Enhancing outcomes in the management of treatment resistant depression: a focus on atypical antipsychotics

Abstract:  Clinical trials indicate that over 50% of depressed patients show an inadequate response to antidepressant therapy, and that incomplete recovery from major depressive disorder (MDD) increases the risk of chronicity and recurrence. Recovery, complete remission of symptoms, and a return to baseline psychosocial function, should be the goal of therapy. Poor response to adequate antidepressant treatment has been termed treatment resistant depression (TRD). Issues such as adherence, missed diagnosis of psychotic depression, bipolar disorder, or comorbid anxiety must be investigated as reasons why patients have not responded to initial therapeutic strategies. Beyond ensuring optimal use of the index antidepressant, treatment strategies for TRD include switching to another antidepressant, and augmentation or combination with two or more agents. Since little comparative data exist it is important to consider side-effect burden, partial response, and previous medication history when deciding between strategies. In patients with TRD, adding or augmenting with lithium, tri-iodothyronine or atypical antipsychotics have demonstrated benefits. Augmentation with atypical antipsychotics, including risperidone, olanzapine, ziprasidone, and quetiapine, show promising results in terms of improving remission rates. Other interventions, including non-pharmacologic strategies and investigational physical treatments, have demonstrated some benefits, but availability and patient preference should also be considered. With today's therapeutic alternatives, full remission of depression is an attainable goal. For some patients, combination and augmentation strategies earlier in treatment may increase the likelihood of remission.     

Setting Up a Successful Vagus Nerve Stimulation Service for Patients With Difficult-to-Treat Depression

BackgroundA substantial number of patients with major depressive disorder (MDD) do not sufficiently remit after the first lines of antidepressant treatments, making them vulnerable to poor clinical outcomes. Patients who have not had adequate resolution of their depressive symptoms after four antidepressant treatments and/or have been experiencing their current episode of MDD for two years or more (with insufficient responses to adequate antidepressant treatments) should be evaluated for antidepressant vagus nerve stimulation (VNS Therapy). Adjunctive VNS Therapy is a promising long-term treatment option for patients with difficult-to-treat depression (DTD), offering significantly improved remission rates in comparison with usual treatments. However, VNS Therapy requires specialized treatment centers to support patients.Materials and MethodsIn this narrative review, we aim to outline the necessary steps for setting up an antidepressant VNS Therapy service in an efficient manner.ResultsEstablishing a VNS Therapy service requires several high-level considerations: initiation of a collaborative multidisciplinary team of health care professionals; developing a surgical pathway for implantation; consideration of reimbursement and health care coverage; setting up a specialist clinic to identify optimal candidates for VNS Therapy; educating patients and their families about VNS Therapy; and training health care providers on patient-specific VNS Therapy treatment and long-term treatment management.ConclusionsAntidepressant VNS Therapy is a promising treatment option for the long-term treatment of patients with DTD. We have successfully initiated four VNS Therapy service centers for DTD in the United States, Austria, and Germany. Based on our experiences and lessons learned, herein, we have provided advice to psychiatric centers planning to set up a VNS Therapy service for their patients with DTD.     

Clinical efficacy and achievement of a complete remission in depression: increasing interest in treatment with escitalopram

