Deep Brain Stimulation for Depression: An Emerging Indication.

Depression is a heterogenous disorder, with roughly 30% of patients deemed resistant to conventional treatments. In these cases, neurosurgical interventions such as lesion procedures or deep brain stimulation offer possible therapeutic options. Here, we review neurosurgical interventions for treatment-resistant depression, focusing on the recent advancements and future directions of deep brain stimulation.

Deep brain stimulation for obsessive-compulsive disorder.

Neurosurgical interventions have been used for decades to treat severe, refractory obsessive-compulsive disorder (OCD). Deep brain stimulation (DBS) is a neurosurgical procedure that is used routinely to treat movement disorders such as Parkinson's disease and essential tremor. Over the past two decades, DBS has been applied to OCD, building on earlier experience with lesional procedures. Promising results led to Humanitarian Device Exemption (HDE) approval of the therapy from the United States Food and Drug Administration in 2009. In this review, the authors describe the development of DBS for OCD, the most recent outcome data, and areas for future research.

Sex differences in emotional perception: Meta analysis of divergent activation.

Behavioral and physiological sex differences in emotional reactivity are well documented, yet comparatively few neural differences have been identified. Here we apply quantitative activation likelihood estimation (ALE) meta-analysis across functional brain imaging studies that each reported clusters of activity differentiating men and women as they participated in emotion-evoking tasks in the visual modality. This approach requires the experimental paradigm to be balanced across the sexes, and thus may provide greater clarity than previous efforts. Results across 56 emotion-eliciting studies (n=1907) reveal distinct activation in the medial prefrontal cortex, anterior cingulate cortex, frontal pole, and mediodorsal nucleus of the thalamus in men relative to women. Women show distinct activation in bilateral amygdala, hippocampus, and regions of the dorsal midbrain including the periaqueductal gray/superior colliculus and locus coeruleus. While some clusters are consistent with prevailing perspectives on the foundations of sex differences in emotional reactivity, thalamic and brainstem regions have not previously been highlighted as sexually divergent. These data strongly support the need to include sex as a factor in functional brain imaging studies of emotion, and to extend our investigative focus beyond the cortex.

Rethinking the Use of Neutral Faces as a Baseline in fMRI Neuroimaging Studies of Axis-I Psychiatric Disorders.

Major Axis-I disorders including major depressive disorder (MDD), bipolar disorder (BD), anxiety disorder, and schizophrenia are associated with a host of aberrations in the way social stimuli are processed. Face perception tasks are often used in neuroimaging research of emotion processing in both healthy and patient populations, and to date, there exists a mounting body of evidence, both behavioral and within the brain, indicating that emotional faces compared to neutral faces are processed abnormally by those with Axis-I disorders relative to healthy control (HC) groups. The use of neutral faces as a "baseline control condition" is predicated on the assumption that neutral faces are processed in the same way HCs and individuals with major Axis-I disorders. In this paper, existing fMRI studies examining the way neutral faces are processed in groups with Axis-I disorders involving socioaffective perception are reviewed. In reviewing available studies, a consistent pattern of results demonstrated that these disorders are associated with abnormal frontolimbic activity in response to neutral faces and in particular within the amygdala and prefrontal regions such as the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) compared to HC groups. Specifically, increased amygdala activation was consistently reported in response to neutral faces in anxiety disorders and schizophrenia. Abnormal medial PFC activity was reported in patients with MDD, and patients with BD exhibit decreased activity in the DLPFC and ACC relative to HCs. In addition, specific suggestions to overcome these obstacles with new research and additional analyses are discussed.

Epigenetic modification of OXT and human sociability.

Across many mammalian species there exist genetic and biological systems that facilitate the tendency to be social. Oxytocin is a neuropeptide involved in social-approach behaviors in humans and others mammals. Although there exists a large, mounting body of evidence showing that oxytocin signaling genes are associated with human sociability, very little is currently known regarding the way the structural gene for oxytocin (OXT) confers individual differences in human sociability. In this study, we undertook a comprehensive approach to investigate the association between epigenetic modification of OXT via DNA methylation, and overt measures of social processing, including self-report, behavior, and brain function and structure. Genetic data were collected via saliva samples and analyzed to target and quantify DNA methylation across the promoter region of OXT We observed a consistent pattern of results across sociability measures. People that exhibit lower OXT DNA methylation (presumably linked to higher OXT expression) display more secure attachment styles, improved ability to recognize emotional facial expressions, greater superior temporal sulcus activity during two social-cognitive functional MRI tasks, and larger fusiform gyrus gray matter volume than people that exhibit higher OXT DNA methylation. These findings provide empirical evidence that epigenetic modification of OXT is linked to several overt measures of sociability in humans and serve to advance progress in translational social neuroscience research toward a better understanding of the evolutionary and genetic basis of normal and abnormal human sociability.

