Бисфенол А, эндокринная дисфункция и патогенез шизофрении

In recent years, numerous substances have been identified as so-called ‘‘endocrine disruptors’’ because exposure to them results in disruption of normal endocrine function with possible adverse health outcomes. The pathologic and behavioral abnormalities attributed to exposure to endocrine disruptors like bisphenol-A (BPA) have been studied in animals. Mental conditions ranging from cognitive impairment to autism have been linked to BPA exposure by more than one investigation. Concurrent with these developments in BPA research, schizophrenia research has continued to find evidence of possible endocrine or neuroendocrine involvement in the disease. Sufficient information now exists for a comparison of the neurotoxicological and behavioral pathology associated with exposure to BPA and other endocrine disruptors to the abnormalities observed in schizophrenia. This review summarizes these findings and proposes a theory of endocrine disruption, like that observed from BPA exposure, as a pathway of schizophrenia pathogenesis

BPA is a common ingredient of many plastic and resin products including food and drink containers, internal linings of food cans, and dental enamels. Also known as 2,2-bis(4-hydroxyphenyl) propane, BPA was invented in the 20th century and is manufactured by combining acetone and phenol. Emerging research indicates BPA is an estrogenic EDC that alters or interferes with normal endocrine development in various vertebrate and invertebrate species.

Effects of Bisphenol-A and Other Endocrine Disruptors Compared With Abnormalities of Schizophrenia: An Endocrine-Disruption Theory of Schizophrenia

Отсутствие эффективности в РКИ: зипрасидон при биполярной депрессии и ламотриджин при депрессии

Both bipolar depression and refractory unipolar depression are highly difficult to treat. Because few randomized controlled trials (RCTs) address these conditions, clinicians often try medications either from the same class as proven-effective agents or that are effective for related conditions. These two large, well-conducted RCTs remind us that such clinical strategies may be neither sound nor effective.

What Lamotrigine and Ziprasidone Are Not Good For 

Предиктор эффективности терапии эсциталопрамом

A recent Loyola study found that the blood test for a protein called vascular endothelial growth factor (VEGF) could help predict successful treatment. The researchers found that among depressed patients who had higher than normal levels of VEGF, more than 85 percent experienced partial or complete relief after taking escitalopram (Lexapro).

 Blood Test May Predict Antidepressant Effectiveness

Ранняя диагностика шизофрении

The study of the preventive potential of pre-onset or psychosis-risk intervention requires a common and reliable diagnosis of a risk syndrome with which to construct samples that we can track and treat and that can be replicated by independent clinical investigators. Yung and McGorry10 created the Comprehensive Assessment of At-Risk Mental States (CAARMS), a structured interview for diagnosing the psychosis-risk syndrome. Our team at Yale developed the Structured Interview for Psychosis-Risk Syndromes (SIPS); this tool is used to rate the severity/frequency of key prodromal symptoms and can be used to determine the presence or absence of several psychosis-risk syndromes. It can also be used to estimate the severity of these symptoms and syndromes, including the boundary of transition from the prodrome to psychosis, called “conversion.”
The interrater reliability of the SIPS is satisfactory. Moreover, the SIPS has proved to be a valid predictor of psychosis insofar as psychosis developed over the next 2.5 years in approximately 33% of a large sample of treatment-seeking persons meeting SIPS criteria. In essence, approximately 1 of 3 persons who met an SIPS prodromal diagnosis became psychotic, which amounts to a risk for psychosis that is more than 400 times the risk for the average individual. Some of the remaining two-thirds of the sample who met an SIPS prodromal diagnosis and in whom psychosis did not develop remained prodromally symptomatic and eventually met criteria for schizotypal personality disorder; in others, Axis I disorders, such as depression, developed; and in many, prodromal symptoms remitted with time without sequelae (J. Addington et al, unpublished data, 2010).

Treatment research in psychosis risk has just begun, and initial findings show promise. Combined antipsychotic (risperidone) and individual psychotherapy, antipsychotic therapy alone (olanzapine), and psychotherapy (cognitive-behavioral therapy) alone all show that onset of psychosis in prodromal samples can be delayed, but often with substantial adverse effects (eg, weight gain with olanzapine). Most recently, a randomized trial of v-3 fatty acids delayed onset of psychosis with virtually no adverse effects. In this study, the risk to benefit ratio is remarkably good, and if the results can be replicated, they should essentially eliminate concerns about untoward adverse effects in false-positive cases. Overall, however, many more treatment studies are needed before integrated guidelines can be formulated.

