Sidney H. Kennedy

Deep Brain Stimulation for Treatment-Resistant Depression

Treatment-resistant depression is a severely disabling disorder with no proven treatment options once multiple medications, psychotherapy, and electroconvulsive therapy have failed. Based on our preliminary observation that the subgenual cingulate region (Brodmann area 25) is metabolically overactive in treatment-resistant depression, we studied whether the application of chronic deep brain stimulation to modulate BA25 could reduce this elevated activity and produce clinical benefit in six patients with refractory depression. Chronic stimulation of white matter tracts adjacent to the subgenual cingulate gyrus was associated with a striking and sustained remission of depression in four of six patients. Antidepressant effects were associated with a marked reduction in local cerebral blood flow as well as changes in downstream limbic and cortical sites, measured using positron emission tomography. These results suggest that disrupting focal pathological activity in limbic-cortical circuits using electrical stimulation of the subgenual cingulate white matter can effectively reverse symptoms in otherwise treatment-resistant depression.

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009

The Canadian Network for Mood and Anxiety Treatments published guidelines for the management of bipolar disorder in 2005, with updates in 2007 and 2009. This third update, in conjunction with the International Society for Bipolar Disorders, reviews new evidence and is designed to be used in conjunction with the previous publications.The recommendations for the management of acute mania remain largely unchanged. Lithium, valproate, and several atypical antipsychotic agents continue to be first-line treatments for acute mania. Monotherapy with asenapine, paliperidone extended release (ER), and divalproex ER, as well as adjunctive asenapine, have been added as first-line options.For the management of bipolar depression, lithium, lamotrigine, and quetiapine monotherapy, as well as olanzapine plus selective serotonin reuptake inhibitor (SSRI), and lithium or divalproex plus SSRI/bupropion remain first-line options. Lurasidone monotherapy and the combination of lurasidone or lamotrigine plus lithium or divalproex have been added as a second-line options. Ziprasidone alone or as adjunctive therapy, and adjunctive levetiracetam have been added as not-recommended options for the treatment of bipolar depression. Lithium, lamotrigine, valproate, olanzapine, quetiapine, aripiprazole, risperidone long-acting injection, and adjunctive ziprasidone continue to be first-line options for maintenance treatment of bipolar disorder. Asenapine alone or as adjunctive therapy have been added as third-line options.

Deep Brain Stimulation for Treatment-Resistant Depression: Follow-Up After 3 to 6 Years

OBJECTIVE A prevalence of at least 30% for treatment-resistant depression has prompted the investigation of alternative treatment strategies. Deep brain stimulation (DBS) is a promising targeted approach involving the bilateral placement of electrodes at specific neuroanatomical sites. Given the invasive and experimental nature of DBS for treatment-resistant depression, it is important to obtain both short-term and long-term effectiveness and safety data. This report represents an extended follow-up of 20 patients with treatment-resistant depression who received DBS to the subcallosal cingulate gyrus (Brodmanns area 25). METHOD After an initial 12-month study of DBS, patients were seen annually and at a last follow-up visit to assess depression severity, functional outcomes, and adverse events. RESULTS The average response rates 1, 2, and 3 years after DBS implantation were 62.5%, 46.2%, and 75%, respectively. At the last follow-up visit (range=3-6 years), the average response rate was 64.3%. Functional impairment in the areas of physical health and social functioning progressively improved up to the last follow-up visit. No significant adverse events were reported during this follow-up, although two patients died by suicide during depressive relapses. CONCLUSIONS These data suggest that in the long term, DBS remains a safe and effective treatment for treatment-resistant depression. Additional trials with larger samples are needed to confirm these findings.

