Карипразин

Forest Laboratories Inc. and Gedeon Richter announced in September the preliminary results from an eight-week phase 2 clinical trial of the antipsychotic agent cariprazine for the treatment of bipolar depression.

A total of 233 patients were randomized to enter one of two active (low dose or high dose) treatment arms or receive a placebo. The primary endpoint was the Montgomery-Asberg Depression Rating Scale (MADRS) score. Although the overall difference observed between the drugtreated and placebo-treated groups was not statistically significant, over the course of the trial there was evidence of a clinically relevant treatment effect in the high-dose arm of the study compared with placebo. Approximately 9 percent of patients discontinued the study early due to adverse events in the high-dose study arm compared with 3 percent in the placebo arm. The companies are considering conducting an additional phase 2 dose-response trial examining a wider range of doses.

Med Check

A large case-control study based on Danish birth and psychiatric records has added more evidence to back the theory that an association exists between mothers' infection with herpes simplex virus 2 (HSV-2) and the risk of schizophrenia in their children.
Data Show Reason for Concern if Mothers Carry Herpes Virus

Ботокс против головной боли

Botox Approved for Headache Prophylaxis in Chronic Migraine

Серотониновая система и шизофрения

Specifically, the study revealed that serotonin signals through the serotonin 2A receptor by recruiting a regulatory protein called β-arrestin2. The actions of serotonin at the receptor were found to be far different than those produced by hallucinogenic N-methyltryptamines, a class of naturally occurring substances found in several plants and in minute amounts in the human body.

These substances are also found in the abused drug DMT.

The N-methyltryptamines activate the serotonin 2A receptor independently of β-arrestin2, researchers said.

The serotonin and the N-methyltryptamines both produce what is known as a head twitch response in animal models. Researchers determined that any interruption in the exclusive serotonin pathway prevents that response to serotonin but has no effect on N-methyltryptamine-induced head twitches.

This difference in response points to a distinct divergence in the signaling pathways utilized by these two neurotransmitters.

“Despite the fact that they activate the same receptor, serotonin leads to the assembly of a number of proteins associated with the receptor that the metabolites of serotonin do not produce,” Bohn said. “But whether the lack of this complex formation is why compounds like DMT lead to hallucinations is not clear.”

Serotonin Discovery Points to New Therapies for Schizophrenia, Depression

пролонгированная форма рисперидона vs кветиапин

Chronic management of schizophrenia and schizoaffective disorders is frequently complicated by symptomatic relapse. An open-label, randomized, active-controlled, 2-year trial evaluated 710 patients with schizophrenia or related disorders who were switched from stable treatment with oral risperidone, olanzapine, or conventional neuroleptics to risperidone long-acting injectable (RLAI) or oral quetiapine. Primary effectiveness evaluation was time-to-relapse. Safety evaluations included adverse events (AEs) reported for the duration of the study, Extrapyramidal Symptom Rating Scale (ESRS), clinical laboratory tests, and vital signs. A total of 666 patients (n=329 RLAI, n=337 quetiapine) were evaluable for effectiveness measures. Baseline demographics were similar between treatment groups. Kaplan–Meier estimate of time-to-relapse was significantly longer with RLAI (p < 0.0001). Relapse occurred in 16.5% of patients with RLAI and 31.3% with quetiapine. RLAI and quetiapine were both safe and well tolerated. Weight gain affected 7% of patients with RLAI and 6% with quetiapine, with mean end point increases of 1.25±6.61 and 0±6.55 kg, respectively. There were no significant between-group differences in weight gain. ESRS total scores decreased similarly after randomization to either RLAI or quetiapine. Extrapyramidal AEs occurred in 10% of patients with RLAI and 6% with quetiapine. Treatment-emergent potentially prolactin-related AEs were reported in 15 (5%) patients with RLAI and 5 (2%) patients with quetiapine; hyperprolactinemia was reported in 43 (13.1%) patients with RLAI and 5 (1.5%) patients with quetiapine. Somnolence occurred in 2% of patients with RLAI and 11% with quetiapine. To our knowledge, this is the first report of a randomized clinical trial directly comparing relapse prevention with a second-generation long-acting injectable antipsychotic and oral therapy. Time-to-relapse in stable patients with schizophrenia or schizoaffective disorder was significantly longer in patients randomized to RLAI compared with those randomized to oral quetiapine. Both antipsychotics were generally well tolerated.

Relapse Prevention in Schizophrenia and Schizoaffective Disorder with Risperidone Long-Acting Injectable vs Quetiapine: Results of a Long-Term, Open-Label, Randomized Clinical Trial

Болезнь Хантингтона и каннабиноидная система

The biology of Huntington's is only partially understood. It's caused by mutations in the huntingtin gene, which lead to the build-up of damaging proteins in brain cells, especially in the striatum. But exactly how this produces symptoms is unclear.

