complicated by tricyclic antidepressant switching: case report

The use of carbamazepine in a depressed bipolar patient with a history of manic switching with tricyclic antidepressants is described. Carbamazepine effectively treated the depression and mania was avoided.     

Antidepressant-associated maniform states in acute treatment of patients with bipolar-I depression

Medical records of 158 patients with bipolar depression were analysed for the incidence of a switch from depression to maniform states (mania and hypomania). Relation to psychopharmacological treatment was investigated. Thirty-nine (25%) patients of the total sample had switched to a maniform state during the treatment period in the hospital. Among that group the phenomenon occurred in 23 patients (15%) as a hypomania and in 16 patients (10%) as a mania. Patients with a switch were significantly more often treated with tricyclic antidepressants (TCA) than patients without switch (79.5% vs 51.3%). Mood stabilising medication might reduce the risk for switching, especially in patients treated with TCA; however, it seems not totally sufficient, since 59% of the switched patients received mood stabilisers. The switch phenomenon was not associated with sociodemographic or clinical data. Received: 23 September 1998 / Accepted: 28 September 1998     

Antidepressant treatment in bipolar versus unipolar depression

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.     

Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP-BD

OBJECTIVE: Practice guidelines have advised against treating patients with antidepressants during bipolar mixed states or dysphoric manias. However, few studies have examined the outcomes of patients with co-occurring manic and depressive symptoms who are treated with antidepressants plus mood stabilizing drugs. METHOD: The authors compared outcomes in patients with bipolar disorder who received a mood stabilizing agent with versus without an antidepressant for a bipolar depressive episode accompanied by > or = 2 concurrent manic symptoms. The 335 participants were drawn from the first 2,000 enrollees in the National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Kaplan-Meier survival curves and Cox regression models were used to compare time to recovery. General linear models examined the relationship between antidepressant use or mania symptom load at the study entry and mania or depression symptom severity at the 3-month follow-up. RESULTS: Adjunctive antidepressant use was associated with significantly higher mania symptom severity at the 3-month follow-up. The probability of recovery at 3 months was lower among patients with higher baseline depression severity. Antidepressant use neither hastened nor prolonged time to recovery once potential confounding factors were covaried in a Cox regression model. CONCLUSIONS: In bipolar depression accompanied by manic symptoms, antidepressants do not hasten time to recovery relative to treatment with mood stabilizers alone, and treatment with antidepressants may lead to greater manic symptom severity. These findings are consistent with those from the STEP-BD randomized trial for pure bipolar depression, in which adjunctive antidepressants did not yield higher recovery rates than did mood stabilizer monotherapy.     

The long-term course of rapid-cycling bipolar disorder

BACKGROUND: Rapid cycling among patients with bipolar affective disorders is important because of its implications for long-term prognosis and for the use of antidepressants. To our knowledge, no prospective study has, as yet, described the course of this phenomenon beyond 5 years. METHODS: From 345 patients with bipolar I or bipolar II disorder followed up for a mean (SD) of 13.7 (6.1) years as part of the National Institute of Mental Health Collaborative Depression Study, 89 (25.8%) were identified who, during 1 or more years of follow-up, manifested a pattern that met DSM-IV criteria for rapid cycling. These patients were compared with the remaining bipolar patients by demographics, overall affective morbidity, morbidity during specific treatment conditions, and the likelihood of suicidal behavior. Analyses assessed whether the use of tricyclic antidepressants for depressive symptoms was associated with the persistence of rapid cycling or with tendencies to switch from depressive to manic or hypomanic phases. RESULTS: The 89 patients who showed a rapid cycling pattern were significantly more likely to have had an illness onset before 17 years of age and were more likely to make serious suicide attempts. In 4 of 5 cases, rapid cycling ended within 2 years of its onset. Resolutions were not associated with decreases in tricyclic antidepressant use. Throughout follow-up, patients prone to rapid cycling experienced more depressive morbidity than other bipolar patients, particularly when lithium carbonate was being used without tricyclic antidepressants. The use of these antidepressants was not more likely in the weeks preceding shifts from depression to mania or hypomania. CONCLUSIONS: These results indicate that bipolar patients who develop a rapid cycling pattern suffer substantial depressive morbidity and are at high risk for serious suicide attempts. These findings do not implicate tricyclic antidepressants or, by inference, serotonin reuptake inhibitors in the promotion of affective instability.     