Early Antecedents and Detection of Schizophrenia

Оланзапин при резистентной мании

Objective

To examine the safety and efficacy of olanzapine monotherapy in treatment-resistant bipolar mania.
Method

Subjects (n = 18) who were acutely manic, did not respond to lithium, anticonvulsants, and neuroleptics, and/or had intolerable side effects to them in previous manic episodes were openly treated with olanzapine monotherapy (5–40 mg/d) for 12 weeks. The primary and secondary outcomes included the change from baseline to endpoint in Young Mania Rating Scale (YMRS) total score, Clinical Global Impression for Bipolar Disorder-Severity Scale (CGI-S), 17-item Hamilton Depression Rating Scale (HAM-D) and Positive and Negative Syndrome Scale (PANSS), and response and remission rate.
Results

The mean change in YMRS total score from baseline to endpoint was −23.3 ± 8.4 (p < 0.001). Fifteen (88.5%) patients achieved response (≥50% reduction in YMRS total score) and 14 (77.8%) achieved remission (YMRS total score ≤9 at endpoint). Mean changes from baseline to endpoint in CGI-S for mania and PANSS total score were significant, but not the changes in HAM-D total score or CGI-S for depression. The most common adverse events were sedation, self-reported weight gain, ≥7% increase in body weight, dizziness, and akathisia.

Safety and efficacy of olanzapine monotherapy in treatment-resistant bipolar mania: a 12-week open-label study

РКИ варениклина при шизофрении

The aim of this study is to examine the effects of treatment with varenicline, a partial agonist at the α4β2 and full agonist at the α7 nicotine acetylcholine receptor, on cognitive impairments in people with schizophrenia. In all, 120 clinically stable people with schizophrenia participated in randomized, double-blind, placebo-controlled 8-week trial. Antipsychotic and concomitant medication doses remained fixed throughout the study. Varenicline was titrated up to 1 mg twice daily for weeks 2–8. Neuropsychological, clinical, and safety assessments were administered at baseline and weeks 1, 2, 4, and 8. In the primary analyses of neurocognitive differences at week 8, no varenicline–placebo differences were significant. In secondary longitudinal analyses, varenicline improved compared with placebo on the Digital Symbol Substitution Test (p=0.013) and the Wisconsin Card Sorting Test non-perseverative errors (p=0.043). Some treatment effects were different between smokers and non-smokers. In smokers, Continuous Performance Test hit reaction time (p=0.008) and Stroop Interference (p=0.004) were reduced for varenicline compared with placebo, while there were no treatment differences in non-smokers. No significant treatment main effects or interactions were noted for total scores on the Positive and Negative Syndrome Scale or the Scale for the Assessment for Negative Symptoms. Our findings suggest beneficial effects of adjunctive varenicline treatment with antipsychotics for some cognitive impairments in people with schizophrenia. In some cases, effects of treatment varied between smokers and non-smokers. Further study is required to assess the functional significance of these changes.

Adjunctive Varenicline Treatment with Antipsychotic Medications for Cognitive Impairments in People with Schizophrenia: A Randomized Double-Blind Placebo-Controlled Trial

Галлюцинации

Hallucinations: Common features and causes

Ухудшение депрессивной симптоматики у группы больных в исследовании дулоксетина

New research shows that while many antidepressants help most people who take them, a small group of people who take them will actually feel more depressed than if they had just been taking a placebo or sugar pill.

 Some People Feel Worse on Antidepressants Like Cymbalta

Do Antidepressants Make Some People Worse?

Взаимодействие рецепторов серотонина и глутамата как возможный механизм психоза

Serotonin (5HT) and glutamate are two neurotransmitters. Up until now, it was thought that they acted independently. A given neuron might have receptors for both serotonin and glutamate, but they didn't interact: serotonin would never affect the glutamate receptors, and vice versa.
The new research overturns that view. Authors Miguel Fribourg and colleagues ofMount Sinai School of Medicine show, in a series of elegant experiments in mice, that different receptors can cluster together, forming a complex. The two receptors, serotonin's 5HT2A and glutamate's mGluR2, can talk to each other.

