Treatment-emergent Affective Switch Research Articles

Full-spectrum efficacy of cariprazine across manic and depressive symptoms of bipolar I disorder in patients experiencing mood episodes: Post hoc analysis of pooled randomized controlled trial data

IntroductionPatients with bipolar I disorder may experience mood destabilization or treatment-emergent affective switch (TEAS) from one symptom pole to the other spontaneously or following treatment. Optimal treatment should address symptoms from both poles without precipitating destabilization. MethodsThese were pooled post hoc analyses of data from randomized, double-blind, placebo-controlled studies of cariprazine 3–12 mg/d for bipolar I mania (NCT00488618, NCT01058096, NCT01058668) and cariprazine 1.5 mg/d or 3 mg/d for bipolar I depression (NCT01396447, NCT02670538, NCT02670551). Changes from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6 and Young Mania Rating Scale (YMRS) total score at week 3 were analyzed in each indication using a mixed-effects model for repeated measures. Percentages of patients with increasing levels of endpoint response and TEAS (bipolar mania = MADRS total score ≥ 19; bipolar depression = YMRS score ≥ 16) were determined. ResultsCariprazine significantly reduced manic and depressive symptoms in patients with bipolar I disorder mood episodes. In patients with a manic episode and up to mild baseline depressive symptoms, cariprazine also significantly reduced depressive symptoms. In patients with a depressive episode and manic symptoms in remission at baseline, numerical reduction (without statistical significance) in YMRS indicated no worsening of mania. In both indications, cariprazine-treated patients had numerically greater response rates (presenting symptom pole) than placebo-treated patients; lower percentages of cariprazine- than placebo-treated patients had TEAS at visits where data were collected. LimitationsPost hoc analysis. ConclusionResults suggested that cariprazine had full-spectrum efficacy across symptoms from both poles in patients with bipolar I disorder mood episodes; TEAS risk was low. Patient-level response suggested that improvement was clinically relevant.

Treatment of bipolar depression: clinical practice vs. adherence to guidelines-data from a Bavarian drug surveillance project.

Pharmacotherapy of bipolar depression (BPD) is confronted with major clinical challenges, like limited evidence-based treatment options, regular cases of treatment resistance, and risk of treatment-emergent affective switches. Medical guidelines can support practitioners to make decisions based on current scientific evidence. The objective of this study is to evaluate to what extent recommendations of the 2019 German S3 guidelines "Diagnosis and Treatment of Bipolar Disorders" are reflected in clinical practice in inpatient treatment. We conducted a descriptive analysis of prescription numbers in 2,627 patients with BPD in a naturalistic inpatient setting analyzing data from the ongoing Bavarian multicenter drug safety project Pharmaco-Epidemiology and Vigilance (Pharmako-EpiVig) from the years 2014-2022. Of the patients, 38% were not administered any drug explicitly recommended for treatment of BPD, that is, quetiapine, lamotrigine, carbamazepine, or olanzapine. Only 6% of the patients received monotherapy with one of those drugs. Of the patients, 34% were administered ≥4 psychotropic drugs simultaneously. Patients received 912 different therapy regimens of mono or combination therapy with mood stabilizers (MS), atypical antipsychotics (AAP), and antidepressants. Of the patients, 72% received an antidepressant and 6% without concomitant prescription of an AAP or MS. Prescription rates of venlafaxine (21% to 14%) and tricyclic antidepressants (9% to 6%) decreased significantly from the first (2014-2016) to the last (2020-2022) observed time period. Of the patients, 60% received an MS. Prescription rate of valproate (22% to 14%) decreased significantly, while lithium prescription increased significantly (29% to 35%). Of the patients, 71% were administered an AAP. Quetiapine was the most prescribed drug overall (43%). Only two patients were administered a combination of olanzapine and fluoxetine. Our results demonstrate a substantial gap between guideline recommendations and current clinical practice. The remarkable heterogeneity in treatment regimens, with no discernible dominant treatment approach, is in part a reflection of the complexity of bipolar disorder but also substantiates the need of comprehensive recommendations regarding combination therapies. Increase in lithium prescription is an encouraging development due to its unique efficacy in maintenance treatment. To improve the quality of clinical practice guideline implementation, more randomized controlled trials shouldbeconducted in the future to prospectively investigate different implementation strategies.

