Neurocognitive impairment in bipolar disorder patients: functional implications

Background: Functional recovery among treated bipolar disorder (BPD) patients is far less likely than syndromal and even symptomatic recovery. We hypothesized that increasingly well‐documented aspects of cognitive impairment may contribute to poor functional outcomes in BPD patients, and reviewed the available research on the topic. Methods: Computerized literature searching identified 12 studies with 13 comparisons that simultaneously evaluated cognitive and functional status in euthymic (n = 8) or non‐euthymic (n = 5 comparisons) adult BPD patients versus otherwise similar healthy controls. Results: In 6/8 studies of euthymic BPD patients and 5/5 studies of non‐euthymic BPD patients, neurocognitive impairment was significantly associated with impaired psychosocial functioning, even after adjusting for residual mood symptoms and relevant demographic and clinical variables. Cognitive status was consistently assessed with standardized, performance‐based neuropsychological tests, but functional status usually was based on subjective self‐appraisals. Approximately 55% of BPD patients were unemployed. Conclusions: Available studies are limited by subjective assessments of functional status rather than objective, performance‐based measures. Nevertheless, they support the hypothesis that enduring aspects of cognitive impairment found even in euthymic BPD patients are associated with inferior functioning. These findings encourage further studies with better assessment methods and greater rehabilitative efforts in BPD patients.     

CSF inflammatory markers and neurocognitive function after addition of maraviroc to monotherapy darunavir/ritonavir in stable HIV patients: the CINAMMON study

CINAMMON is a phase IV, open-label, single-arm, pilot study assessing maraviroc (MVC) in the central nervous system (CNS) when added to darunavir/ritonavir monotherapy (DRV/r) in virologically suppressed HIV-infected subjects. CCR5 tropic participants on DRV/r were recruited. Participants remained on DRV/r for 12 week (w) (control phase). MVC 150 mg qd was added w12–w36 (intervention phase). Lumbar puncture (LP) and neurocognitive function (Cogstate) examinations scheduled at baseline, w12 and w36; MRI before w12, again at w36. Primary endpoint was CSF inflammatory marker changes during intervention phase. Secondary endpoints included changes in NC function and MRI parameters. CSF/plasma DRV/r concentrations measured at w12 and w36, MVC at w36. Nineteen patients recruited, 15 completed (17M, 2F). Dropouts: headache (2), knee problem (could not attend, 1), personal reasons (1). Mean age (range) 45.4 years (27.2–65.1), 13/19 white, 10/19 MSM. No changes in selected CSF markers were seen w12–w36. Overall NC function did not improve w12–w36: total age adjusted z score improved by 0.27 (weighted paired t test; p?=?0.11); for executive function only, age adjusted z score improved by 0.54 (p?=?0.03). MRI brain parameters unchanged. DRV plasma:CSF concentration ratio unchanged between w12 (132) and w36 (112; p?=?0.577, Wilcoxon signed-rank). MVC plasma:CSF concentration ratio was 35 at w36. No changes in neuroinflammatory markers seen. In this small study, addition of 24w MVC 150 mg qd to stable DRV/r monotherapy showed possible improvement in executive function with no global NC effect. Learning effect cannot be excluded. This effect should be further evaluated.     

Neurocognitive impairment is worse in HIV/HCV-coinfected individuals with liver dysfunction

Journal of NeuroVirology - Infections with HIV and hepatitis C virus (HCV) can individually and jointly contribute to neurocognitive impairment (NCI). Rates of NCI in HIV/HCV-coinfected persons...     

