Real-world effectiveness of vortioxetine in outpatients with major depressive disorder: functioning and dose effects.

BACKGROUND: Functional recovery is an important treatment goal in major depressive disorder (MDD). This study assessed the real-world effectiveness of vortioxetine in patients with MDD, with particular focus on functioning; dose-response was also assessed. METHODS: This was a non-interventional, prospective, multicenter study conducted in Greece. Adult outpatients with MDD (n = 336) initiating vortioxetine (5-20 mg/day flexible dosing) as treatment for a current major depressive episode were followed for 3 months. Analyses were stratified according to vortioxetine dosage at 3 months: 5-10 mg/day versus 15-20 mg/day. Functioning was assessed using the Sheehan Disability Scale (SDS). RESULTS: Mean ± standard error SDS total score decreased (improved) from 18.7 ± 0.3 at baseline to 12.9 ± 0.3 after 1 month of vortioxetine treatment and 7.8 ± 0.4 after 3 months (p < 0.001 vs. baseline for all comparisons). Functional recovery (SDS score ≤ 6) was achieved in 14.6% of patients after 1 month of treatment and 48.4% of patients after 3 months. Improvement from baseline in SDS total and domain scores at 3 months was more pronounced in patients receiving vortioxetine 15-20 mg/day than in those receiving vortioxetine 5-10 mg/day. The mean ± standard error change in SDS total score from baseline was 9.2 ± 0.8 in the 5-10 mg/day group and 12.1 ± 0.4 in the 15-20 mg/day group (p < 0.001). Limitations of this study include its non-interventional study design and lack of a control group or active comparator. CONCLUSIONS: Statistically significant and clinically relevant improvements in functioning were seen in patients with MDD treated with vortioxetine in a real-world setting. Higher doses of vortioxetine were associated with significantly greater improvements in functioning.

Obsessive compulsive symptoms are associated with better functioning independently of cognition in schizophrenia.

OBJECTIVES: Although the relationship of obsessive-compulsive symptoms (OCSs) with both cognition and social functioning (SF) has already been the focus of research in schizophrenia, the moderation of the relationship of OCSs with SF by cognition has not been explored to date. We investigated the association of OCSs with SF and its interaction with cognition in schizophrenia. METHODS: We recruited 110 schizophrenia patients and assessed OCSs (Yale-Brown Scale), schizophrenia symptoms (Positive and Negative Syndrome Scale), SF (Strauss-Carpenter Scale) and cognition. 51 patients had one obsessive-compulsive symptom or more, whereas 59 patients had no obsessive compulsive-symptom, according to the Yale-Brown Scale. We mainly investigated: a) the predictive effect of OCSs on SF, controlling for cognition, illness duration and symptoms' severity and b) the moderating effect of cognition on the OCSs-SF relationship. RESULTS: The mean score of OCSs for patients having at least one symptom was 13.43 (SD=8.32). Higher OCSs predicted increased SF (B=0.98, t=2.41, df=88, p=0.018). This relationship was driven by the association of compulsions with job functioning (B=0.074, t=2.029, df=88, p=0.046). Patients without OCSs demonstrated worse functioning compared with those having at least one obsessive-compulsive symptom (mean difference=2.496, t=3.732, df=88, p<0.001). We failed to find evidence that cognition moderates the effect of OCSs on SF. CONCLUSION: There may be a beneficial effect of OCSs on SF in patients with schizophrenia which is independent of their cognitive performance.

Episodic Visual Learning/Memory and Attentional Flexibility in Patients With Major Depressive Disorder After Clinically Effective Electroconvulsive Therapy.

OBJECTIVES: This study is a follow-up of a previous one reporting that the neuropsychological profile of pharmacoresistant patients with major depressive disorder referred for electroconvulsive therapy (ECT, ECT group) contrasted with that of their pharmacorespondent counterparts (NECT group). The NECT group exhibited severe visuospatial memory and minor executive deficits; the ECT group presented the reverse pattern. In that same ECT group, the current follow-up study examined the effects of clinically effective ECT on both cognitive domains 2 months later. METHODS: Fifteen ECT patients were administered Hamilton Depression (HAMD-24), Hamilton Anxiety (HAMA), Mini-Mental State Examination Scales and 5 tests of Cambridge Neuropsychological Test Automated Battery at intake (pre-ECT), end of ECT course (post-ECT), and 2 months thereafter (follow-up). RESULTS: Electroconvulsive therapy was effective in relieving clinical depression. After a post-ECT decline, the patients exhibited significant improvement in both Cambridge Neuropsychological Test Automated Battery, paired associate learning, and Stockings of Cambridge. By contrast, their major pre-ECT deficit in intra/extradimensional set shifting remained virtually unaffected. CONCLUSIONS: Our findings suggest that attentional flexibility deficits may constitute a neuropsychological trait-like feature of pharmacoresistant, ECT-referred major depressive disorder patients. However, this deficit does not seem generalized, given patient improvement in episodic visual learning/memory and some indication of improvement in spatial planning after ECT.