Trying to trust: Brain activity during interpersonal social attitude change.

Interpersonal trust and distrust are important components of human social interaction. Although several studies have shown that brain function is associated with either trusting or distrusting others, very little is known regarding brain function during the control of social attitudes, including trust and distrust. This study was designed to investigate the neural mechanisms involved when people attempt to control their attitudes of trust or distrust toward another person. We used a novel control-of-attitudes fMRI task, which involved explicit instructions to control attitudes of interpersonal trust and distrust. Control of trust or distrust was operationally defined as changes in trustworthiness evaluations of neutral faces before and after the control-of-attitudes fMRI task. Overall, participants (n = 60) evaluated faces paired with the distrust instruction as being less trustworthy than faces paired with the trust instruction following the control-of-distrust task. Within the brain, both the control-of-trust and control-of-distrust conditions were associated with increased temporoparietal junction, precuneus (PrC), inferior frontal gyrus (IFG), and medial prefrontal cortex activity. Individual differences in the control of trust were associated with PrC activity, and individual differences in the control of distrust were associated with IFG activity. Together, these findings identify a brain network involved in the explicit control of distrust and trust and indicate that the PrC and IFG may serve to consolidate interpersonal social attitudes.

Altruistic behavior: mapping responses in the brain.

Altruism is an important social construct related to human relationships and the way many interpersonal and economic decisions are made. Recent progress in social neuroscience research shows that altruism is associated with a specific pattern of brain activity. The tendency to engage in altruistic behaviors is associated with greater activity within limbic regions such as the nucleus accumbens and anterior cingulate cortex in addition to cortical regions such as the medial prefrontal cortex and temporoparietal junction. Here, we review existing theoretical models of altruism as well as recent empirical neuroimaging research demonstrating how altruism is processed within the brain. This review not only highlights the progress in neuroscience research on altruism but also shows that there exist several open questions that remain unexplored.

Considering Eligibility for Studies of Deep Brain Stimulation for Treatment-Resistant Depression: Insights From a Clinical Trial in Unipolar and Bipolar Depression.

BACKGROUND: While electroconvulsive therapy (ECT) is the most effective treatment for major depression (major depressive disorder [MDD]), deep brain stimulation (DBS) has shown efficacy in patients who have not received benefit from ECT. Studies of DBS are small, and a better understanding of which eligibility criteria lead to exclusion may help achieve a more appropriate balance between scientific rigor and generalizability in future trials. We assessed the rate and reasons for exclusion from a study of DBS for treatment-resistant MDD and bipolar type II (BPII) depression. METHODS: One thousand ninety-eight adults were screened for a study of DBS for MDD or BPII. Reasons for exclusion were documented. Descriptive statistics were calculated for each reason for exclusion for the entire sample as well as the self-reported MDD and BPII subgroups. RESULTS: Ninety-eight percent (98%) of patients screened were excluded. Exclusion due to lack of interest or inability to relocate to the study site was high (41%). Following this, primary reasons for exclusion were lack of prior ECT and presence of psychiatric/general medical comorbidity. Patients with MDD were more likely to be excluded because of inadequate ECT, whereas patients with BPII depression were more likely to be excluded for comorbid psychiatric diagnoses and not meeting minimum severity criteria. CONCLUSIONS: A surprisingly high number of potential participants were excluded because of lack of adequate ECT. This suggests that many patients self-identifying as "treatment resistant" have not truly exhausted available, evidence-based treatments. Overall exclusion rate was high, with key differences in exclusion reasons between the MDD and BPII subgroups. These findings can inform design of future clinical trials for treatment-resistant unipolar and bipolar depression.Clinicaltrials.gov Identifier: NCT00367003.

I know how you feel: the warm-altruistic personality profile and the empathic brain.