Use of antidepressants to treat depression in bipolar disorder

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.     

A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group

BACKGROUND: More treatment options for bipolar depression are needed. Currently available antidepressants may increase the risk of mania and rapid cycling, and mood stabilizers appear to be less effective in treating depression than mania. Preliminary data suggest that lamotrigine, an established antiepileptic drug, may be effective for both the depression and mania associated with bipolar disorder. This is the first controlled multicenter study evaluating lamotrigine monotherapy in the treatment of bipolar I depression. METHODS: Outpatients with bipolar I disorder experiencing a major depressive episode (DSM-IV, N = 195) received lamotrigine (50 or 200 mg/day) or placebo as monotherapy for 7 weeks. Psychiatric evaluations, including the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), Mania Rating Scale, and the Clinical Global Impressions scale for Severity (CGI-S) and Improvement (CGI-I) were completed at each weekly visit. RESULTS: Lamotrigine 200 mg/day demonstrated significant antidepressant efficacy on the 17-item HAM-D, HAM-D Item 1, MADRS, CGI-S, and CGI-I compared with placebo. Improvements were seen as early as week 3. Lamotrigine 50 mg/day also demonstrated efficacy compared with placebo on several measures. The proportions of patients exhibiting a response on CGI-I were 51%, 41%, and 26% for lamotrigine 200 mg/day, lamotrigine 50 mg/day, and placebo groups, respectively. Adverse events and other safety results were similar across treatment groups, except for a higher rate of headache in the lamotrigine groups. CONCLUSION: Lamotrigine monotherapy is an effective and well-tolerated treatment for bipolar depression.     

Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to mood stabilizers

Introduction: Bipolar patients with breakthrough major depressive episodes despite ongoing adequately‐dosed mood stabilizer medication were randomized in a double‐blind manner to one of three antidepressants with different mechanisms of action: bupropion, sertraline, or venlafaxine. Preliminary data are presented on the switch rates into hypomania or mania for the antidepressants as a group prior to unblinding the specific individual drug efficacy and tolerability data in this ongoing clinical trial.

Methods: Subjects included 64 bipolar patients who participated at five sites in a 10‐week double‐blind trial for depression and a 1‐year blinded continuation maintenance phase for responders. Nonresponders were re‐randomized such that there were 95 acute treatment phases. In the acute phase, doses were titrated to clinical response, side effects, or maximum dose of bupropion (450 mg/day), sertraline (200 mg/day), or venlafaxine (375 mg/day). Daily ratings on the National Institute of Mental Health‐Life Chart Methodology (NIMH‐LCM) were inspected for the degree of improvement on the Clinical Global Impressions scale as revised for bipolar illness (CGI‐BP) and the occurrence of hypomania or mania.

Results: Thirty‐five (37%) of the 95 acute treatment phases were associated with a much or very much improved rating in depression on the CGI‐BP. Thirteen (14%) of these 95 acute trials of antidepressants as adjuncts to mood stabilizers were associated with switches, seven into hypomania and six into mania. Forty‐two patients elected to go into the continuation phase in 48 instances. Sixteen (33%) of the continuation phase trials were associated with mood switches, 10 into hypomania and six into mania.

Conclusions: In this randomized double‐blind prospective study of three second‐generation antidepressants (bupropion, sertraline, and venlafaxine) in bipolar patients whose depression broke through ongoing treatment with mood stabilizers, switches into hypomania or mania occurred in 14% of the acute phases and 33% of the continuation phases. Individual data on each drug will be assessed in the next phase of the study after more subjects are recruited and the blind is broken.     