A systematic review of the evidence on the treatment of rapid cycling bipolar disorder.

OBJECTIVE: Rapid cycling is associated with longer illness duration and greater illness severity in bipolar disorder. The aim of the present study was to review the existing published randomized trials investigating the effect of treatment on patients with rapid cycling bipolar disorder. METHODS: A MEDLINE search was conducted using combinations of the following key words: bipolar and rapid or rapid-cycling or rapid cycling and randomized. The search was conducted through July 16, 2011, and no conference proceedings were included. RESULTS: The search returned 206 papers and ultimately 25 papers were selected for review. Only six randomized, controlled trials specifically designed to study a rapid cycling population were found. Most data were derived from post hoc analyses of trials that had included rapid cyclers. The literature suggested that: (i) rapid cycling patients perform worse in the follow-up period; (ii) lithium and anticonvulsants have comparable efficacies; (iii) there is inconclusive evidence on the comparative acute or prophylactic efficacy of the combination of anticonvulsants versus anticonvulsant monotherapy; (iv) aripiprazole, olanzapine, and quetiapine are effective against acute bipolar episodes; (v) olanzapine and quetiapine appear to be equally effective to anticonvulsants during acute treatment; (vi) aripiprazole and olanzapine appear promising for the maintenance of response of rapid cyclers; and (vii) there might be an association between antidepressant use and the presence of rapid cycling. CONCLUSION: The literature examining the pharmacological treatment of rapid cycling is still sparse and therefore there is no clear consensus with respect to its optimal pharmacological management. Clinical trials specifically studying rapid cycling are needed in order to unravel the appropriate management of rapid cycling bipolar disorder.

Treatment of mixed bipolar states.

Mixed bipolar states are associated with more severe symptoms and outcome. Our aim is to review the literature examining their treatment. We conducted a literature search of randomized clinical studies and post-hoc analyses on mixed bipolar states' treatment. Remarkably, there is only one double-blind, placebo-controlled trial, recruiting a mixed episode cohort, and one post-hoc analysis of this trial, while most data come from post-hoc analyses of trials including both manic and mixed patients. Improvement of manic symptoms in mixed episodes is similar to that seen in pure manic episodes and independent of baseline depressive features. The magnitude of response to manic symptoms' treatment probably exceeds that of depressive symptoms, which appear to resolve later. Valproate and carbamazepine are effective in acute mixed episodes, but the efficacy of lithium appears questionable. Atypical antipsychotic monotherapy improves both manic and depressive symptoms. Mood-stabilizer-atypical antipsychotic combination increases this effect. Atypical antipsychotic-antidepressant combination against acute mixed depression does not increase the risk for mania, although its superior efficacy vs. atypical antipsychotic monotherapy cannot be supported by current data. As regards prophylaxis, atypical antipsychotic monotherapy is associated with a lower incidence of and a longer time to relapse of any kind. The augmentation of lithium or divalproex with atypical antipsychotics increases prophylactic efficacy. Lithium or divalproex monotherapy have not been associated with significant prophylactic benefits following mixed mania. New, randomized prospective trials involving homogeneous cohorts of mixed bipolar patients are needed in order to delineate the appropriate pharmacological treatment of mixed states.

Dopamine in anorexia nervosa: a systematic review.

Anorexia nervosa (AN) is a chronic relapsing psychiatric disorder with a largely unknown pathophysiology. Dopamine has been implicated in the pathophysiology of the disorder by preclinical and clinical evidence. Preclinical studies have examined two main characteristics of AN: reduction in food intake (diet restriction) and hyperactivity. Diet restriction has been associated with reduced dopamine levels in the hypothalamus, hippocampus, and the dorsal striatum. Animal hyperactivity following diet restriction has been linked to increased dopamine in the hypothalamus. Increased dopamine in the nucleus accumbens was associated with food administration, but not food expectation. Tyrosine and dopaminergic antagonists normalized anorexia-like behaviors in animal models of AN, but did not restore body weight. Clinical studies on the etiology of AN have produced contradictory findings. Cerebrospinal fluid concentrations of dopamine and its metabolites have been reported to be decreased or normal under conditions of low weight, whereas they tended to normalize when the weight was restored. Plasma and urinary levels of dopamine and its metabolites have been found to be normal, increased, and decreased. Neuroendocrine studies suggest that dopaminergic neurotransmission is increased in AN. However, recent neuroimaging studies lend support to the increase in binding of dopaminergic receptors in the striatum, which favors the opposite theory that intrasynaptic dopamine is indeed decreased. Genetic studies implicate dopamine D2 receptors, the dopamine transporter, and the enzyme COMT. There are promising results with respect to the use of atypical antipsychotics against symptoms of AN beyond weight gain, but further trials are required.