The current status of recommendations for non-invasive neuromodulation therapy in severe mental disorders

Introduction There is an increasing rate of treatment resistance in severe psychiatric disorders (SPDs), which indicates the necessity for finding new therapeutic interventions, because of the significant negative impact these disorders have on the patient’s quality of life, functionality, and other important parameters. In clinical practice, SPDs are estimated to represent up to 30-60% of all diagnosed cases. Schizophrenia spectrum disorders (SSD), major depressive disorder (MDD), and bipolar disorders (BDs) are associated with lower response to a large variety of therapeutic approaches. In this context, new technologies should be considered for SPDs, and non-invasive neuromodulation techniques can be explored as add-ons to ongoing therapeutic interventions.ObjectivesA literature review was conducted to detect the available evidence to support recommendations for neuromodulation techniques in SPDs.MethodsThree electronic databases (PubMed, Cochrane, Google Scholar) were searched for papers corresponding to the keywords “treatment-resistant psychiatric disorders” and “neuromodulation” or “electroconvulsive therapy” (ECT) or “transcranial magnetic stimulation” (TMS) or “transcranial direct current stimulation” (tDCS), published from the beginning of the respective databases up to July 2023.Results After the initial search, 1258 papers surfaced, but only 72 remained to be included in the analysis, after filtering them according to the inclusion and exclusion criteria. TMS may improve both depressive and manic symptoms, but also reports of polarity changes were found, indicating the need for careful monitoring of treatment-emergent affective switches (TEAS). TMS may also improve cognitive functions, although not sufficient evidence was found to support this observation clearly. The efficacy of temporoparietal TMS in schizophrenia has not been proven with certainty, although this intervention may improve positive symptoms. ECT was an effective and well-tolerated intervention for severe mood episodes, SSD, and BDs. Depressive symptoms responded to tDCS in bipolar/monopolar patients, but reports of TEAS in the BDs population have been reported.ConclusionsNon-invasive neuromodulation techniques may represent an efficient option in patients with SPD, but more good-quality trials are needed before this recommendation is formulated in clinical guidelines.Disclosure of InterestNone Declared

Brain stimulation treatment for bipolar disorder.

Bipolar disorders are clinically complex, chronic and recurrent disorders. Few treatment options are effective across hypomanic, manic, depressive and mixed states and as continuation or maintenance treatment after initial symptom remission. The aim of this review was to provide an up-to-date overview of research on the efficacy, tolerability and cognitive effects of electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), magnetic seizure therapy (MST), deep brain stimulation (DBS) and vagus nerve stimulation (VNS). References included in this review were identified through multiple searches of the Embase, PubMed/MEDLINE and APA PsycINFO electronic databases for articles published from inception until February 2022. Published reviews, meta-analyses, randomised controlled trials and recent studies were prioritised to provide a comprehensive and up-to-date overview of research on brain stimulation in patients with bipolar disorders. The evidence base for brain stimulation as an add-on or alternative to pharmacological and psychological treatments in patients with bipolar disorders is limited but rapidly expanding. Brain stimulation treatments represent an opportunity to treat all bipolar disorder states, including cognitive dysfunction during euthymic periods. Whilst findings to date have been encouraging, larger randomised controlled trials with long-term follow-up are needed to clarify important questions regarding treatment efficacy and tolerability, the frequency of treatment-emergent affective switches and effects on cognitive function.

Role of MAOI drugs as triggers of manic episodes in bipolar disorders: A case report and a narrative review

IntroductionUse of Monoamine Oxidase Inhibitors (MAOIs) has experimented an important reduction in recent years, being replaced by other antidepressant drugs (ADs) associated with a better safety profile. Its use has been restricted to instructed professionals treating resistant and atypical depression. Thus, treatment-emergent affective switch (TEAS) induced by MAOIs is a rare event nowadays.ObjectivesTo describe a manic episode associated to a one-year-long treatment with phenelzine, a MAOI agent.MethodsWe present the case of a 47-year-old man hospitalized in our acute psychiatric unit after presenting compatible clinical symptoms with a manic episode. He showed severe irritability, decreased need for sleep, pressured speech, increased energy and goal-directed activities. The patient had started phenelzine a year ago for the treatment of major depressive episode resistant to previous pharmacological essayed treatments. No previous history of TEAS was reported, although he had already taken other ADs and mood-stabilizer treatments in the past.ResultsSeveral studies reported the effectiveness of MAOIs for the treatment of monopolar depressive episodes resistant to other ADs, especially when atypical symptoms were observed. Data on the use of MAOIs for the treatment of drug-resistant bipolar depressive episodes is scarce. Few studies have described a good response without showing and increased risk of TEAS.ConclusionsAs MAOIs have fallen out of favour with modern psychiatry, there is scarce evidence on the prevalence of TEAS in patients undergoing treatment with these drugs. Further research is needed in order to accurately define these complex relationships.DisclosureNo significant relationships.

