Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial.

BACKGROUND: Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted. METHODS: Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. Randomisation was computer generated with a block size of three at each site before the site started the study. The primary outcome was frequency of response (defined as a 40% or greater reduction in depression severity from baseline) averaged over months 4-6 of the double-blind phase. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients were followed up for up to 24 months. The study is registered at ClinicalTrials.gov, number NCT00617162. FINDINGS: Before the futility analysis, 90 participants were randomly assigned to active (n=60) or sham (n=30) stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery. INTERPRETATION: This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy. FUNDING: Abbott (previously St Jude Medical).

Atypical psychotic symptoms and Dandy-Walker variant.

New-onset psychotic symptoms often respond well to antipsychotic treatment; however, symptoms may be difficult to treat when an underlying brain malformation is present. Here, we present a case of atypical psychotic symptoms in the context of a congenital cerebellar malformation (Dandy-Walker variant). The patient ultimately improved with paliperidone palmitate after multiple antipsychotic medication trials (both oral and one long-acting injectable) were ineffective. Neuroimaging may provide valuable diagnostic and prognostic information in cases of new-onset psychosis with atypical features and treatment resistance, even in the absence of neurologic signs and symptoms.

Metabolic syndrome in bipolar disorder and schizophrenia: dietary and lifestyle factors compared to the general population.

OBJECTIVE: Since a poor diet is often cited as a contributor to metabolic syndrome for subjects diagnosed with bipolar disorder and schizophrenia, we sought to examine dietary intake, cigarette smoking, and physical activity in these populations and compare them with those for the general population. METHODS: Individuals diagnosed with bipolar disorder (n = 116) and schizophrenia (n = 143) were assessed for dietary intake, lifestyle habits, and metabolic syndrome and compared to age-, gender-, and race-matched subjects from the National Health and Nutrition Examination Survey (NHANES) 1999-2000. Additionally, matched subgroups within the patient populations were compared to elicit any differences. RESULTS: As expected, the metabolic syndrome rate was higher in the samples with bipolar disorder (33%) and schizophrenia (47%) compared to matched NHANES controls (17% and 11%, respectively), and not different between the patient groups. Surprisingly, both subjects with bipolar disorder and those with schizophrenia consumed fewer total calories, carbohydrates and fats, as well as more fiber (p < 0.03), compared to NHANES controls. No dietary or activity differences between patient participants with and without metabolic syndrome were found. Subjects with schizophrenia had significantly lower total and low-density cholesterol levels (p < 0.0001) compared to NHANES controls. Subjects with bipolar disorder smoked less (p = 0.001), exercised more (p = 0.004), and had lower body mass indexes (p = 0.009) compared to subjects with schizophrenia. CONCLUSIONS: Counter to predictions, few dietary differences could be discerned between schizophrenia, bipolar disorder, and NHANES control groups. The subjects with bipolar disorder exhibited healthier behaviors than the patients with schizophrenia. Additional research regarding metabolic syndrome mechanisms, focusing on non-dietary contributions, is needed.

Risk factors associated with metabolic syndrome in bipolar and schizophrenia subjects treated with antipsychotics: the role of folate pharmacogenetics.

Folate has been implicated in cardiovascular disease with atypical antipsychotic (AAPs) use, and individuals with methylenetetrahydrofolate reductase (MTHFR) and catechol-O-methyl transferase (COMT) variants are at greater risk. This study examined the relationship between the MTHFR 677C/T, MTHFR 1298A/C, and COMT Val158Met variants; metabolic syndrome; and lifestyle measures in schizophrenia and bipolar subjects. A total of 237 subjects with bipolar or schizophrenia receiving an antipsychotic for at least 6 months were included in this cross-sectional analysis. Subjects were screened for the metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel III criteria) and MTHFR 677C/T, MTHFR 1298A/C, and Val158Met genotypes. In addition, serum folate and homocysteine were measured along with lifestyle factors. The subject's mean age was 44.7 (SD, 11.7) years; 72% were white, and 51% male; 61% were receiving an AAP; the mean body mass index was 32.6 (SD, 8.2) kg/m, and 48% were current smokers. Overall, 41% met metabolic syndrome criteria (n = 98). There were no differences in age, sex, AAP exposure, or body mass index between genotype groups. Metabolic syndrome was related to age, smoking, and the MTHFR 677T and COMT 158Val alleles (χ = 34.4, P < 0.0001). In addition, AAP use showed a trend association with metabolic syndrome (χ = 3.21, P = 0.07). These data support our previous reports and add more data pointing to folate's role in mediating a link between mental illness and cardiovascular disease. Use of this information clinically may help to reduce the risk for AAP metabolic complications in those whose clinical care necessitates the use of AAPs.