Sexual dysfunction before antidepressant therapy in major depression

BACKGROUND Decreased sexual interest and function both occur as a consequence of antidepressant medication use, and are especially associated with serotonin reuptake inhibitors (SRIs). However, few investigators have reported the base rate for disturbances in sexual desire, arousal and orgasm or ejaculation in patients with major depression (MD) prior to antidepressant treatment. The purpose of this report is to define the frequency of sexual dysfunction (SD) in 134 patients with MD and examine the relationship between SD and demographic, clinical and personality variables. METHOD A consecutive series of 55 male and 79 female MD patients diagnosed by SCID-DSM IV assessment completed a series of psychometric measures including a Sexual Function Questionnaire, which asked about change in sexual interest and function as well as sexual activity during the preceding month. RESULTS Only 50% of women and 75% of men reported sexual activity during the preceding month. Over 40% of men and 50% of women reported decreased sexual interest. Reduced levels of arousal were more common in both men and women (40-50%) than ejaculatory or orgasm difficulties (15-20%). In women, problems with arousal and orgasm correlated with higher neuroticism and lower extraversion. There was no relationship between SD and personality measures in men. While age at onset of depression and number of prior episodes showed a modest correlation with SD measures, there were no correlations with severity of depression or specific symptoms clusters. LIMITATIONS AND CONCLUSIONS Although limited by a relatively small sample of drug free patients with MD, and by the absence of a non-depressed comparison sample, these results emphasize the importance of factors beyond specific drug effects in the assessment of antidepressant related sexual dysfunction.

Differences in Brain Glucose Metabolism Between Responders to CBT and Venlafaxine in a 16-Week Randomized Controlled Trial

OBJECTIVE Neuroimaging investigations reveal changes in glucose metabolism (fluorine-18-fluorodeoxyglucose positron emission tomography [PET]) associated with response to disparate antidepressant treatment modalities, including cognitive behavior therapy (CBT), antidepressant pharmacotherapies, and deep brain stimulation. Using a nonrandomized design, the authors previously compared changes following CBT or paroxetine in depressed patients. In this study, the authors report changes in fluorine-18-fluorodeoxyglucose PET in responders to CBT or venlafaxine during a randomized controlled trial. METHODS Subjects meeting DSM-IV-TR criteria for a major depressive episode and a diagnosis of a major depressive disorder received a fluorine-18-fluorodeoxyglucose PET scan before randomization and after 16 weeks of antidepressant treatment with either CBT (N=12) or venlafaxine (N=12). Modality-specific and modality-independent regional brain metabolic changes associated with response status were analyzed. RESULTS Response rates were comparable between the CBT (7/12) and venlafaxine (9/12) groups. Response to either treatment modality was associated with decreased glucose metabolism bilaterally in the orbitofrontal cortex and left medial prefrontal cortex, along with increased metabolism in the right occipital-temporal cortex. Changes in metabolism in the anterior and posterior parts of the subgenual cingulate cortex and the caudate differentiated CBT and venlafaxine responders. CONCLUSIONS Responders to either treatment modality demonstrated reduced metabolism in several prefrontal regions. Consistent with earlier reports, response to CBT was associated with a reciprocal modulation of cortical-limbic connectivity, while venlafaxine engaged additional cortical and striatal regions previously unreported in neuroimaging investigations.

Placebo-controlled trial of agomelatine in the treatment of major depressive disorder.

The efficacy and safety of flexible dosing with the antidepressant agomelatine (25-50 mg/day) was evaluated in a 6-week, double-blind, randomized, placebo-controlled study involving 212 patients who met Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) criteria for major depressive disorder-current major depressive episode. Patients receiving agomelatine (25 mg and 50 mg/day) had a significantly lower mean Hamilton Rating Scale for Depression (HAM-D) score at endpoint compared with those who received placebo (14.1 +/- 7.7 vs. 16.5 +/- 7.4, p = 0.026). Agomelatine significantly improved the response rate (49.1%; p = 0.03), time to first response (p = 0.032), and Clinical Global Impression-Severity of Illness score (p = 0.017), compared with placebo. These results were confirmed in a subgroup of patients with greater symptom severity. Agomelatine 50 mg also appeared to be effective and well tolerated in patients who failed to show improvement after 2 weeks on a dose of 25 mg/day. These results support the prescription of agomelatine 25 mg as the usual therapeutic dose, and suggest that increasing the dose to 50 mg may be beneficial for some patients without reducing tolerability.