Lurasidone-induced mania: A case report

IntroductionLurasidone is an atypical antipsychotic agent with potential antidepressant effects through its antagonist activity at the 5-HT7 receptor. Although treatment-emergent affective switch (TEAS) induced by second-generation antipsychotics are not frequent, several cases have been reported. To our knowledge, there is no evidence of lurasidone-induced TEAS.ObjectivesTo describe a case of lurasidone-induced mania.MethodsWe describe a clinical case of a patient admitted to our psychiatric outpatient unit who developed a manic episode, presumably induced by the introduction of lurasidone. We also conduct a review of the literature on this subject.ResultsA 37-year-old man diagnosed with obsessive-compulsive disorder (OCD) and an alcohol use disorder was hospitalized due to OCD decompensation with depressive symptomatology and suicidal thoughts, and for alcohol detoxification process. Since he had a previous history of clomipramine-induced TEAS, he was started on lurasidone up to 111mg to avoid the use of antidepressants, showing a progressive improvement of depressive symptoms. Thus, the patient was discharged when alcohol detoxification process was completed. Eight days after discharge, the patient began to show manic symptoms, so he had to be readmitted. Lurasidone was discontinued and valproic acid up to 1000mg/day as mood stabilizer was added, presenting a positive remission of manic symptoms.ConclusionsAccording to our experience, lurasidone may have induced an affective switch in this patient. Based on our findings, patients and psychiatrists should monitor possible lurasidone-induced mood switching. However, further research is needed in order to back-up this one case report findings.DisclosureNo significant relationships.

Cariprazine-induced mania: A case series report.

Bipolar depression is the most prevalent phase of bipolar disorder (BD). There is a risk of inducing treatment-emergent affective switches (TEAS) with antidepressants (ADs). Hence, clinical guidelines do not recommend their use in monotherapy. Cariprazine is a dopamine-serotonin partial agonist, with a recent FDA approval as a monotherapy for BD type 1 (BD-I) depression. To our knowledge, there is no significant evidence of cariprazine-induced TEAS in bipolar depression. We describe three clinical cases of patients admitted to our acute psychiatric ward who developed manic episodes after the introduction of low doses of cariprazine. Two of the patients met the DSM-5 criteria for BD-I, and one for schizoaffective disorder, bipolar type. All patients were initially treated with low doses of cariprazine (1.5mg) during a depressive phase. All three cases were simultaneously treated with mood stabilizers, regardless of which they switched to a manic episode when cariprazine was initiated. In our review of previous studies assessing the efficacy and side effects profile of cariprazine in BD-I, TEAS have not been found to be significant. However, according to our experience, cariprazine may induce affective switches in BD-I patients. Patients and psychiatrists should receive information regarding early warning symptoms and monitor possible cariprazine-induced mood switching.

Depression treatment in women and men with bipolar affective disorder: a comparative study