Enhancing effects of lithium on memory are not by-products of learning or attentional deficits.

We recently reported that chronic lithium (LiCl), at therapeutic plasma levels, enhanced spatial working memory and retention of an aversive contingency. Here we examine the possibility that these effects be secondary to LiCl effects on the ability to ignore irrelevant stimuli or on fear conditioning. In Experiment 1, rats subjected to >30 daily intraperitoneal injections of LiCl (2mmol/kg) or saline underwent conditioned emotional response training (CER: 2 CS pairings with 1-s, 1-mA shock) after 40 pre-exposures either to the CS (latent inhibition-LiCl/latent inhibition-saline, n=8) or to another stimulus (control-LiCl/control-saline, n=8). In Experiment 2, eight LiCl and eight saline animals were trained in on-the-baseline (VI-60s) CER (1-s, 0.15-mA shock in CS-signalled periods) in the Skinner box. In Experiment 1, LiCl animals showed normal latent inhibition. In both experiments, their fear conditioning was unimpaired. Therefore, the previously reported memory improvement under chronic lithium cannot be attributed to changes in the ability to ignore irrelevant stimuli or in fear conditioning.

Enhancing effects of chronic lithium on memory in the rat.

BACKGROUND: In spite of recent enrichment of neurochemical and behavioural data establishing a neuroprotective role for lithium, its primary effects on cognitive functioning remain ambiguous. This study examines chronic lithium effects on spatial working memory and long-term retention. METHODS: In three discrete experiments, rats subjected to 30 daily intraperitoneal injections (2mmol/kg) of lithium (lithium groups: serum lithium=0.5+/-0.4mEq/l, 12h post-injection) or saline (controls) were trained in 0-s delay T-maze alternation and then tested in 30-, 45- and 60-s delay alternation (Experiments 1, 2, 3, respectively). Animals from Experiment 1 were further tested in one-trial step-through passive avoidance under mild shock parameters (0.5mA, 1s). Retention was assessed 6h later. Daily lithium or saline injections continued throughout behavioural testing. RESULTS: Lithium animals were indistinguishable from controls during 0-delay alternation baseline (Experiments 1-3, accuracy>88%) but showed significantly higher accuracy than controls at 30- and 45-s delays (93% versus 85% and 92% versus 82%, Experiments 1 and 2, respectively). At 60-s delay (Experiment 3) this beneficial effect of lithium was no longer apparent (lithium and control accuracy=78%). In Experiment 4, the shock used did not support 6-h passive avoidance retention in controls, whereas lithium animals showed significant step-through latency increases. CONCLUSIONS: Chronic lithium enhanced spatial working memory and promoted long-term retention of a weak aversive contingency. The results suggest that lithium may have potential as a cognitive enhancer.

Plasma homocysteine, folate and B12 in chronic schizophrenia.

Elevated plasma levels of the amino acid homocysteine have been associated with schizophrenia, particularly in young male patients. Among other factors, low folate and vitamin B12 levels have been implicated in the increase in homocysteine. In order to investigate this association, we determined plasma homocysteine, folate and B12 levels in 97 (67 males and 30 females) inpatients with chronic schizophrenia and 103 (46 males and 57 females) controls. Patients and controls did not differ in folate or B12 levels, after adjusting for age. Patients with schizophrenia had higher plasma homocysteine than controls (mean=15.42 micromol/l in cases versus 11.54 micromol/l in controls: F(1,195)=17.978; p<0.001). This difference persisted after controlling for folate and B12 concentrations. Both male and female patients had increased plasma homocysteine compared to controls [(males: mean=16.61 micromol/l in cases versus mean=13.72 in controls: F(1,110)=5.54; p=0.020) (females: mean=12.78 micromol/l in cases versus mean=9.79 micromol/l in controls: F(1,84)=13.54; p<0.001)]. When dividing our sample into two age groups (age < and > or =50 years), both young and older females and younger males with schizophrenia had increased plasma homocysteine compared to controls. We therefore suggest that homocysteinemia is a general risk factor for schizophrenia. We further suggest that it is not limited to young male patients and is not necessarily associated with low folate or B12 levels.