Such a prevalent disease as Major Depressive Disorder (MDD), associated with prominent impairment in physical and social functioning, implies as well an increased morbidity and mortality. Long-term treatments are required due to the frequent occurrence of relapses. Patient compliance is a core factor in both acute and continuation treatment, closely related to tolerability issues. We have partially reviewed the literature published on PubMed since 2004 which assess the relative antidepressant efficacy of escitalopram and comparator antidepressants in adult patients who met DSM-IV criteria for major depressive disorder (MDD). Clinically important differences exist between commonly prescribed antidepressants. These analyses are in favor of a superior efficacy and tolerability of long-term escitalopram treatment (10 to 20mg/day) compared with active controls, including selective serotonin re-uptake inhibitors (SSRIs) (paroxetine, citalopram, bupropion, fluoxetine, fluvoxamine, sertraline), serotonin/noradrenaline reuptake inhibitors (SNRIs) (venlafaxine, milnacipran and duloxetine) and noradrenergic and specific serotonergic antidepressants (NaSSAs) (mirtazapine). Cipriani et al. (2009) have performed a network meta-analysis of 12 new generation antidepressants. They have shown that clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favor of escitalopram and sertraline in acute treatment, defined as 8-week treatment. Kasper et al. (2009) conducted a post-hoc pooled analysis of data from two 6-month randomized controlled trials that revealed superior efficacy and tolerability of escitalopram when compared with paroxetine. The pooled analysis of four randomized, double-blind, active comparator, 6-month trials in MDD, by Wade et al. (2009), showed that short-term outcomes may predict long-term treatment compliance and outcomes. A higher probability of achieving remission was associated with responding after 8 weeks and with completing 6 months of treatment. Furthermore, Week 24 complete remission (MADRS≤5) was significantly (P<0,01) higher for escitalopram (51.7%) than for the pooled comparators (45.6%). And after 6 months, fewer patients discontinued treatment with escitalopram (15.9%) than with the pooled comparators (23.9%) (P<0.001). This fragmentary review of the literature shows that it is necessary to adopt a stringent definition of remission in depression, especially in clinical trials; a MADRS total score less or equal to 10 to define remission, a MADRS total score less or equal to 5 to define complete remission, and moreover no MADRS single item greater than 1 to define symptom-free remission. In all these meta-analyses, the superiority of escitalopram compared with other antidepressants was confirmed for both acute and long-term treatment of MDD, especially in harshly depressed patients.     

Adequacy of, attitudes toward, and adherence to treatments by suicidal and nonsuicidal depressed patients

We examined differences in treatments received, and attitudes and adherence to them between suicidal and nonsuicidal patients with major depressive disorder (MDD). Psychiatric MDD patients with no suicidal behavior (N = 92), suicidal ideation (N = 92), or attempts (N = 34) were compared during 6 months of follow-up in the Vantaa Depression Study (VDS). Patients with suicidal behavior received antidepressants or adequate antidepressant treatment significantly more often, had more frequent appointments with psychiatrists, more psychotherapeutic support, and more favorable attitudes toward antidepressant treatment than nonsuicidal patients. However, after adjusting for the confounding severity of depression, the significance of these differences was lost. Adherence to treatment was similar in the patient groups. Overall, among psychiatric patients with MDD, those known to be suicidal have higher suicide risk and should receive more intensive treatment. However, suicidal behavior per se does not seem to markedly influence treatments provided nor should it be associated with negative attitudes or poor adherence to treatments.     

Escitalopram in the long-term treatment of major depressive disorder.

BACKGROUND: Escitalopram has been proven safe and efficacious in the treatment of major depressive disorder (MDD) in short-term studies. The long-term clinical tolerability and response to treatment are presented from a 12-month open-label study with a total exposure time to escitalopram of 486 patient years. METHODS: Patients (n = 590) with MDD entered the study after completing one of two 8-week, double-blind, placebo-controlled, lead-in studies in primary care. Escitalopram was administered at doses of 10 or 20 mg/day (dose based on physician's clinical judgement) with an average exposure to escitalopram of 315 days. The primary efficacy parameter was the Montgomery Asberg Depression Rating Scale (MADRS) total score. RESULTS: The overall withdrawal rate was 26%; and the withdrawal rate due to adverse events was 9%. The most common adverse events were headache, back pain, upper respiratory tract infection, rhinitis and nausea, with an incidence ranging from 11% to 17%. No new types of adverse events were seen after the acute period of 8 weeks, and the incidence declined with time. At baseline (entry into the 12-month study), patients had a mean MADRS total score of 14.2, which decreased to 10.5 after 8 weeks and 7.2 after 52 weeks (LOCF). The percentage of patients in remission (MADRS total score 相似文献   

A randomized trial of a specific adherence enhancement program in sertraline-treated adults with major depressive disorder in a primary care setting

Adherence to drug therapy is a limitation in treatment success for major depressive disorder (MDD). The influence of RHYTHMS, an information and ongoing interactive program designed by Pfizer Pharmaceuticals, to address patient adherence to sertraline therapy was evaluated in a primary care setting using a randomized, double-blind, parallel group controlled trial over 29 weeks. Remission was the primary outcome evaluated. At study completion, no statistically significance between group differences was noted for remission rates, treatment adherence or mean Hamilton Depression Rating Scale (HDRS) score. However, the RHYTHMS group reported significantly greater satisfaction with knowledge received about depression and its treatment and demonstrated significantly greater satisfaction with treatment received. We conclude that the application of RHYTHMS in a primary care setting has a substantial role in improving satisfaction with sertraline treatment by patients with MDD.     