Objective: to compare depression treatment efficacy with and without antidepressants (ADs) in men and women with bipolar affective disorder (BAD).Patients and methods. We enrolled 100 patients with BAD (F31.3–F31.5 according to ICD-10), including 50 women aged 33.0 [23.0; 50.2] years and 50 men aged 37.5 [29.5; 47.2] years using prospective and retrospective methods. Various antidepressants, normothymics, antipsychotics combinations were used to treat depression. We performed a comparative analysis of treatment efficacy with and without antidepressants in men and women subgroups. Clinical assessment at the baseline and the end of 1, 2, 4, 6-th week of therapy (or at discharge) included a specially developed clinical examination chart and the following psychometric scales: Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression – Severity of illness (CGI-S), Clinical Global Impression – Improvement (CGI-I).Results and discussion. Women tended to have a slower improvement in the condition compared to men. Maximum reduction in MADRS score and a CGI-I, CGI-S higher frequency of clinical improvement and remission was observed in men and women who did not receive antidepressants than patients who did not receive antidepressants. When BAD type was included in the analysis, in patients treated with antidepressants, transient symptoms of the opposite pole occurred in 24.7% of patients of both sexes with bipolar affective I disorder (BAD I) and in 16.8% with bipolar affective II disorder (BAD II). There were no significant gender differences in patients with BAD I, while women predominated in BAD II group (22.5% compared to 7.8% men). No significant treatment-emergent affective switch was observed with tricyclic antidepressants and selective serotonin and norepinephrine reuptake inhibitors in both groups (21; 16.7; 16.7% in men and 28; 21.8; 12.5% in women, respectively). The assessment of intermission revealed that women were significantly more likely to have shorter periods between phases (42% compared to 22% in men). In addition, women were significantly more likely to have shorter periods between phases (42% compared to 22% in men) when the intermission duration was included in the analysis. In some patients with severe depression and infective first-line therapy (anticonvulsants and atypical antipsychotics), antidepressants prescription can increase treatment effectiveness. However, several factors should be considered, such as BAD type and variant, depression severity, treatment-emergent affective switch in history, and gender.Conclusion. A decision about antidepressants' dosage and treatment duration requires a dynamic follow-up of the patient in order to discontinue the antidepressants as fast as possible and decrease the risk of treatment-emergent affective switch and shortening of remission period.

A retrospective analysis of bipolar depression treated with transcranial magnetic stimulation.

IntroductionTreatment options are limited for patients with bipolar depression. Antidepressants added to mood stabilizers even carry risks of precipitating mixed/manic episodes. Transcranial magnetic stimulation (TMS) may provide a safe and effective option for these patients.MethodsDatabase analysis of the TMS Service at Sheppard Pratt Health System identified patients with bipolar disorder type I (BD1) or II (BD2) in a pure depressive phase at initiation of TMS. Records were reviewed for response and remission rates based on MADRS scores, time to effect, and adverse events, notably treatment‐emergent affective switching. All had failed at least two prior treatments for depression, were currently on at least one mood stabilizer and off antidepressants. Stimulation parameters targeted left dorsolateral prefrontal cortex: 120% motor threshold, 10 pulses per second (pps) × 4s, intertrain interval (ITI) 26s, 75 trains (37.5 min/session) for 3,000 pps total, 5 sessions/week for 30 total treatments, or until remission criteria were met.ResultsA total of 44 patients with BD were identified, representing 15% of the total TMS population. 77% of those who completed a course of TMS met response criteria, and 41% of subjects who completed at least 25 treatments met remission criteria. Subjects with BD1 were more likely to respond, remit, or suffer an adverse event than those with BD2. No patient met clinical criteria for a manic/mixed episode, but four (10%) discontinued due to concerns of activation.ConclusionsTMS is effective in the bipolar depressed population where episode focused intervention can be specifically offered. Risk of psychomotor agitation must be closely monitored.

Treating Depression in the Context of Mania or Mania Risk in Youth

Bipolar disorder (BD) is a heritable and episodic psychiatric disorder that is increasingly being recognized to take onset in childhood or adolescence. Youth with a parent or sibling with BD may also be at risk for mania, but frequently present with depression. In a busy clinical practice, treating depression in the context of mania or risk for mania can be obfuscated by a number of factors, including clinical heterogeneity and co-occurring conditions, changes in symptom presentation over the course of development, and treatment-emergent affective switching. In this review, we critically appraise recently published literature pertinent to the use of nonpharmacological and pharmacological strategies for the treatment of depression in youth with or at familial risk for BD. We used available data and extrapolate from adult studies to present reasonable treatment options in the context of a limited evidence base. Initial consideration of nonpharmacologic approaches such as psychotherapy, engaging in resilience-promoting strategies, and using omega-3 fatty acid supplementation is suggested given the low risk involved in implementation. Pharmacological treatment is guided by a combination of presenting symptoms, response to previous treatment trials or family history of previous responses, reported adverse effects, and patient and family preference. We conclude with a research update on emerging evidence-based treatment of bipolar I depression in youth. High-risk youth are more susceptible to developing antidepressant-induced mania (AIM), but the risks may be cautiously managed by starting at low doses, slow titrations, close monitoring for emerging adverse effects, and consideration of mood stabilizers and atypical antipsychotics with any emergence of persistent hypomania or mania that is not reversed by lowering or discontinuing antidepressant dosing.