COMT and MTHFR polymorphisms interaction on cognition in schizophrenia: an exploratory study.

The investigation of the catechol-O-methyltransferase (COMT-[rs4680]) and methylenetetrahydrofolate reductase (MTHFR-[rs1801133]) polymorphisms' interaction might shed light into the pathogenetic mechanisms of the cognitive dysfunction in schizophrenia. In an exploratory study, we hypothesized that the MTHFR 677T allele which has been related to a hypoactive MTHFR enzyme would augment the unfavorable effects of COMT Val158 homozygosity which has been associated with COMT enzyme hyperfunction. 90 schizophrenia patients and 55 healthy volunteers were assessed on psychomotor speed, pattern and spatial recognition memory (SRM), spatial working memory (SWM), attentional flexibility and planning (Stockings of Cambridge-SOC). IQ scores in a random subgroup of patients were also measured. A significant COMT×MTHFR interaction on SWM (p=0.048) and planning (p=0.026) was revealed in both groups. Among COMT-Val/Val participants, MTHFR-C/C made more SWM errors (p=0.033) and solved fewer SOC problems (p=0.025) than MTHFR-T carriers. In patients, there was a significant COMT×MTHFR interaction on full scale IQ (p=0.035): among COMT-Met carriers, MTHFR-T carriers performed significantly worse than MTHFR-C/C (p=0.021), which was driven by a COMT×MTHFR interaction involving performance IQ (p=0.047). In conclusion, COMT and MTHFR polymorphisms interacted on cognition, suggesting that the MTHFR enzyme activity might moderate the effects of the COMT enzyme. In contrast to our initial hypothesis, the MTHFR T-allele attenuated the cognitive effects of COMT Val homozygosity. In this preliminary study, we propose that dopaminergic and intracellular methylation mechanisms could interact on cognitive deficits in schizophrenia.

Developing models of how cognitive improvements change functioning: mediation, moderation and moderated mediation.

BACKGROUND: Cognitive remediation (CRT) affects functioning but the extent and type of cognitive improvements necessary are unknown. AIM: To develop and test models of how cognitive improvement transfers to work behaviour using the data from a current service. METHOD: Participants (N49) with a support worker and a paid or voluntary job were offered CRT in a Phase 2 single group design with three assessments: baseline, post therapy and follow-up. Working memory, cognitive flexibility, planning and work outcomes were assessed. RESULTS: Three models were tested (mediation - cognitive improvements drive functioning improvement; moderation - post treatment cognitive level affects the impact of CRT on functioning; moderated mediation - cognition drives functioning improvements only after a certain level is achieved). There was evidence of mediation (planning improvement associated with improved work quality). There was no evidence that cognitive flexibility (total Wisconsin Card Sorting Test errors) and working memory (Wechsler Adult Intelligence Scale III digit span) mediated work functioning despite significant effects. There was some evidence of moderated mediation for planning improvement if participants had poorer memory and/or made fewer WCST errors. The total CRT effect on work quality was d=0.55, but the indirect (planning-mediated CRT effect) was d=0.082 CONCLUSION: Planning improvements led to better work quality but only accounted for a small proportion of the total effect on work outcome. Other specific and non-specific effects of CRT and the work programme are likely to account for some of the remaining effect. This is the first time complex models have been tested and future Phase 3 studies need to further test mediation and moderated mediation models.

Doubtful association of antipsychotic polypharmacy and high dosage with cognition in chronic schizophrenia.

Despite consistent recommendations for antipsychotic monotherapy, antipsychotic polypharmacy (the use of two or more antipsychotic agents) and the administration of excessive doses (higher than 1000 mgr/day of chloropromazine equivalents) is a common practice in schizophrenia. The therapeutic and adverse effects of this practice are poorly studied, in particular with regards to the cognitive symptoms of the disease. In this cross-sectional study we investigated the cognitive effects of antipsychotic polypharmacy and excessive doses in 53 patients with chronic schizophrenia using non-verbal cognitive tasks involving speed of movement, memory and executive functions. No significant difference in performance scores was found between the groups under polypharmacy and monotherapy, or the groups receiving either excessive or normal doses of antipsychotics. Since these groups did not also differ in demographic, clinical, other pharmacologic parameters, in the relative anticholinergic potency of antipsychotics, or in intelligence scores, we raise doubts about the association of polypharmacy and excessive doses with non-verbal cognitive performance in chronic schizophrenia.