Special considerations in the treatment of patients with bipolar disorder and medical co-morbidities

BACKGROUND: The pharmacological treatment of bipolar disorder has dramatically improved with multiple classes of agents being used as mood-stabilizers, including lithium, anticonvulsants, and atypical antipsychotics. However, the use of these medications is not without risk, particularly when a patient with bipolar disorder also has comorbid medical illness. As the physician who likely has the most contact with patients with bipolar disorder, psychiatrists must have a high index of suspicion for medical illness, as well as a basic knowledge of the risks associated with the use of medications in this patient population. METHODS: A review of the literature was conducted and papers addressing this topic were selected by the authors. RESULTS AND DISCUSSION: Common medical comorbidities and treatment-emergent illnesses, including obesity, diabetes mellitus, dyslipidemia, cardiac disease, hepatic disease, renal disease, pulmonary disease and cancer are reviewed with respect to concomitant use of mood stabilizers. Guidance to clinicians regarding effective monitoring and treatment is offered. CONCLUSIONS: Mood-stabilizing medications are necessary in treating patients with bipolar disorder and often must be used in the face of medical illness. Their safe use is possible, but requires increased vigilance in monitoring for treatment-emergent illnesses and effects on comorbid medical illness

Number of risk genotypes is a risk factor for major depressive disorder: a case control study

BACKGROUND: The objective of the study was to determine the genetic basis of Major Depressive Disorder, and the capacity to respond to antidepressant treatment. An association study of 21 candidate polymorphisms relevant to monoamine function and the mechanism of antidepressant response was conducted in 3 phenotypically distinct samples: a group with chronic or recurrent depression unable to respond to antidepressants (non-responders) (n = 58), a group capable of symptomatic improvement with or without treatment (responders) (n = 39), and volunteer controls (n = 85). The responders and non-responders constituted a larger group of depressed subjects. METHODS: A candidate gene approach was employed to asses the genetics basis of Major Depressive Disorder. The genotypic frequencies of selected polymorphisms were compared between the controls and depressed subjects. To asses the genetics basis of the capacity to respond to antidepressant treatment, the responders were compared to the non-responders. Candidate genes were chosen based on functional studies and proximity to whole genome linkage findings in the literature. Risk genotypes were identified by previous functional studies and association studies. RESULTS: A statistically significant difference in genotype frequency for the SLC6A4 intron 2 VNTR was detected between the subjects with a history of depression and controls (p = 0.004). Surprisingly, a statistically significant difference was detected between responders and non-responders for the DRD4 exon III VNTR genotype frequencies (p = 0.009). Furthermore, a difference between the controls and depressed subjects as well as between the controls and non-responders was detected for the number and distribution of risk genotypes in each group. CONCLUSION: An association between several monoamine-related genes and Major Depressive Disorder is supported. The data suggest that the two depressive phenotypes are genetically different, inferring that the genetic basis for the capacity to respond to standard antidepressant treatment, and the genetic susceptibility to Major Depressive Disorder may be independent. In addition, a proof of concept is provided demonstrating that the number of risk genotypes may be an indication of susceptibility of major depressive disorder and the severity of the disorder

Multimodal functional and structural neuroimaging investigation of major depressive disorder following treatment with duloxetine

Background: Longitudinal neuroimaging studies of major depressive disorder (MDD) have most commonly assessed the effects of antidepressants from the serotonin reuptake inhibitor class and usually reporting a single measure. Multimodal neuroimaging assessments were acquired from MDD patients during an acute depressive episode with serial measures during a 12-week treatment with the serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine. Methods: Participants were medication-free MDD patients (n = 32; mean age 40.2 years) in an acute depressive episode and healthy controls matched for age, gender, and IQ (n = 25; mean age 38.8 years). MDD patients received treatment with duloxetine 60 mg daily for 12 weeks with an optional dose increase to 120 mg daily after 8 weeks. All participants had serial imaging at weeks 0, 1, 8, and 12 on a 3 Tesla magnetic resonance imaging (MRI) scanner. Neuroimaging tasks included emotional facial processing, negative attentional bias (emotional Stroop), resting state functional MRI and structural MRI. Results: A significant group by time interaction was identified in the anterior default mode network in which MDD patients showed increased connectivity with treatment, while there were no significant changes in healthy participants. In the emotional Stroop task, increased posterior cingulate activation in MDD patients normalized following treatment. No significant group by time effects were observed for happy or sad facial processing, including in amygdala responsiveness, or in regional cerebral volumes. Reduced baseline resting state connectivity within the orbitofrontal component of the default mode network was predictive of clinical response. An early increase in hippocampal volume was predictive of clinical response. Conclusions: Baseline resting state functional connectivity was predictive of subsequent clinical response. Complementary effects of treatment were observed from the functional neuroimaging correlates of affective facial expressions, negative attentional bias, and resting state. No significant effects were observed in affective facial processing, while the interaction effect in negative attentional bias and individual group effects in resting state connectivity could be related to the SNRI class of antidepressant medication. The specificity of the observed effects to SNRI pharmacological treatments requires further investigation. Trial registration: Registered at clinicaltrials.gov (NCT01051466)