Failure to clear intra-monocyte HIV infection linked to persistent neuropsychological testing impairment after first-line combined antiretroviral therapy

HIV-associated neurocognitive disorders (HAND) persist despite plasma HIV RNA suppression with antiretrovirals (ARV). Sequestered reservoirs in the central nervous system and circulating monocytes are theorized to contribute to persistent brain injury. We previously demonstrated that elevated intracellular HIV DNA from circulating cells was associated with HAND in ARV-treated and ARV-naive subjects. We now report that failure to suppress intra-monocyte HIV DNA 3.5 years after initiating ARV is linked to persistent HAND and subjects with dementia are least likely to suppress intra-monocyte HIV DNA at 3.5 years. These findings suggest that antiviral strategies may need to target intra-monocyte HIV DNA.     

Electroconvulsive therapy vs. paroxetine in treatment-resistant depression — a randomized study

Failure to respond to adequate pharmacological treatment for major depression is now the most common indication for the use of electroconvulsive therapy (ECT). The advantages of ECT with respect to both speed and quality of response are clinically important issues, but surprisingly few studies have examined the efficacy of ECT in relation to newer antidepressant agents such as selective serotonin reuptake inhibitors (SSRIs). A total of 39 subjects with major depression and with at least two failed antidepressant trials (mean 4.9 trials) were randomized to either paroxetine treatment (n= 18) or right unilateral (RUL) ECT (n=21). Up to the end of the study treatment we found a reduction in the HAMD score of 59% for the ECT group and of 29% for the paroxetine group (P<0.001 paired t-test). In the ECT group, 71% of subjects fulfilled the response criteria (at least a 50% decrease in total HAMD score). The present study found ECT to be superior to paroxetine in medication-resistant major depression, in terms of both degree and speed of response.     

Neuropsychological impairment in deficit vs. non-deficit schizophrenia

This study aimed to assess the severity and specificity of cognitive impairments that affect individuals with deficit versus non-deficit schizophrenia. We compared 26 patients with the deficit subtype of schizophrenia (SZ-D) and 79 with non-deficit schizophrenia (SZ-ND) to 316 healthy adults (NC). All study participants completed a battery with 19 individual cognitive measures. After adjusting their test performance for age, sex, race, education and estimated premorbid IQ, we derived regression-based T-scores for each measure and the six derived cognitive domains including attention, psychomotor speed, executive function, verbal fluency, visual memory, and verbal memory. Multivariate analyses of variance revealed significant group effects for every individual measure and domain of cognitive functioning (all ps<0.001). Post hoc comparisons revealed that patients with SZ-D performed significantly worse than NCs in every cognitive domain. They also produced lower scores than the SZ-ND group in every domain, but only the difference for verbal fluency reached statistical significance. The correlations of the effect sizes shown by the SZ-D and SZ-ND patients were of intermediate magnitude for the individual tests (r=0.56, p<0.01) and higher, but not statistically significant for the cognitive domains (r=0.79, p=0.06). Patients with SZ-D demonstrate cognitive deficits that are both common and distinct from those shown by patients with SZ-ND. Their impairment of verbal fluency is consistent with the observation that poverty of speech is a clinically significant feature of patients with SZ-D.     

Double-blind, randomized, controlled trial of rasagiline as monotherapy in early Parkinson's disease patients.

Rasagiline (N-propargyl-1(R)-aminoindan) mesylate is a potent, selective, and irreversible monoamine oxidase-B inhibitor. This study was designed to evaluate the safety, tolerability, and preliminary efficacy of rasagiline monotherapy in early Parkinson's disease (PD) patients not receiving levodopa. The study was performed as a multicenter, parallel-group, double-blind, randomized, placebo-controlled, 10-week study. Fifty-six PD patients were randomly assigned to rasagiline mesylate 1, 2, or 4 mg once daily, or placebo. A 3-week dose-escalation period was followed by a 7-week maintenance phase. At week 10, the mean (+/-SE) changes from baseline in total Unified Parkinson's Disease Rating Scale (UPDRS) score were -1.8 (+/-1.3), -3.6 (+/-1.7), -3.6 (+/-1.2), and -0.5 (+/-0.8) in the rasagiline 1, 2, and 4 mg/day and placebo groups, respectively. Analysis of responders showed that 28% of patients (12 of 43) receiving rasagiline had an improvement in total UPDRS score of greater than 30%, compared with none of the patients receiving placebo (P < 0.05, Fisher's exact test). The frequency and types of adverse events reported by rasagiline-treated and placebo-treated patients were similar. These results suggest that rasagiline monotherapy is well tolerated and efficacious in early PD.     