Could Suicide Be Fostered Through the Potential Antidepressant Mechanism of Biological Agents? A Psychodermatological Approach to Existing Bibliography

Background: Bipolar disorder (BD) is a biological condition that affects between 2% and 5% of the population. Despite this, it is often underdiagnosed as unipolar depression, which increases the possibility of prescribing errors. This could foster episodes of inverse polarity (“switching”) which, in turn, raises the risk of suicide. Objective: This work reviews the existing literature for evidence that while biological agents could improve the mood of patients with psoriasis treated with these drugs, this same favorable antidepressant effect on humor may trigger a switch into mania, favoring attempted and completed suicide in undiagnosed bipolar patients treated for psoriasis with the abovementioned agents. Method: A systematic review of the literature was performed for evidence. Based on their titles and abstracts, 48 relevant articles from 18 countries in English, Spanish, and French from 2004 to 2019 were selected for this review. Results: Inherently, all antidepressants can be associated with treatment-emergent affective switch (TEAS). Biological agents may modify the neurotransmitter levels either improving or worsening the mood. A plausible hypothesis arises on the double-edged nature of biological agents: they would have an antidepressant effect that would be beneficial to treat the psychiatric comorbidity of the patient with psoriasis. However, this same antidepressant effect, in a patient with genetic vulnerability for depression with a concomitant inflammatory disease, could trigger a mood alteration. Conclusion: Both BD and psoriasis should be considered as a multisystem entity with a common physiopathology. Consequently, it is vital to emphasize the importance of the initial psychiatric evaluation.

Mixed States: Modelling and Management.

Our current conceptualisation of mixed states, defined as co-occurring manic and depressive symptoms, is unlikely to advance our knowledge or inform clinical practice. Episodes of mixed states can no longer be coded in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), and the 'mixed features specifier' fails to capture the most common mixed state presentations. This reflects a lack of understanding of both the importance of mixed states and their underlying pathophysiology. Indeed, research into the nature of mixed states is scarce and uninformative, and most clinical practice guidelines fail to provide advice regarding their management. In this paper, we proffer a reconceptualisation of mixed states that provides a framework for informing clinical practice and research. It is based on the ACE model, which deconstructs mood disorders into three domains of symptoms: activity, cognition, and emotion. Symptoms within each domain vary independently over time and in different directions (towards either excitation or inhibition). By deconstructing mood disorders into component domains, mixed states can be explained as the product of different domains varying 'out of sync'. In most cases, the aetiology of mixed states is unknown. Alongside such idiopathic mixed states, we describe three potential causes of mixed states that are important to consider when formulating management: transitions, ultradian cycling, and treatment-emergent affective switches. In addition to providing guidance on the identification of various kinds of mixed states, we discuss practical strategies for their management, including the monitoring of ACE domains and functioning, to inform the use of psychoeducation and lifestyle changes, psychotherapy, pharmacology, and electroconvulsive therapy.

Efficacy and Safety of Transcranial Direct Current Stimulation as an Add-on Treatment for Bipolar Depression