Typical and atypical antipsychotics in bipolar depression

BACKGROUND: Symptomatic bipolar patients experience more depressive than manic symptoms, but fewer studies have been designed for bipolar depression than for bipolar mania. Since the antipsychotic agents have been shown to diminish depressive symptoms during the treatment of mania, atypical agents are now being studied for use in bipolar depression. DATA SOURCES: English-language articles published from 1980 through July 2004 and cited in MEDLINE were searched using the keywords antipsychotics, typical antipsychotics, atypical antipsychotics, bipolar depression, bipolar disorder, manic-depressive illness, placebo, and clinical trial. The generic and brand names of individual antipsychotics were also entered as keywords. Peer-reviewed abstracts of placebo-controlled studies assessing acute or long-term efficacy in bipolar depression presented at major scientific meetings were also reviewed. STUDY SELECTION: Use of a depression rating scale was required for inclusion of studies of the atypical antipsychotic agents in our analysis. DATA SYNTHESIS: Twenty-one randomized trials and 13 nonrandomized prospective trials were identified. In the only 2 acute, double-blind, placebo-controlled studies of antipsychotics in bipolar depression, the effect size of olanzapine was small (0.32) compared with the effect sizes of quetiapine (0.91-1.09, depending on dose). The effect size in acute mania of olanzapine at week 4 and quetiapine at week 3 was 0.50 and 0.39, respectively. Both olanzapine and quetiapine have been shown to be superior to placebo in the acute treatment of bipolar I depression. In addition, olanzapine has been shown to be more effective than placebo in delaying relapse into bipolar depression. With the exception of a 6-month perphenazine study, there are no other randomized studies of typical antipsychotics that support the conclusion that this class of medication worsens bipolar depression. CONCLUSION: Emerging data suggest that the atypical antipsychotic agents have a role in the acute and long-term treatment of bipolar depression. No convincing data support the impression that the typical antipsychotic agents worsen bipolar depression.     

Switch to mania upon discontinuation of antidepressants in patients with mood disorders: a review of the literature.

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.     

Efficacy of antidepressants in juvenile depression: meta-analysis

BACKGROUND: The safety of antidepressants in children and adolescents is being questioned and the efficacy of these drugs in juvenile depression remains uncertain. AIMS: To assess antidepressant efficacy in juvenile depression. METHOD: Systematic review and meta-analysis of randomised controlled trials (RCTs) comparing responses to antidepressants, overall and by type, v. placebo in young people with depression. RESULTS: Thirty drug-placebo contrasts in RCTs lasting 8 weeks (median) involved 3069 participants (512 person-years) of average age 13.5 years. Meta-analysis yielded a modest pooled drug/placebo response rate ratio (RR=1.22, 95% CI 1.15-1.31), with little separation between antidepressant types. Findings were similar for response rate differences and corresponding number needed to treat (NNT): overall NNT=9; tricyclic antidepressants NNT=14 > serotonin reuptake inhibitors NNT=9 > other antidepressants NNT=8. Numbers needed to treat decreased with increasing age: children (NNT=21) > mixed ages (NNT=10) > adolescents (NNT=8). CONCLUSIONS: Antidepressants of all types showed limited efficacy in juvenile depression, but fluoxetine might be more effective, especially in adolescents. Studies in children and in severely depressed, hospitalised or suicidal juvenile patients are needed, and effective, safe and readily accessible treatments for juvenile depression are urgently required.     

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).     

The effectiveness of antidepressants in the treatment of chronic non-cancer pain--a review

Antidepressants are often applied in the treatment of chronic pain. Analgesic action of tricyclic antidepressants (TCAs) has been extensively studied and proven. TCAs are associated with a number of adverse effects which are inconvenient for patients. The newer antidepressants have fewer side effects and equivalent efficacy on mood disorders. This article reviews the available publications (mainly placebo-controlled trials) concerning the efficacy of these medications in the treatment of chronic pain. The data regarding selective serotonin reuptake inhibitors (SSRI) are conflicting. Trazodone (a serotonin-reuptake inhibitor as well as a postsynaptic serotonin receptor antagonist) does not appear to be effective for the treatment of chronic pain. No placebo-controlled studies are available for noradrenergic and specific serotoninergic antidepressant (NaSSA)--mirtazapine and noradrenaline reuptake inhibitor (NaRI)--reboxetine. Bupropion, a noradrenaline and dopamine-reuptake inhibitor appears to be effective in the treatment of neuropathic pain. Venlafaxine--selective serotonin and noradrenergic reuptake inhibitors (SNRI) was shown to be effective in the treatment of different kinds of pain. Duloxetine (SNRI) is effective in relieving both the emotional and painful physical symptoms of depression. Additional randomized, controlled trials are necessary to fully evaluate the role of new antidepressants in the treatment of chronic pain.