Topiramate and phenytoin pharmacokinetics during repetitive monotherapy and combination therapy to epileptic patients

PURPOSE: To evaluate the potential pharmacokinetic interactions between topiramate (TPM) and phenytoin (PHT) in patients with epilepsy by studying their pharmacokinetics (PK) after monotherapy and concomitant TPM/PHT treatment. METHODS: Twelve patients with epilepsy stabilized on PHT monotherapy were enrolled in this study, with 10 and seven patients completing the phases with 400 and 800 mg TPM daily doses, respectively. TPM was added at escalating doses, and after stabilization at the highest tolerated TPM dose, PHT doses were tapered. Serial blood and urine samples were collected for PK analysis during the monotherapy phase or the lowest PHT dose after taper and the concomitant TPM/PHT phase. Potential metabolic interaction between PHT and TPM also was studied in vitro in human liver microsomal preparations. RESULTS: In nine of the 12 patients, PHT plasma concentrations remained stable, with a mean (+/-SD) area under the curve (AUC) ratio (combination therapy/monotherapy) of 1.13 +/- 0.17 (range, 0.89-1.23). Three patients had AUC ratios of 1.25, 1.39, and 1.55, respectively, and with the addition of TPM (800, 400, and 400 mg daily, respectively), their peak PHT plasma concentrations increased from 15 to 21 mg/L, 28 to 36 mg/L, and 27 to 41 mg/L, respectively. Human liver microsomal studies with S-mephenytoin showed that TPM partially inhibited CYP2C19 at very high concentrations of 300 microM (11% inhibition) and 900 microM (29% inhibition). Such high plasma concentrations would correspond to doses in humans that are 5 to 15 times higher than the recommended dose (200-400 mg). TPM clearance was approximately twofold higher during concomitant TPM/PHT therapy CONCLUSIONS: This study provides evidence that the addition of TPM to PHT generally does not cause clinically significant PK interaction. PHT induces the metabolism of TPM, causing increased TPM clearance, which may require TPM dose adjustments when PHT therapy is added or is discontinued. TPM may affect PHT concentrations in a few patients because of inhibition by TPM of the CYP2C19-mediated minor metabolic pathway of PHT.     

Neurocognitive impairment in patients with co-occurring bipolar disorder and alcohol dependence upon discharge from inpatient care

The current study explored the neurocognitive functioning of patients with co-occurring bipolar disorder and alcohol dependence upon discharge from inpatient care. The study compared scores of neuropsychological tests among three groups of bipolar I inpatients without a history of neurological injury or illness: 1) patients meeting DSM-IV diagnostic criteria for alcohol dependence in the past 6 months (n=13), 2) patients diagnosed with alcohol dependence in full remission (n=9), and 3) patients without a history of a substance use disorder (SUD; n=41). Analyses indicated that patients with co-occurring alcohol dependence exhibited more severe impairment on tests of executive functioning (i.e. Stroop Color-Word Interference Test, Wisconsin Card Sorting Test) than patients without SUD. In addition, the group meeting diagnostic criteria for alcohol dependence in the past 6 months exhibited greater decrements in verbal (California Verbal Learning Test--II) and visual (Rey Complex Figure Test) memory. Analysis further indicated that patients in full SUD remission scored lower on measures of fluid intelligence (Wechsler Abbreviated Scale of Intelligence--Performance IQ). Consistent with previous reports, in the current sample, co-occurring alcohol dependence predicted higher rates of disability status. It is possible that cognitive deficits of greater severity in dually diagnosed patients contribute to this unfavorable outcome. Recognizing the extent of cognitive impairment in dually diagnosed patients may facilitate the effort to ameliorate their condition.     