When should you move beyond first-line therapy for depression?

The probability of achieving and sustaining symptomatic remission in major depressive disorder (MDD) with first-line pharmacotherapy is approximately 30%. Ample documentation shows that the maximal therapeutic effect obtained with antidepressant pharmacotherapy is approximately 4 to 6 weeks, perhaps longer for individuals receiving manual-based psychotherapies. Emerging evidence also indicates that early (ie, at 2 weeks) symptomatic improvement (ie, ≥ 20% improvement on the 17-item Hamilton Depression Rating Scale score) positively predicts remission at weeks 6 to 8 (nonimprovement at week 2 may be a more robust negative predictor of nonremission at weeks 6 to 8). Notwithstanding the identification of early positive/negative remission prediction, a subgroup of individuals receiving pharmacotherapy evinces initial improvement beyond week 6 of treatment. Available evidence does not support a claim that any antidepressant or class of antidepressants offers a faster onset of action. Identifying moderators and/or predictors of response is a priority research vista; hitherto, no biomarker has emerged as a reliable predictor of treatment efficacy, tolerability, or safety. Emerging evidence suggests that electrophysiological measures, ie, frontal quantitative electro encephalography (QEEG) may be capable of identifying antidepressant remitters within 1 to 2 weeks of exposure. Taken together, practitioners are often faced with the critical question as to when to move beyond index therapy for treating depressive symptoms as part of MDD.     

Applying antidepressant study results to clinical practice

Although some controversy surrounds the efficacy of antidepressants, meta-analytic studies confirm that antidepressants are a useful treatment, particularly in patients with moderate-to-severe depression. Evidence indicates that treating patients for 6 to 8 weeks before switching or augmenting medications, monitoring and addressing tolerability and adherence problems, and using measurement-based care and an algorithm can optimize treatment outcomes in patients with depression. Applying antidepressant study results to clinical practice can help to ensure that patients with depression receive effective treatment, but information from drug registration studies is of limited use in clinical practice.     

Tolerability issues during long-term treatment with antidepressants.

Depressive disorders are highly prevalent in the general population. Long-term treatment with antidepressants consolidates the improvement obtained during the acute phase of the treatment and prevents relapses and recurrences of the disorder. On the other hand, there is growing evidence that antidepressant side effects may limit patients' quality of life and social functioning, as well as affect patients' health and treatment adherence. Most studies concerning antidepressant treatment have focused on short-term tolerability, ignoring both early-onset persistent side effects and late-onset side effects that are reported during long-term treatment. Nevertheless, these long-term treatment side effects are likely to have a dramatic impact on patient outcome and treatment adherence. Common long-term side effects of antidepressants are weight gain, sexual dysfunction, sleep disturbances, fatigue, apathy, and cognitive impairment (e.g., working memory dysfunction). Usual strategies for the management of these long-term side effects are: changing drug daily schedule, various augmentation therapies, antidepressant switches, drug-holidays, and dose tapering, with the latter two strategies being strongly discouraged on the basis of concerns that patients' depressive episodes may return. Selective serotonin reuptake inhibitors (SSRIs) and atypical antidepressants (e.g., venlafaxine, bupropion, and nefazodone) show a relatively favorable short-term as well as long-term tolerability compared with older drugs (e.g., tricyclics and monoamine oxidase inhibitors). Therefore, clinicians are likely to prefer them in usual practice, especially among patients requiring maintenance treatment. The present review focuses on management of long-term side effects.     