More effective, tolerable interventions for bipolar depression treatment are needed. Transcranial direct current stimulation (tDCS) is a novel therapeutic modality with few severe adverse events that showed promising results for unipolar depression. To determine the efficacy and safety of tDCS as an add-on treatment for bipolar depression. A randomized, sham-controlled, double-blind trial (the Bipolar Depression Electrical Treatment Trial [BETTER]) was conducted from July 1, 2014, to March 30, 2016, at an outpatient, single-center academic setting. Participants included 59 adults with type I or II bipolar disorder in a major depressive episode and receiving a stable pharmacologic regimen with 17-item Hamilton Depression Rating Scale (HDRS-17) scores higher than 17. Data were analyzed in the intention-to-treat sample. Ten daily 30-minute, 2-mA, anodal-left and cathodal-right prefrontal sessions of active or sham tDCS on weekdays and then 1 session every fortnight until week 6. Change in HDRS-17 scores at week 6. Fifty-nine patients (40 [68%] women), with a mean (SD) age of 45.9 (12) years participated; 36 (61%) with bipolar I and 23 (39%) with bipolar II disorder were randomized and 52 finished the trial. In the intention-to-treat analysis, patients in the active tDCS condition showed significantly superior improvement compared with those receiving sham (βint = -1.68; number needed to treat, 5.8; 95% CI, 3.3-25.8; P = .01). Cumulative response rates were higher in the active vs sham groups (67.6% vs 30.4%; number needed to treat, 2.69; 95% CI, 1.84-4.99; P = .01), but not remission rates (37.4% vs 19.1%; number needed to treat, 5.46; 95% CI, 3.38-14.2; P = .18). Adverse events, including treatment-emergent affective switches, were similar between groups, except for localized skin redness that was higher in the active group (54% vs 19%; P = .01). In this trial, tDCS was an effective, safe, and tolerable add-on intervention for this small bipolar depression sample. Further trials should examine tDCS efficacy in a larger sample. clinicaltrials.gov Identifier: NCT02152878.

Are antidepressants a double-edged sword? Treatment emergent affective switch or antidepressant discontinuation syndrome.

Are antidepressants a double-edged sword? Treatment emergent affective switch or antidepressant discontinuation syndrome.

Antidepressant dose and treatment response in bipolar depression: Reanalysis of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) data

The aim of this study is to evaluate whether an adjunct antidepressant therapy at a higher dose to a mood stabilizer would make a difference in the treatment of bipolar depression. This is a post-hoc analysis of the data from the randomized treatment for acute depression of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), in which patients with bipolar depression were randomly assigned to treatment with a mood stabilizer plus adjunctive antidepressant drugs or placebo. According to the highest dose received in the course of treatment, the subjects were divided into one of the following three groups: high-dose, low-dose and placebo groups. The primary and secondary outcomes were durable recovery (which was operationally defined as eight consecutive weeks with </ = 2 symptoms) and treatment-emergent affective switch (i.e. transition to mania or hypomania), respectively. In the evaluable 333 subjects, subjects in both the high-dose (n = 102) and placebo groups (n = 169) more significantly achieved durable recovery than the low-dose group (n = 62) (odds ratio = 3.013 [p = 0.009], 2.899 [p = 0.008], respectively). No significant association was found between the dose status and treatment-emergent affective switch (p = 0.614). The allocation to either high- and low-dose antidepressants was not randomized and the dose was guided by a case-by-case decision, which hampers to draw a firm conclusion on dose–response issues and renders the findings as preliminary. Nevertheless, higher doses of adjunctive antidepressant drugs seem to have potential for yielding greater clinical improvement without increasing any risk of manic switch compared to lower doses, at least in carefully selected patients. The ClinicalTrials.gov identifierNCT00012558.

Why Personalized Treatment Decisions Are Important

Why Personalized Treatment Decisions Are Important

Antidepressant-induced mania in obsessive compulsive disorder

Serotonin-reuptake inhibitors have come forth to become the mainstay of treatment in obsessive compulsive disorder (OCD), predominantly as a result of evidence from clinical psychopharmacological response studies. Comorbid psychiatric disorders frequent OCD patients, most often depression. Although selective serotonin reuptake inhibitors are effective in the treatment of both OCD and depressive disorder, all antidepressants are associated with treatment-emergent affective switch. We present a 48-year-old patient with OCD, on antidepressants, initially for OCD and later for depression as well. She switched to mania after 20 years of treatment, which responded to olanzapine and divalproex sodium.

Pharmacotherapeutic trends in 2231 psychiatric inpatients with bipolar depression from the International AMSP Project between 1994 and 2009