Effects of 12 Months of Vagus Nerve Stimulation in Treatment-Resistant Depression: A Naturalistic Study

Background: The need for effective, long-term treatment for recurrent or chronic, treatment-resistant depression is well established. Methods: This naturalistic follow-up describes outpatients with nonpsychotic major depressive (n = 185) or bipolar (I or II) disorder, depressed phase (n = 20) who initially received 10 weeks of active (n = 110) or sham vagus nerve stimulation (VNS) (n = 95). The initial active group received another 9 months, while the initial sham group received 12 months of VNS. Participants received antidepressant treatments and VNS, both of which could be adjusted. Results: The primary analysis (repeated measures linear regression) revealed a significant reduction in 24-item Hamilton Rating Scale for Depression (HRSD24) scores (average improvement, .45 points [SE = .05] per month (p \u3c .001). At exit, HRSD24 response rate was 27.2% (55/202); remission rate (HRSD24 ≤ 9) was 15.8% (32/202). Montgomery Asberg Depression Rating Scale (28.2% [57/202]) and Clinical Global Impression-Improvement (34.0% [68/200]) showed similar response rates. Voice alteration, dyspnea, and neck pain were the most frequently reported adverse events. Conclusions: These 1-year open trial data found VNS to be well tolerated, suggesting a potential long-term, growing benefit in treatment-resistant depression, albeit in the context of changes in depression treatments. Comparative long-term data are needed to determine whether these benefits can be attributed to VNS

Effects of 12 Months of Vagus Nerve Stimulation in Treatment-Resistant Depression: A Naturalistic Study

Background: The need for effective, long-term treatment for recurrent or chronic, treatment-resistant depression is well established. Methods: This naturalistic follow-up describes outpatients with nonpsychotic major depressive (n = 185) or bipolar (I or II) disorder, depressed phase (n = 20) who initially received 10 weeks of active (n = 110) or sham vagus nerve stimulation (VNS) (n = 95). The initial active group received another 9 months, while the initial sham group received 12 months of VNS. Participants received antidepressant treatments and VNS, both of which could be adjusted. Results: The primary analysis (repeated measures linear regression) revealed a significant reduction in 24-item Hamilton Rating Scale for Depression (HRSD24) scores (average improvement, .45 points [SE = .05] per month (p \u3c .001). At exit, HRSD24 response rate was 27.2% (55/202); remission rate (HRSD24 ≤ 9) was 15.8% (32/202). Montgomery Asberg Depression Rating Scale (28.2% [57/202]) and Clinical Global Impression-Improvement (34.0% [68/200]) showed similar response rates. Voice alteration, dyspnea, and neck pain were the most frequently reported adverse events. Conclusions: These 1-year open trial data found VNS to be well tolerated, suggesting a potential long-term, growing benefit in treatment-resistant depression, albeit in the context of changes in depression treatments. Comparative long-term data are needed to determine whether these benefits can be attributed to VNS

Other race effect on amygdala response during affective facial processing in major depression

Objective: The other race effect, also known as own race bias, refers to the enhanced ability to recognize faces belonging to one’s own race relative to faces from another race. The other race effect is associated with increased amygdala response in healthy individuals. The amygdala is a key node in emotion processing which shows impaired functioning in depression and has been proposed to be a marker of depressive state. We investigated the impact of the other race effect on amygdala responses in depression. Methods: Participants were 30 individuals with major depression (mean age39.4 years) and 23 healthy individuals (mean age: 38.8 years) recruited from the community. Participants were Asian, Black/African American and Caucasian. During a functional MRI scan, participants viewed Caucasian faces which displayed a range of sad expressions. A region of interest analysis of left and right amygdala responses was performed. Results: Increased bilateral amygdala responses were observed in response to the Caucasian face stimuli in participants who were Asian or Black/African American as compared to Caucasian participants in both healthy individuals and individuals with major depression. There was no significant group by race interaction effect. Conclusions: Increased amygdala responses associated with the other race effect were evident in both individuals with major depression and in healthy participants. Increased amygdala responses with the other race effect is a potential confound of the neural correlates of facial processing in healthy participants and in mental health disorders. The implications of the other race effect on impairments in interpersonal functioning in depression require further investigation