The ability to empathize with other people is a critical component of human social relationships. Empathic processing varies across the human population, however it is currently unclear how personality traits are associated with empathic processing. This study was designed to test the hypothesis that specific personality traits are associated with behavioral and biological indicators of improved empathy. Extraversion and Agreeableness are personality traits designed to measure individual differences in social-cognitive functioning, however each trait-dimension includes elements that represent interpersonal social functioning and elements that do not represent interpersonal social functioning. We tested the prediction that interpersonal elements of Extraversion (Warmth) and Agreeableness (Altruism) are associated with empathy and non-interpersonal elements of Extraversion and Agreeableness are not associated with empathy. We quantified empathic processing behaviorally (empathic accuracy task using video vignettes) and within the brain (fMRI and an emotional perspective taking task) in 50 healthy subjects. Converging evidence shows that highly warm and altruistic people are well skilled in recognizing the emotional states of other people and exhibit greater activity in brain regions important for empathy (temporoparietal junction and medial prefrontal cortex) during emotional perspective taking. A mediation analysis further supported the association between warm-altruistic personality and empathic processing; indicating that one reason why highly warm-altruistic individuals may be skilled empathizers is that they engage the temporoparietal junction and medial prefrontal cortex more. Together, these findings advance the way the behavioral and neural basis of empathy is understood and demonstrates the efficacy of personality scales to measure individual differences in interpersonal social function.

Interpersonal reactivity and the attribution of emotional reactions.

The ability to identify the cause of another person's emotional reaction is an important component associated with improved success of social relationships and survival. Although many studies have investigated the mechanisms involved in emotion recognition, very little is currently known regarding the processes involved during emotion attribution decisions. Research on complementary "emotion understanding" mechanisms, including empathy and theory of mind, has demonstrated that emotion understanding decisions are often made through relatively emotion- or cognitive-based processing streams. The current study was designed to investigate the behavioral and brain mechanisms involved in emotion attribution decisions. We predicted that dual processes, emotional and cognitive, are engaged during emotion attribution decisions. Sixteen healthy adults completed the Interpersonal Reactivity Index to characterize individual differences in tendency to make emotion- versus cognitive-based interpersonal decisions. Participants then underwent functional MRI while making emotion attribution decisions. We found neuroimaging evidence that emotion attribution decisions engage a similar brain network as other forms of emotion understanding. Further, we found evidence in support of a dual processes model involved during emotion attribution decisions. Higher scores of personal distress were associated with quicker emotion attribution decisions and increased anterior insula activity. Conversely, higher scores in perspective taking were associated with delayed emotion attribution decisions and increased prefrontal cortex and premotor activity. These findings indicate that the making of emotion attribution decisions relies on dissociable emotional and cognitive processing streams within the brain.

The tendency to trust is reflected in human brain structure.

Trust is an important component of human social life. Within the brain, the function within a neural network implicated in interpersonal and social-cognitive processing is associated with the way trust-based decisions are made. However, it is currently unknown how localized structure within the healthy human brain is associated with the tendency to trust other people. This study was designed to test the prediction that individual differences in the tendency to trust are associated with regional gray matter volume within the ventromedial prefrontal cortex (vmPFC), amygdala and anterior insula. Behavioral and neuroimaging data were collected from a sample of 82 healthy participants. Individual differences in the tendency to trust were measured in two ways (self-report and behaviorally: trustworthiness evaluation of faces task). Voxel based morphometry analyses of high-resolution structural images (VBM8-DARTEL) were conducted to test for the association between the tendency to trust and regional gray matter volume. The results provide converging evidence that individuals characterized as trusting others more exhibit increased gray matter volume within the bilateral vmPFC and bilateral anterior insula. Greater right amygdala volume is associated with the tendency to rate faces as more trustworthy and distrustworthy (U-shaped function). A whole brain analysis also shows that the tendency to trust is reflected in the structure of dorsomedial prefrontal cortex. These findings advance neural models that associate the structure and function of the human brain with social decision-making and the tendency trust other people.

A 6 week randomized double-blind placebo-controlled trial of ziprasidone for the acute depressive mixed state.

OBJECTIVE: To examine the efficacy of ziprasidone vs. placebo for the depressive mixed state in patients with bipolar disorder type II or major depressive disorder (MDD). METHODS: 73 patients were randomized in a double-blinded, placebo-controlled study to ziprasidone (40-160 mg/d) or placebo for 6 weeks. They met DSM-IV criteria for a major depressive episode (MDE), while also meeting 2 or 3 (but not more nor less) DSM-IV manic criteria. They did not meet DSM-IV criteria for a mixed or manic episode. Baseline psychotropic drugs were continued unchanged. The primary endpoint measured was Montgomery-Åsberg Depression Rating Scale (MADRS) scores over time. The mean dose of ziprasidone was 129.7±45.3 mg/day and 126.1±47.1 mg/day for placebo. RESULTS: The primary outcome analysis indicated efficacy of ziprasidone versus placebo (p = 0.0038). Efficacy was more pronounced in type II bipolar disorder than in MDD (p = 0.036). Overall ziprasidone was well tolerated, without notable worsening of weight or extrapyramidal symptoms. CONCLUSIONS: There was a statistically significant benefit with ziprasidone versus placebo in this first RCT of any medication for the provisional diagnostic concept of the depressive mixed state. TRIAL REGISTRATION: Clinicaltrials.gov NCT00490542.

Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression.

CONTEXT: Deep brain stimulation (DBS) may be an effective intervention for treatment-resistant depression (TRD), but available data are limited. OBJECTIVE: To assess the efficacy and safety of subcallosal cingulate DBS in patients with TRD with either major depressive disorder (MDD) or bipolar II disorder (BP). DESIGN: Open-label trial with a sham lead-in phase. SETTING: Academic medical center. Patients  Men and women aged 18 to 70 years with a moderate-to-severe major depressive episode after at least 4 adequate antidepressant treatments. Ten patients with MDD and 7 with BP were enrolled from a total of 323 patients screened. Intervention  Deep brain stimulation electrodes were implanted bilaterally in the subcallosal cingulate white matter. Patients received single-blind sham stimulation for 4 weeks followed by active stimulation for 24 weeks. Patients then entered a single-blind discontinuation phase; this phase was stopped after the first 3 patients because of ethical concerns. Patients were evaluated for up to 2 years after the onset of active stimulation. MAIN OUTCOME MEASURES: Change in depression severity and functioning over time, and response and remission rates after 24 weeks were the primary efficacy end points; secondary efficacy end points were 1 year and 2 years of active stimulation. RESULTS: A significant decrease in depression and increase in function were associated with chronic stimulation. Remission and response were seen in 3 patients (18%) and 7 (41%) after 24 weeks (n = 17), 5 (36%) and 5 (36%) after 1 year (n = 14), and 7 (58%) and 11 (92%) after 2 years (n = 12) of active stimulation. No patient achieving remission experienced a spontaneous relapse. Efficacy was similar for patients with MDD and those with BP. Chronic DBS was safe and well tolerated, and no hypomanic or manic episodes occurred. A modest sham stimulation effect was found, likely due to a decrease in depression after the surgical intervention but prior to entering the sham phase. CONCLUSIONS: The findings of this study support the long-term safety and antidepressant efficacy of subcallosal cingulate DBS for TRD and suggest equivalent safety and efficacy for TRD in patients with BP. Trial Registration  clinicaltrials.gov Identifier: NCT00367003.

Misdiagnosis of bipolar disorder in children and adolescents: a comparison with ADHD and major depressive disorder.

BACKGROUND: Controversy surrounds the frequency of underdiagnosis vs overdiagnosis of bipolar disorder (BD) in children and adolescents compared with diagnoses of attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD). METHODS: Sixty-four children and adolescents (age 7 to 18) treated in a community setting were systematically assessed for diagnostic and treatment histories. Best estimate consensus diagnosis was made using DSM-IV criteria. RESULTS: ADHD was overdiagnosed (all patients with ADHD had received the diagnosis, as did 38% of patients with MDD and 29% of patients with BD, respectively), while MDD was partially underdiagnosed and partially overdiagnosed (57% of MDD patients received the diagnosis, 43% did not; 33% of patients with BD were incorrectly diagnosed with MDD). BD was underdiagnosed, not overdiagnosed (38% received the diagnosis, 62% did not; BD was not diagnosed in the ADHD sample, and in only 5% of the patients with MDD). The absence of a positive family history predicted misdiagnosis of BD (relative risk = 2.48, 95% confidence interval 1.10 to 5.56). Observational treatment response to stimulants was equally high in all groups (75% to 82%). CONCLUSIONS: In the first controlled study on this topic, BD was not over-diagnosed in children and adolescents, as it is often claimed, and ADHD was. Stimulant response was nonspecific and diagnostically uninformative. Studies with larger samples are needed to replicate or refute these results.

Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety.