The two new papers show that cannabinoids play an important role. First off, Van Laere et al used PET imaging to measure levels of CB1 receptors in the brain of patients in various stages of Huntington's. CB1 is the main cannabinoid receptor in the brain; it responds to natural endocannabinoid neurotransmitters, and also to THC, the active ingredient in marijuana.

They found serious reductions in all areas of the brain compared to healthy people, and interestingly, the loss of CB1 receptors occurred early in the course of the disease:

If so, drugs that activate CB1 - like THC - might be able to slow down the progression of the disease, and indeed it did: Huntington's mice given THC injections stayed healthier for longer, although they eventually succumbed to the disease. Further experiments showed that mutant huntingtin switches off expression of the CB1 receptor gene, explaining the loss of CB1.

Cannabinoids in Huntington's Disease

Поддерживающая терапия в комбинации с психосоциальным вмешательством

Xiaofeng Guo, M.D., and Jinguo Zhai, M.D., and colleagues evaluated this combination of therapies in 1,268 patients with early-stage schizophrenia treated from 2005 to 2007. A total of 633 were randomly assigned to receive schizophrenia drugs plus a psychosocial intervention involving 48 one-hour group sessions.

The psychosocial intervention included four evidence-based practices: psychoeducation (instruction for families and caregivers about mental illness), family intervention (teaching coping and socializing skills), skills training and cognitive behavioral therapy.

The other 635 patients received medication alone.

Rates of treatment discontinuation or change were 32.8 percent in the combined treatment group, compared with 46.8 percent in the medication-only group. The risk of relapse was lower among patients in the combination group, occurring in 14.6 percent of patients in that group and 22.5 percent of patients in the medication-only group.

The combined treatment group also exhibited greater improvements in insight, social functioning, activities of daily living and on four domains of quality of life, and a significantly higher proportion of them were employed or received education. There were no significant differences in either frequency or type of adverse events between the groups.

Early Meds, Counseling Aid Schizophrenia

Кетамин

Ketamine and the next generation of antidepressants with a rapid onset of action

Антидепрессивные свойства наркоза кетамином при ЭСТ

Background: Reports of the superiority of the antidepressant effect of ketamine during the conduct of electroconvulsive therapy (ECT) have been limited. We conducted an open-label trial of ketamine to determine whether ketamine as the anesthetic during ECT would provide a greater antidepressant effect than the antidepressant effect obtained with propofol.

Methods: Between April 2006 and April 2007, 31 inpatients with treatment-resistant depression gave written consent for ECT and to participate in this study. An anesthesiologist who was unaware of the mental symptoms of the subjects assigned them to receive propofol or ketamine anesthetic according to the preferences of the patients, and the patients underwent 8 ECT sessions for 4 weeks. The Hamilton Depression Rating Scale (HDRS) was valuated before ECT and after the completion of the second, fourth, sixth, and eighth ECT sessions.

Results: The HDRS scores improved earlier in the ketamine group, with decreases in HDRS scores that were significantly greater in the ketamine group.

Conclusions: The results suggested that it is possible to improve symptoms of depression earlier by using ketamine anesthesia.

Rapid Antidepressant Effect of Ketamine Anesthesia During Electroconvulsive Therapy of Treatment-Resistant Depression: Comparing Ketamine and Propofol Anesthesia

Индивидуальное дозирование антипсихотиков

Paralleling the preclinical evidence, are there clinical data to suggest antipsychotic tolerance with continuous treatment? Work with first-episode schizophrenia has confirmed three findings related to antipsychotic treatment: (a) response to lower doses; (b) sensitivity to side effects; and (c) comparatively high response rate.[2,21] In contrast, the more chronic stages of schizophrenia are associated with higher antipsychotic doses and diminished clinical response,[22,23] keeping in mind that the chronic population is more heterogeneous and includes a larger proportion of refractory patients who may be receiving higher doses. While antipsychotic tolerance has been raised to account for a progressive decline in response,[24] nonadherence and/or illness progression are routinely endorsed as more viable explanations. That as many as 25% of individuals on depot antipsychotic therapy relapse[25] tempers the nonadherence argument, but at the same time does not rule out alternative explanations, eg, a discrete breakthrough episode vs tolerance per se. In contrast, the preclinical description of behavioral dopamine supersensitivity closely parallels the notion of "supersensitivity psychosis" and withdrawal dyskinesias reported clinically, linked to D2 upregulation as a result of ongoing antipsychotic exposure and observed in the face of drug discontinuation.[26–28]

Antipsychotic Dosing: How Much but Also How Often?