Early add‐on treatment vs alternative monotherapy in patients with partial epilepsy

Aim. The aim of this study was to evaluate the impact of two different therapeutic strategies in patients with partial seizures who were intractable to the first prescribed antiepileptic drug (AED); alternative monotherapy vs early add‐on treatment. Methods. We conducted an open, cluster‐randomised, prospective, controlled trial in patients with persistent partial seizures, despite treatment with one AED, who were never administered any other AEDs. Neurologists were randomised to two strategies: in group A, an alternative monotherapy with a second AED was employed; in group B, add‐on treatment with a second AED was employed. The primary outcome was the percentage of seizure‐free patients during a two‐month period after six months of treatment. The secondary outcomes were: (i) the percentage of patients achieving a 50% reduction in the number of seizures at six months; (ii) the quality of life based on the Quality Of Life In Epilepsy scale; and (iii) tolerability. Results. A total of 143 neurologists were included and randomised, and 264 patients were evaluated. At six months, the primary outcome was 51% in group A and 45% in group B (p=0.34). The percentage of patients achieving a 50% reduction in the number of seizures at six months was 76% in group A and 84% in group B (p=0.53). The quality of life and the tolerability did not significantly differ between the two groups. Conclusions. Alternative monotherapy or early treatment initiation with another AED drug resulted in similar efficacy, and the side effects associated with monotherapy and combined therapies were similar, which suggests that individual susceptibility is more important than the number and burden of AEDs used.     

Venlafaxine monotherapy in bipolar type II depressed patients unresponsive to prior lithium monotherapy

Amsterdam JD, Wang G, Shults J. Venlafaxine monotherapy in bipolar type II depressed patients unresponsive to prior lithium monotherapy. Objective: We examine the safety and efficacy of venlafaxine monotherapy in bipolar type II (BP II) patients with major depressive episode (MDE) who were unresponsive to prior lithium monotherapy. We hypothesized that venlafaxine would be superior to lithium with a low hypomanic conversion rate. Method: Seventeen patients who were unresponsive to prior lithium monotherapy were crossed to venlafaxine monotherapy for 12 weeks. The primary outcome was within‐subject change in total Hamilton Depression Rating (HAM‐D) score over time. Secondary outcomes included the change in Young Mania Rating (YMRS) and clinical global impressions severity (CGI/S) and change (CGI/C) scores. Results: Venlafaxine produced significantly greater reductions in HAM‐D (P < 0.0005), CGI/S (P < 0.0005), and CGI/C (P < 0.0005) scores vs. prior lithium. There was no difference in mean YMRS scores between treatment conditions (P = 0.179). Conclusion: Venlafaxine monotherapy may be a safe and effective monotherapy of BP II MDE with a low hypomanic conversion rate in lithium non‐responders.     

Sleep in schizophrenic patients on and off haloperidol therapy. Clinically stable vs relapsed patients.

We examined the state-dependent contribution of neuroleptic withdrawal and psychotic relapse in influencing sleep measures. Eighteen clinically stable male schizophrenic patients taking haloperidol were studied with 3 nights of polysomnography for baseline measures and again after neuroleptic withdrawal. Sleep measures were also obtained at the point of relapse (n = 9) or after a 6-week drug-free period if the patient remained clinically stable (n = 9). Neuroleptic withdrawal led to a global deterioration of rapid eye movement and non-rapid eye movement sleep and a reduction of rapid eye movement latency in both groups. Relapsers differed from nonrelapsers in that they had a larger decrease in total sleep time, sleep efficiency, total non-rapid eye movement sleep, and stage 2 sleep. The level of psychosis was inversely correlated with sleep efficiency, total sleep time, and stage 4 sleep in the drug-free patients. Our data suggest that clinical state needs to be identified in sleep studies of drug-free patients.