Pharmacological treatment of bipolar depression is a complex and controversial issue, and its real-world practice remains largely unknown. Observational analysis of the pharmacotherapy of 2231 psychiatric inpatients with a current episode of bipolar depression. The study was based on cross-sectional prescription data from European psychiatric hospitals that had been repeatedly collected between 1994 and 2009 through the collaborative Drug Safety in Psychiatry (AMSP) program. Overall 81.3% of patients received antidepressants (AD) (7.8% monotherapy), 57.9% antipsychotics (AP), 50.1% anticonvulsants (AC), 47.5% tranquilizers, and 34.6% lithium (Li). Use over time was stable for AD, decreased for Li, and increased for AC, AP and tranquilizers. Pronounced increases were specifically observed for quetiapine, lamotrigine and valproate. Use of tricyclic AD decreased but its prevalence was still 11.8% in 2009. Venlafaxine was used by 19.5% in 2009. We also observed an increase of polypharmacy combining AD, AP, AC and Li. From 2006 to 2009 37.0% received concomitant treatment with three, and 6.4% even with all four of those drug classes. Observational cross-sectional study without follow-up or additional clinical information. Monotherapy with antidepressants and any use of tricyclic AD and venlafaxine still has a considerable prevalence in bipolar depression, but this is controversial due to the reported risk of treatment emergent affective switches. Triple and quadruple therapy is not evidence-based but increasingly used in clinical practice. This may reflect an attempt to overcome treatment failure, and further studies should evaluate efficacy and safety of this common practice.

Dr. Goldberg Replies

Back to table of contents Previous article Next article Letters to the EditorFull AccessDr. Goldberg RepliesJOSEPH F. GOLDBERG M.D.,JOSEPH F. GOLDBERG M.D.Search for more papers by this author,Published Online:1 Jul 2009https://doi.org/10.1176/appi.ajp.2009.09030331rrAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Dr. Liebowitz offers an interesting anecdotal observation about the potential importance of diurnal variation in bipolar depression and its possible relationship to mood stabilizer response. Unfortunately, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study did not obtain data on this clinical characteristic during depressive episodes. Existing literature on the phenomenology of bipolar depression has not identified diurnal variation as a feature that is more common in bipolar than unipolar depression, in contrast to other constructs such as reversed vegetative signs (1) . However, some investigators have hypothesized that diurnal mood variation may reflect disruptions of circadian rhythms in healthy volunteers (2) , suggesting a possible role in cyclical or highly recurrent mood disorders. Dr. Liebowitz also raises the hypothesis that short-acting antidepressant preparations may be less prone than longer-acting formulations to induce affective polarity switch. STEP-BD found no differences in treatment-emergent affective switch in bipolar depressed patients who underwent equipoise randomization to adjunctive bupropion sustained-release, paroxetine, or placebo in conjunction with mood stabilizers (3) . Lack of efficacy appears to be an overall greater risk than induction of mania for most depressed bipolar patients who receive adjunctive antidepressants. The STEP-BD study did not evaluate depression outcomes with highly noradrenergic antidepressants, such as venlafaxine, but their apparent higher risk for induction of mania relative to predominantly serotonergic or dopaminergic antidepressants (4) would seem to prompt caution if one chose to expose a bipolar patient to other noradrenergic agents, especially those not studied in bipolar disorder, such as atomoxetine. Norwalk, Conn.The author’s disclosures accompany the original article.This letter (doi: 10.1176/appi.ajp.2009.09030331rr) was accepted for publication in April 2009.

Antidepressant-associated chronic irritable dysphoria (ACID) in STEP-BD patients

Background It has been proposed that antidepressants can induce a chronic, dysphoric, irritable state in bipolar patients (called ACID for antidepressant-associated chronic irritable dysphoria). This phenomenon has only been described in case series format, and has not been prospectively validated. Methods Prospective data from the first 1500 patients (62.7% with bipolar I, 30.1% with bipolar II, and 7.2% with NOS) treated in the STEP-BD database were examined and those who were euthymic for at least one month at study entry, subsequently developed a depressive episode, and were then followed for one year were identified. Outcome of those who received an antidepressant for this depressive episode ( n = 27) was compared to those who did not ( n = 56), with particular attention given to the presence of the proposed symptom triad of ACID, namely dysphoria, irritability, and middle insomnia. Results Patients treated with antidepressants were ten times more likely to develop ACID than those who were not (Hazard ratio = 9.95, CI = 1.103–89.717, P = 0.04). However, the hazard ratio dropped to 1.05 ( P = 0.99) when corrected for significant covariates, notably past antidepressant-related manic switch and sex. Discussion This study does not support the existence of ACID as an independent phenomenon. Rather, ACID appears to be part of a broader spectrum of antidepressant treatment-emergent affective switches.