Improving adherence to antidepressants: a systematic review of interventions

BACKGROUND: Effectiveness of antidepressant medication is reduced by patients' nonadherence. Several interventions to improve adherence in patients diagnosed with unipolar depression have been tested. OBJECTIVE: To systematically review the effectiveness of interventions that aimed to improve adherence to antidepressant medication in patients with unipolar depression. METHOD: Systematic review of English-language articles of randomized controlled trials obtained by a computerized literature search of MEDLINE (1966-January 2002) using the terms patient compliance, patient dropout, treatment refusal, patient education, adherence, clinical trial, randomized controlled trial, controlled trial, depressive disorder, and depression; PSYCINFO (1984-January 2002) using the terms random, clinical, control, trial, adherence, compliance, noncompliance, dropouts, patient education, depression, major depression, affective disorders, and dysthymic disorder; EMBASE (1980-January 2002) using the terms patient compliance, patient dropouts, illness behavior, treatment refusal, patient education, clinical trial, controlled study, randomized controlled trial, and depression; and the Cochrane Controlled Trials Register (no restrictions) using the terms random*, complian*, adheren*, pharmacotherapy, regimen*, educat*, medicat*, depression, and depressive disorder. RESULTS: Educational interventions to enhance adherence failed to demonstrate a clear benefit on adherence and depression outcome. However, collaborative care interventions tested in primary care demonstrated significant improvements in adherence during the acute and continuation phase of treatment and were associated with clinical benefit, especially in patients suffering from major depression who were prescribed adequate dosages of antidepressant medication. CONCLUSION: We found evidence to support the introduction of interventions to enhance adherence with antidepressant medication in primary care, not only because of better adherence but also because of better treatment results. Because collaborative care interventions require additional resources, a better understanding of the mode of action of different programs is needed to reduce avoidable costs. The effectiveness of educational interventions needs more evidence.     

The Current Situation on Major Depressive Disorder in China: Research on Mechanisms and Clinical Practice

Depression is the most disabling disorder worldwide that accounts for the highest proportion of global burden attributable to mental disorders. Major depressive disorder(MDD) is characterized by deep sadness, reduced energy,vegetative nervous system dysregulation, cognitive dysfunction, and even a high suicidal tendency. Although other treatment choices are available, antidepressant medication is the front-line treatment option for MDD. Regarding clinical efficacy, only ~50% of patients respond to frontline antidepressants, and <33% obtain remission. Currently, objective indexes to guide clinical decisions are still lacking. Furthermore, knowledge about the neurobiological mechanisms underlying discrepant antidepressant outcomes is still also fragmentary. In the present review, we discuss the current research progress and clinical opinions on MDD in China.     

Outcomes in major depressive disorder: the evolving concept of remission and its implications for treatment.

It is increasingly recognised that major depressive disorder can be a chronic condition with many patients experiencing recurrent episodes. Remission from a depressive episode implies the absence or near absence of depressive symptoms. However, for many patients the periods between depressive episodes are not symptom free. Residual symptoms are predictors of relapse or recurrence, and may be associated with residual psychosocial impairment. In clinical studies, remission is commonly defined using a cut-off score on a rating scale for depressive symptoms, such as a score of < or = 7 on the 17-item Hamilton scale. However, there is debate about which scales and cut-offs are optimal and full-length rating scales are not widely used in clinical practice. In spite of such issues, it seems clear that a therapy should aim at the most complete remission possible. Unfortunately, recent studies have highlighted that in clinical practice usually only a low rate of remission is achieved. Although long-term treatment with antidepressants can reduce the risk of relapse or recurrence only a minority of patients in clinical practice achieve this as treatment is often prematurely stopped due to long-term side effects such as sleep disturbance, sexual dysfunctioning and weight gain. Therefore, it represents an unmet need to come up with antidepressant drugs of greater efficacy and improved tolerability as such treatments could lead to more complete remission in more patients.     

Medication use patterns and two-year outcome in first-admission patients with major depressive disorder with psychotic features

OBJECTIVE: This study examined the patterns and predictors of medication use and 24-month course/outcome in first-admission patients with major depressive disorder with psychotic features (MDD/P). METHOD: An epidemiological sample of 87 first-admission patients with research diagnoses of MDD/P received intensive clinical assessments at baseline and at 6- and 24-month follow-ups and telephone assessments at 3-month intervals. Use of medications (antidepressant [AD], antipsychotic [AP], and antimanic agents) was determined from self-reports corroborated by external sources where possible. Outcome was assessed with the Global Assessment of Functioning and consensus evaluations of illness course and time in remission. RESULTS: More patients received APs (77.0%) than ADs (57.5%) at discharge, with almost half (49.4%) receiving these in combination. At 24-month follow-up, 40.2% reported using no medications; 39.1% used ADs, and 32.2% used APs. Only early AD use predicted regular AD use during the 6- to 24-month follow-up. A minority (29%) achieved functional recovery (Global Assessment of Functioning score > or = 71) by 24 months. Although about 60% of the sample achieved a period of complete remission by 24 months, only about 40% had a sustained remission for at least 19 months. Medication use was not predictive of these outcome measures. There was little evidence that changes in medication, augmentation strategies, or electroconvulsive therapy was used to reduce symptoms during the 24-month follow-up. Fewer than half of our subjects received a MDD/P clinical diagnosis at discharge, which appeared to influence medication use patterns over the 24-month follow-up. CONCLUSIONS: These findings suggest that for most of these patients with MDD/P, outcome was suboptimal for both functional and syndromal recovery. The lack of an association between medication use and outcome suggests that medication changing and augmentation strategies, electroconvulsive therapy use, and/or strategies to improve medication adherence might be considered in the treatment of patients with MDD/P who remain low functioning and symptomatic even while receiving pharmacotherapy. Finally, our findings highlight the need for routine systematic diagnostic procedures to ensure appropriate diagnosis and treatment of MDD/P at first admission as well as the need for replication of our findings in a more contemporary sample.     