Volumetric neuroimaging investigations in mood disorders: bipolar disorder versus major depressive disorder

BACKGROUND As patients with mood disorders manifest heterogeneity in phenomenology, pathophysiology, etiology, and treatment response, a biological classification of mental disease is urgently needed to advance research. Patient and methodological variability complicates the comparison of neuroimaging study results and limits heuristic model development and a biologically-based diagnostic schema. OBJECTIVE We have critically reviewed and compared the magnetic resonance neuroimaging literature to determine the degree and directionality of volumetric changes in brain regions putatively implicated in the pathophysiology of major depressive disorder (MDD) versus bipolar disorder (BD). METHODS A total of 140 published magnetic resonance imaging investigations evaluating subjects with BD or MDD were selected to provide a summary and interpretation of volumetric neuroimaging results in MDD and BD. Further commentary on the pathophysiological implications, and putative cellular and pharmacological mechanisms, is also provided. RESULTS While whole brain volumes of patients with mood disorders do not differ from those of healthy controls, regional deficits in the frontal lobe, particularly in the anterior cingulate and the orbitofrontal cortex, appear to consistently differentiate subjects with mood disorders from the general population. Preliminary findings also suggest that subcortical structures, particularly the striatum, amygdala, and hippocampus, may be differentially affected in MDD and BD. CONCLUSIONS Structural neuroimaging studies have consistently identified regional abnormalities in subjects with mood disorders. Future studies should strive to definitively establish the influence of age and medication.

The role of physical activity in the development and maintenance of eating disorders.

This study was intended to establish the pathogenic significance of sport and exercise in the development of eating disorders. Hospitalized eating disordered patients and an age-matched control group were assessed. Historical and current physical activity data were collected. An indepth interview was also conducted to ascertain the age of onset of the diagnostic symptoms for eating disorders, and to determine whether: (i) exercising predated dieting; (ii) patients had been involved in competitive athletics; (iii) exercise was excessive; and (iv) weight loss was inversely related to level of exercise. The results indicated that patients were more physically active than controls from adolescence onwards, and prior to the onset of the primary diagnostic criteria for anorexia nervosa. A content analysis of the interview data indicated that 78% of patients engaged in excessive exercise, 60% were competitive athletes prior to the onset of their disorder, 60% reported that sport or exercise pre-dated dieting, and 75% claimed that physical activity levels steadily increased during the period when food intake and weight loss decreased the most. Together our results suggest that overactivity should not be routinely viewed as a secondary symptom in anorexia nervosa, equivalent to other behaviours. For a number of anorexic women, sport/exercise is an integral part of the pathogenesis and progression of self-starvation.

A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression.

OBJECT Deep brain stimulation (DBS) has been recently investigated as a treatment for major depression. One of the proposed targets for this application is the subcallosal cingulate gyrus (SCG). To date, promising results after SCG DBS have been reported by a single center. In the present study the authors investigated whether these findings may be replicated at different institutions. They conducted a 3-center prospective open-label trial of SCG DBS for 12 months in patients with treatment-resistant depression. METHODS Twenty-one patients underwent implantation of bilateral SCG electrodes. The authors examined the reduction in Hamilton Rating Scale for Depression (HRSD-17) score from baseline (RESP50). RESULTS Patients treated with SCG DBS had an RESP50 of 57% at 1 month, 48% at 6 months, and 29% at 12 months. The response rate after 12 months of DBS, however, increased to 62% when defined as a reduction in the baseline HRSD-17 of 40% or more. Reductions in depressive symptomatology were associated with amelioration in disease severity in patients who responded to surgery. CONCLUSIONS Overall, findings from this study corroborate the results of previous reports showing that outcome of SCG DBS may be replicated across centers.

Lower dopamine transporter binding potential in striatum during depression.

Previous studies suggest that there is a dopamine lowering process during major depressive episodes (MDE). To investigate this, we measured the dopamine transporter binding potential (DAT BP) in the striatum of depressed and healthy subjects using [11C]RTI-32 PET. The DAT, a predominantly presynaptic receptor, decreases in density after chronic dopamine depletion and the BP is proportional to receptor density. In all striatal regions, subjects with MDE had significantly lower DAT BP. Low striatal DAT BP in MDE is consistent with a downregulation of DAT in response to a dopamine lowering process. There was also a strong, highly significant, inverse correlation between striatal DAT BP and neuropsychological tests of dopamine-implicated symptoms in patients (i.e. patients with lower DAT BP performed better). Lower DAT BP itself reduces extracellular clearance of dopamine. Patients who did not decrease their striatal DAT BP failed to compensate for low dopamine and showed greater impairment on dopamine related tests.