Dietary, lifestyle and pharmacogenetic factors associated with arteriole endothelial-dependent vasodilatation in schizophrenia patients treated with atypical antipsychotics (AAPs).

PURPOSE: Within schizophrenia cardiovascular disease (CVD) is highly prevalent secondary to atypical antipsychotic (AAP) use. Thorough assessments of diet, lifestyle, and endothelial functioning have not been done in this population. Omega 3 Fatty Acids (N-3 FAs) have garnered attention in relation to psychopathology as well as cardioprotection. This study examined the status of endothelial function within the schizophrenia population and determined pharmacogenetic, medication, dietary, and lifestyle factors associated with this functioning. METHODS: Schizophrenia subjects were screened for the metabolic syndrome along with physical activity, smoking, and variants related to folate pharmacogenetics in this cross-sectional analysis. Arteriole endothelial-dependent vasodilatation was measured using non-invasive peripheral arterial tonometry (RH-PAT, EndoPAT2000). A 24h dietary food recall was used to construct intake profiles using the Nutrition Data Systems for Research software (NDSR). We examined associations between AAP use and RH-PAT values, and the influence of N-3 FA dietary intake on this measure. Preliminary data are reported in 83 subjects with a mean age (±s.d.) of 45.89 (±11.49), 64% were Caucasian (n=53), 64% were male (n=53), and 77% were receiving AAP treatment (n=63). RESULTS: A significant positive relationship was found between RH-PAT values and N-3 FA intake (F=17.7(1,16), p=0.0007) in subjects not receiving AAPs. This relationship was lost in those treated with AAPs (F=0.25(1,43), p>0.6). Regression analysis confirmed the interaction effect of AAP treatment on the relationship between RH-PAT and N-3 FAs (p=0.0105). Endothelial dysfunction was also related to folate pharmacogenetic variants. CONCLUSIONS: AAPs may counteract some vascular health benefits of a diet high in N-3 FAs. AAP use may necessitate a higher N-3 FA dose to regain these effects, but additional research is necessary to strengthen the preliminary findings. Pharmacogenetic variants related to folate and homocysteine metabolism may also increase endothelial dysfunction risk.

Deep brain stimulation for refractory obsessive-compulsive disorder.

BACKGROUND: Neurosurgery (anterior capsulotomy) has been beneficial to many patients with debilitating, refractory obsessive-compulsive disorder (OCD), but the irreversibility of the procedure is an important limitation to its use. Nondestructive, electrical stimulation (deep brain stimulation; DBS) has proven an effective alternative to ablative surgery for neurological indications, suggesting potential utility in place of capsulotomy for OCD. METHODS: The effects of DBS for OCD were examined in four patients in a short-term, blinded, on-off design and long-term, open follow-up. The patients had incapacitating illness, refractory to standard treatments. Hardware developed for movement disorder treatment was surgically implanted, with leads placed bilaterally in the anterior limbs of their internal capsules. Patients received stimulation in a randomized "on-off" sequence of four 3-week blocks. Ongoing, open stimulation was continued in consenting patients after the controlled trial. RESULTS: Patients tolerated DBS well. Dramatic benefits to mood, anxiety, and OCD symptoms were seen in one patient during blinded study and open, long-term follow-up. A second patient showed moderate benefit during open follow-up. CONCLUSIONS: It appears that DBS has potential value for treating refractory psychiatric disorders, but additional development work is needed before the procedure is utilized outside of carefully controlled research protocols.