Treatment inadequacy in primary and specialized care patients with depressive and/or anxiety disorders

All guidelines on major depressive disorder (MDD) and anxiety disorders recommend pharmacotherapy and/or psychological treatment for moderate to severe disease. The aim of this cross-sectional study was to investigate treatment inadequacy, both pharmacological and psychological, in a large naturalistic cohort of subjects with MDD and anxiety disorders from the Netherlands Study of Depression and Anxiety. All subjects with a current 6-month diagnosis were included (n=1662). Demographic data, clinical features and actual medication use were assessed in face-to-face interviews. In moderate to severe MDD, 43% of the subjects were not treated sufficiently with antidepressants or psychological treatment. In primary health care patients, this undertreatment was 70%. In moderate to severe anxiety disorders, 44% of the subjects were not treated sufficiently with antidepressants, benzodiazepines or psychological treatment. Among antidepressant users with moderate to severe MDD, 21% of the pharmacotherapy was inadequate with respect to drug choice, dose and every day use. Undertreatment and pharmacotherapeutic inadequacy are common in moderate to severe MDD and anxiety disorders. Both are more pronounced in primary care than in specialized care. This may be partly due to differences in disease recognition and help seeking behaviour.     

Augmentation treatment in major depressive disorder: focus on aripiprazole

Major depressive disorder (MDD) is a disabling psychiatric condition for which effective treatment remains an outstanding need. Antidepressants are currently the mainstay of treatment for depression; however, almost two-thirds of patients will fail to achieve remission with initial treatment. As a result, a range of augmentation and combination strategies have been used in order to improve outcomes for patients. Despite the popularity of these approaches, limited data from double-blind, randomized, placebo-controlled studies are available to allow clinicians to determine which are the most effective augmentation options or which patients are most likely to respond to which options. Recently, evidence has shown that adjunctive therapy with atypical antipsychotics has the potential for beneficial antidepressant effects in the absence of psychotic symptoms. In particular, aripiprazole has shown efficacy as an augmentation option with standard antidepressant therapy in two, large, randomized, double-blind studies. Based on these efficacy and safety data, aripiprazole was recently approved by the FDA as adjunctive therapy for MDD. The availability of this new treatment option should allow more patients with MDD to achieve remission and, ultimately, long-term, successful outcomes.     

Venlafaxine versus stimulant therapy in patients with dual diagnosis ADD and depression

BACKGROUND: Adult attention-deficit disorder (ADD) may either present as chronic depression or be comorbid with major depressive disorder (MDD). The present study examined treatment outcome with antidepressants and/or stimulants in adults with ADD who initially presented with a diagnosis of MDD. METHOD: Seventeen patients with comorbid MDD and ADD were identified: 65% had a history of hyperactivity in childhood, and 41% had a history of treatment nonresponse to two or more antidepressants. Retrospective analysis was performed with patients who received one of three treatments: (i) venlafaxine, bupropion, or tricyclic antidepressant (TCA) monotherapy; (ii) stimulant monotherapy; or (iii) stimulant plus antidepressant therapy. Outcome was based upon change in both MDD and ADD symptoms. RESULTS: Venlafaxine-treated patients (80%) versus patients taking stimulant therapy alone (33%) had at least a moderate reduction in both MDD and ADD symptoms (chi2=2.40, Fisher exact P=.13). Similarly, 88% of patients on stimulants plus antidepressant therapy also showed a reduction in both MDD and ADD symptoms (versus stimulant monotherapy) (chi2 = 7.22, Fisher exact P=.018). There was no difference in response rates between venlafaxine monotherapy and combination stimulant plus antidepressant therapy (chi2=0.13, Fisher exact p=ns). CONCLUSION: Although preliminary in nature, these data suggest that venlafaxine monotherapy may have similar efficacy to a treatment with a combination of stimulant plus antidepressant therapy, and superior to stimulant therapy alone, in patients with comorbid MDD and ADD. Controlled, prospective trials with larger patient samples will be needed to confirm these preliminary observations.     