илоперидон

Fanapt: Deconstructing A Promotional Slide Deck

Лоразепамовый тест

Case material and retrospective studies support the use of both lorazepam and ECT in treating catatonia, but few prospective investigations exist and none employ quantitative monitoring of response. In this study we test their efficacy in an open, prospective protocol, and define a "lorazepam test' with predictive value for treatment. Twenty-eight patients with catatonia were treated systematically with parenteral and/or oral lorazepam for up to 5 days, and with ECT if lorazepam failed. Outcome was monitored quantitatively during the treatment phase with the Bush-Francis Catatonia Rating Scale (BFCRS). In 16 of 21 patients (76%) who received a complete trial of lorazepam (11 with initial intravenous challenge), catatonic signs resolved. A positive response to an initial parenteral challenge predicted final lorazepam response, as did length of catatonic symptoms prior to treatment. Neither demographic variables nor severity of catatonia predicted response to lorazepam. Four patients failing lorazepam responded promptly to ECT. It is concluded that lorazepam and ECT are effective treatments for catatonia. The rating scale has predictive value and displays sensitivity to change in clinical status.

Catatonia. II. Treatment with lorazepam and electroconvulsive therapy.

глутамат, допамин, шизофрения

The new findings unveil the fact that the high levels of dopamine found in people with psychotic symptoms actually occur as a result of changes in another brain chemical, glutamate.

Scientists discovered that brain cells that release glutamate in the hippocampus connect to the striatum and have a direct influence on the activity of dopamine-releasing cells.

Understanding Glutamate and Psychosis Offers Hope for Schizophrenia

шизовирус

TO THE EDITOR: The review article by Alan S. Brown, M.D., M.P.H., and Elena J. Derkits, B.A. (1), published in the March 2010 issue of the Journal, provided further evidence of a possible role of prenatal infection and maternal immune response in the etiology of schizophrenia. The authors also emphasized the importance of gene-environment interplay in neurodevelopmental disturbance leading to schizophrenia. However, the hypothesis of the single prenatal viral or immunological effect on the developing brain as a predisposing factor to schizophrenia cannot explain the variable long-term course of the illness.

A recent discovery of intracellular RNA-based gene inactivation machinery (short interfering RNA-induced silen cing complex) (2) suggested a mechanism of the natural defense against neurotropic viruses. RNA-induced silencing complex is the natural mechanism that prevents viruses from producing functional proteins. Such cellular defense can inhibit production of HIV and poliovirus (2–3). In some cases, the viral infection can be cleared; in other cases a virus can escape (4).

A hypothetical genetic variation in RNA-induced silencing complex may explain a variability of illness progression in schizophrenia: in some affected individuals, RNA-induced silencing complex controls an expression of schizovirus, while in others genetic polymorphism in RNA-induced silencing complex may lead to overstimulation of the cellular defense with temporary silencing of both schizoviral RNA and some host cell RNAs. Such dysregulation in the RNA-induced silencing complex response may increase dopamine production in affected neurons and lead to transient positive symptoms of schizophrenia, a clinical presentation consistent with "cycloid psychosis"(5). In some other patients, the underresponsive defense leads to a fast progression of neuronal damage and early development of deficit schizophrenia (6). In a majority of cases, overstimulation of RNA-induced silencing complex and eventual viral escape from the short interfering RNA inhibition is represented by often intermittent positive psychotic symptoms and progression of negative symptoms. Thus, suggested polymorphisms in the RNA-induced silencing complex genes may be related to genetic vulnerability to schizophrenia and a progression of the disease.

There is a lack of studies of RNA-induced silencing complex activity in humans. It is tempting, however, to suggest that a study of intracellular RNA defense may help to identify infectious agents, predisposing to schizophrenia, and that a development of short interfering RNA therapy may potentially cure some schizophrenia spectrum disorders.

Natural Antiviral Cellular Defense in Relation to Positive and Negative Symptoms of Schizophrenia?

Влияние гипертензии и индекса массы тела на когнитивные функции у больных шизофренией

Objective: In recent years there has been a greater appreciation of the elevated prevalence of cardiovascular risk factors in the schizophrenia population and the liability some treatments have for their development. These vascular risk factors are in turn important risk factors in the development of dementia and more subtle cognitive impairments. However, their impact on the cognitive functions of patients with schizophrenia remains underexplored. The authors investigated whether vascular risk factors influence the cognitive impairments of schizophrenia and whether their effects on cognition in schizophrenia are different from those observed in nonpsychiatric comparison subjects.

Method: The authors compared 100 patients with schizophrenia and 53 comparison subjects on cognitive test performance in 2x2 matrices composed of individual vascular risk factors and group (schizophrenia patients and comparison subjects).

Results: Hypertension exerted a significant negative effect on immediate delayed and recognition memory in both groups. Patients with schizophrenia and hypertension were adversely affected in recognition memory, whereas comparison subjects were not. A body mass index above 25 was associated with negative effects on delayed memory in both groups, although the association fell short of statistical significance.

Conclusions: Given that patients with schizophrenia have a higher prevalence of vascular risk factors than the general population and are undertreated for them, treatment of these risk factors may significantly improve cognitive outcome in schizophrenia.

The Effects of Hypertension and Body Mass Index on Cognition in Schizophrenia