OBJECTIVE: To assess long-term effectiveness and safety of randomized antidepressant discontinuation after acute recovery from bipolar depression. METHOD: In the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, conducted between 2000 and 2007, 70 patients with DSM-IV-diagnosed bipolar disorder (72.5% non-rapid cycling, 70% type I) with acute major depression, initially responding to treatment with antidepressants plus mood stabilizers, and euthymic for 2 months, were openly randomly assigned to antidepressant continuation versus discontinuation for 1-3 years. Mood stabilizers were continued in both groups. RESULTS: The primary outcome was mean change on the depressive subscale of the STEP-BD Clinical Monitoring Form. Antidepressant continuation trended toward less severe depressive symptoms (mean difference in DSM-IV depression criteria = -1.84 [95% CI, -0.08 to 3.77]) and mildly delayed depressive episode relapse (HR = 2.13 [1.00-4.56]), without increased manic symptoms (mean difference in DSM-IV mania criteria = +0.23 [-0.73 to 1.20]). No benefits in prevalence or severity of new depressive or manic episodes, or overall time in remission, occurred. Type II bipolar disorder did not predict enhanced antidepressant response, but rapid-cycling course predicted 3 times more depressive episodes with antidepressant continuation (rapid cycling = 1.29 vs non-rapid cycling = 0.42 episodes/year, P = .04). CONCLUSIONS: This first randomized discontinuation study with modern antidepressants showed no statistically significant symptomatic benefit with those agents in the long-term treatment of bipolar disorder, along with neither robust depressive episode prevention benefit nor enhanced remission rates. Trends toward mild benefits, however, were found in subjects who continued antidepressants. This study also found, similar to studies of tricyclic antidepressants, that rapid-cycling patients had worsened outcomes with modern antidepressant continuation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00012558.

A double-blind, placebo-controlled pilot study of galantamine to improve cognitive dysfunction in minimally symptomatic bipolar disorder.

OBJECTIVE: There is increasing evidence that cognitive impairment is common in patients with bipolar disorder. The purpose of this study was to determine whether galantamine augmentation improved cognition in patients with euthymic bipolar disorder. In addition, the effect of galantamine on clinical measures of functioning and psychopathology was assessed. METHOD: This study was a randomized double-blind, placebo-controlled, parallel design examining the impact of galantamine augmentation on cognition and other clinical measures in 30 patients during the course of 3 months. Sixteen subjects who completed baseline and follow-up second neuropsychological testing were evaluable (10 with galantamine and 6 with placebo). RESULTS: The galantamine group showed improved performance on the California Verbal Learning Test total learning and the placebo group showed improved performance on the 2 Delis-Kaplan Executive Functioning System trail-making conditions and category fluency. CONCLUSIONS: Episodic memory performance was improved in the galantamine treatment group but did not improve in the placebo group. In contrast, performance on 2 of the processing speed measures showed significant improvement in the placebo condition, whereas that of the patients treated with galantamine did not improve. Galantamine may thus have specific benefits for episodic memory, but not processing speed, in patients with cognitive impairment as part of bipolar disorder.

A prospective, open-label study of Aripiprazole mono- and adjunctive treatment in acute bipolar depression.

OBJECTIVE: To examine the efficacy and tolerability of aripiprazole treatment for acute bipolar depression. METHODS: A six-week prospective, nonrandomized, open label study was conducted in depressed bipolar outpatients (types I, II, and NOS), as diagnosed by DSM-IV criteria. Previous treatments were continued unchanged, and new treatments not permitted, except lorazepam up to 2 mg daily. Aripiprazole was dosed flexibly up to a maximum of 30 mg daily, based on tolerability and efficacy. Montgomery-Asberg Depression Rating Scale (MADRS) and Mania Rating Scale (MRS) scores were used to assess changes in mood symptoms. Side effect outcomes were measured. Data was analyzed using last observation carried forward methodology and Analysis of Variance. RESULTS: Twenty patients (15 men, 5 women) with bipolar disorder (10 type I, 7 type II, 3 type NOS) enrolled in the study. Mean endpoint dose was 13.6 mg/d+/-10.0 mg/d. Thirteen (65%) patients completed 6 weeks of treatment. MADRS and MRS scores significantly improved during treatment. 44% of patients who completed at least one week of treatment were considered responders, based on > or =50% decrease in MADRS scores from baseline. Side effect measures were mostly unchanged during treatment. CONCLUSION: Depressive symptoms improved in bipolar patients treated with open-label aripiprazole.

Effectiveness of quetiapine in rapid cycling bipolar disorder: a preliminary study.