Measurement-Based Care for Unipolar Depression

This article outlines the role of measurement-based care in the management of antidepressant treatment for patients with unipolar depression. Using measurement-based care, clinicians and researchers have the opportunity to optimize individual treatment and obtain maximum antidepressant treatment response. Measurement-based care breaks down to several simple components: antidepressant dosage, depressive symptom severity, medication tolerability, adherence to treatment, and safety. Quick and easy-to-use, empirically validated assessments are available to monitor these areas of treatment. Utilizing measurement-based care has several steps—screening and antidepressant selection based upon treatment history, followed by assessment-based medication management and ongoing care. Electronic measurement-based care systems have been developed and implemented, further reducing the burden on patients and clinicians. As more treatment providers adopt electronic health care management systems, compatible measurement-based care antidepressant treatment delivery and monitoring systems may become increasingly utilized.     

Remission of generalized anxiety disorder: a review of the paroxetine clinical trials database

OBJECTIVE: Paroxetine is a potent selective serotonin reuptake inhibitor with antidepressant and anxiolytic activity that is effective in the treatment of generalized anxiety disorder (GAD), improving the core symptoms of anxiety, worry, and tension. The majority of patients with GAD have chronic symptomatology and significant comorbid mood and anxiety disorders that often require ongoing pharmacotherapy. This article reviews the efficacy and tolerability of paroxetine in the short- and long-term treatment of GAD including remission data. DATA SOURCES: Data from more than 1800 outpatients with DSM-IV-defined GAD were analyzed from 3 short-term (8-week) studies and a longer (6-month) relapse prevention study. These studies were all randomized, double-blind, placebo-controlled trials of paroxetine. DATA SYNTHESIS: The results emphasize the benefit of paroxetine treatment in GAD, enabling a substantial proportion of patients to achieve clinical remission and preventing relapse. Long-term treatment with paroxetine also shows good tolerability with no evidence of weight gain. CONCLUSION: Given the high comorbidity of psychiatric depression and anxiety, the long-term efficacy and tolerability of paroxetine are important considerations when selecting a first-line therapy for patients with GAD.     

How do you choose a second-line treatment option for depression?

A majority of patients with major depression do not remit or adequately respond to initial antidepressant therapy. When response is insufficient, a diagnosis of depression and any comorbidities should be confirmed, treatment adherence should be established, and antidepressant dosages should be optimized as tolerated. If response is still insufficient, then implementing second-line treatment strategies is warranted. Second-line strategies of switching to or combining/augmenting the initial agent with one of a variety of antidepressant medications and/or psychotherapies improves remission rates, although no single approach or agent has demonstrated clear superiority over any other. Second-line treatment selections should be driven by safety considerations, patients' symptom profiles, and patient preference. Comorbid medical conditions, especially cardiac and cerebrovascular complications, and potential drug-drug interactions should be considered when making treatment decisions.     

Bipolar disorder maintenance treatment: monitoring effectiveness and safety

Bipolar disorder is a chronic illness that requires long-term treatment, the goal of which is to shorten or prevent mood episodes without increasing cycle frequency, thereby increasing the length of well periods. Treatment guidelines recommend mood stabilizers as first-line medications, and several atypical antipsychotics are also approved as monotherapy or as adjuncts to mood stabilizers for maintenance treatment. Combination therapy with 2 mood stabilizers or with a mood stabilizer and an antipsychotic may be necessary to achieve or maintain remission of the patient's symptoms. When treating patients with mood stabilizers and atypical antipsychotics during the maintenance phase, physicians should systematically monitor for adverse effects, particularly weight gain, and tolerability issues, and address those issues in a timely manner in order to enhance treatment adherence and improve patient outcomes.