OBJECTIVE: The authors examined long-term effectiveness and study retention during open-label quetiapine treatment for rapid cycling bipolar disorder. METHODS: An open-label, nonrandomized trial was conducted in 41 patients with rapid-cycling bipolar disorder (type I=33, type II=7, NOS=1) who received flexibly dosed quetiapine monotherapy (n=19) or add-on therapy (n=22) for up to one year. Linear growth curves were calculated to assess longitudinal changes in depression and mania. RESULTS: Linear growth curves demonstrated highly significant reductions in manic (p<.0001) and depressive (p<.0001) symptoms. Effect sizes were large against manic symptoms (add-on therapy: Cohen's d=0.66; monotherapy: Cohen's d=0.75) but small-to-moderate against depression (monotherapy: d=0.29; add-on therapy: d=0.40). Most patients (68%) prematurely terminated the protocol (mean duration: 18.0+/-16.9 weeks, mean dose: 195.6+/-196.1 mg/day), most often because of the need for additional psychotropic treatments. LIMITATIONS: The study protocol involved an open label design with no placebo or active comparator group. The sample size provided adequate statistical power to detect large but not medium or small within-group effects. Premature dropout during the first six months precluded inferences about longer-term treatment outcome. CONCLUSIONS: These observational findings provisionally suggest some benefit with quetiapine for both manic and depressive symptoms in rapid cycling bipolar disorder, at dosages somewhat lower than previously described either for mania or bipolar depression. The relatively high dropout rate underscores the complexity of rapid cycling bipolar disorder and likely necessity for pharmacotherapy adjustments over time.

Is adjunctive open-label zonisamide effective for bipolar disorder?

OBJECTIVE: To assess the effectiveness and safety of zonisamide in bipolar disorder. METHODS: A chart review was conducted of naturalistic treatment with zonisamide in 35 outpatients meeting DSM-IV criteria for bipolar disorder (9 males, 26 females; mean +/- SD age = 29.2 +/- 12.7; 14 with bipolar disorder type I, 6 with bipolar disorder type II, and 14 with bipolar disorder not otherwise specified). Patients received zonisamide adjunctive therapy between January 1994 and December 2004. Treatment response was defined as a Clinical Global Impressions - Improvement (CGI-I) scale score of +2 (much improved) or + 3 (very much improved). RESULTS: Zonisamide was moderately to markedly effective in 9 subjects (26%). Indication for treatment included depressive (34.3%, [12/35]), manic/hypomanic (28.6%, [10/35]), or mixed (31.4%, [11/35]) symptoms. The mean zonisamide dose was 130 mg/d for a mean duration of treatment of 27.0 +/- 32.3 weeks. Sedation (25%, [4/16]) was the most common side effect; 19/35 (54.3%) reported no side effects. 17/35 (49%) patients terminated early, mostly due to adverse effects (6/35). Using a multivariable model, predictors of response, concurrent mood stabilizers, dose and bipolar subtype (bipolar type I > type II/NOS), were controlled for in this sample. CONCLUSIONS: In 35 persons with bipolar disorder taking standard mood stabilizers and other psychotropic agents, adjunctive zonisamide appears to have modest benefit in global improvement when added to a pre-existing complex medication regimen in patients with bipolar spectrum disorder. These pilot data support the need for larger studies to test the potential efficacy of zonisamide for treatment in mood disorders.

Divalproex in the treatment of acute bipolar depression: a preliminary double-blind, randomized, placebo-controlled pilot study.

OBJECTIVE: To determine the efficacy of divalproex (extended release) in the treatment of acute nonrefractory bipolar depression. METHOD: In a stratified, double-blind, randomized, placebo-controlled trial, 18 acutely depressed bipolar outpatients (DSM-IV criteria) received either divalproex monotherapy (target dose level, 70-90 ng/dL) (N = 9) or placebo (N = 9) for 6 weeks. Patients were recruited between January 2004 and May 2005. Clinical assessment on the Montgomery-Asberg Depression Rating Scale (MADRS) determined primary efficacy. RESULTS: The divalproex treatment group showed significantly greater reduction in MADRS scores compared to placebo (group x time interaction, p = .0078). Absolute effect size of estimated MADRS total score reduction over time was 13.6 points with divalproex versus 1.4 points with placebo (p = .003, linear growth curve model). Standardized effect size was large (Cohen d = 0.81). MADRS item analyses demonstrated improvement in core mood symptoms more than in anxiety or insomnia symptoms. There was also a modest but significant association between MADRS and Mania Rating Scale scores in the divalproex group (r = 0.29, df = 51, p = .03), but not in the placebo group (r = -0.15, df = 35, p = .36). CONCLUSIONS: Divalproex appeared to be an effective treatment for acute nonrefractory bipolar depression, which is consistent with previous small randomized studies. Some evidence of benefit in the depressive mixed state was observed. Confirmation or refutation with larger randomized clinical trials is warranted. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00226343.