A Psychedelic Tale of Two Neurotransmitters

Артериальная гипертензия, липопротеины низкой плотности и депрессия

Abstract
Background
Clinicians generally agree on the association between depression and hypertension. Less clear is if the nature of the link is direct or indirect and if this should be considered confined only to syndromal forms or if it concerns also subsyndromal affective presentations. This study investigated the nature of the association between hypertension and subsyndromal depression in hospitalized hypertensive patients.
Methods
196 hypertensive and 96 non hypertensive inpatients underwent a SCID interview, to exclude patients positive for any Axis I or Axis II diagnosis. Symptomatic Subsyndromal Depression (SSD) was identified according to criteria proposed by Judd. Psychopathological assessment was performed with Anxiety Sensitivity Index (ASI) and Hopkins Symptom Checklist-90 (SCL-90). Clinical assessments included blood pressure measurement, evaluation of general health conditions and screening cardiovascular risk factors (smoke, alcohol, body weight, sedentary life style).
Results
Hypertensives met more frequently criteria for SSD. They also scored higher on ASI and SCL-90. However, those with more severe physical conditions, if compared with more healthy patients, did not show increased psychopathological severity. Similarly, psychopathological symptom severity did not differ among hypertensives positive for other cardiovascular risk factors, commonly more frequent among depressed subjects.
Limitations
Further analyses are needed to explore the potential advantage obtained on blood pressure control by treating SSD.
Conclusions
Hospitalized hypertensives, more frequently satisfied criteria for Symptomatic Subsyndromal Depression. These milder affective forms are probably directly linked to the presence of hypertension, rather than being indirectly associated to physical impairment or to higher prevalence of other cardiovascular risk factors.

Symptomatic subsyndromal depression in hospitalized hypertensive patients

Objective
Serum cholesterol was reported to be associated with depressed mood, but the studies conducted among household population are rare.
Methods
We used the data of 4115 men and 4275 women aged 18 or older, who completed a depression screening interview and had blood collected as a part of the National Health and Nutrition Examination Survey, 2005–2008. The serum concentrations of total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were gender-specifically categorized into lower, intermediate, and upper quartiles. Depression was measured using the Patient Health Questionnaire, a 9-item screening instrument asking about the frequency of depression symptoms over the past 2weeks.
Results
After adjustment for socio-demographics and behavioral risks, a U-shaped association was detected between severe depression and LDL-C among men. The odds ratios (ORs) of severe depression were 5.13 (95% CI=1.74–15.09), 1 (reference) and 2.28 (1.07–4.86) respectively for the men with lower (<169mg/dL), intermediate (169–221mg/dL), and upper quartile (≥222mg/dL) LDL-C. Among women, lower HDL-C was significantly associated with an elevated odds of severe depression [OR=2.96 (1.59–5.52)] compared with upper quartile of HDL-C, the association diminished after adjustment for covariates [OR=1.24 (0.66–2.32)]. No clear pattern of association between cholesterol and moderate depression was observed from either men or women.
Limitation
The inherent limitation of cross-sectional design prevented the authors from investigating causality.
Conclusions
A U-shaped association was identified between LDL-C and severe depression among men. Further studies are necessary to explore the biological mechanism and identify the clinical implication among populations vulnerable to psychiatric disorders.

Low cholesterol is associated with depression among US household population 

Антидепрессивный эффект МРТ

Yes, this study says that having an MRI scan has a powerful antidepressant effect.
They took 51 depressed patients, and gave them all either an MRI scan or a placebo sham scan. The sham was a "scan" in a decommissioned scanner. The magnet was off but they played recorded scannerish sounds to make it believable. Patients were blinded to group.
They found that people in the scanner group improved much more than those in the sham group over two weeks. Actually there were two different kinds of scans, T1 structural MRI and EPI functional MRI, but they were the same

 Does MRI Make You Happy?

Ещё одно неудачное исследование антидепрессанта нового механизма действия

On 8 November, Targacept, a drug company based in Winston-Salem, North Carolina, announced that TC-5214 had performed no better than placebo in one of four phase III trials. The results are a disappointment to clinicians eager for an innovative antidepressant.

TC-5214 is a form of mecamylamine, a blood-pressure drug introduced in the 1950s. It targets nicotinic α4β2 receptors (see ‘Mixed signals’), which normally receive chemical signals from the neurotransmitter acetylcholine. Because excess acetylcholine has been linked to major depression, blocking these signals might relieve the condition.

 Depression drug disappoints

Сравнительный анализ атомоксетина и метилфенидата при СДВГ

Background
Psychostimulants and non stimulants are effective in the treatment of ADHD. Efficacy of both methylphenidate and atomoxetine has been established in placebo controlled trials. Direct comparison of efficacy is now possible due to availability of results from several head-to-head trials of these two medications.
Methods
All published, randomized, open label or double blind trials, comparing efficacy of methylphenidate with atomoxetine, in treatment of ADHD in children, diagnosed using DSM-IVTM criteria were included. The outcome studied was ADHDRS-IVParent:Inv score. The standardized mean difference (SMD) was used as a measure of effect size.
Results
Nine randomized trials comparing methylphenidate and atomoxetine, with a total of 2762 participants were included. Meta-analysis did not find a significant difference in efficacy between methylphenidate and atomoxetine (SMD= 0.09, 95% CI -0.08-0.26) (Z=1.06, p=0.29). Synthesis of data from eight trials found no significant difference in response rates (RR=0.93 95% CI 0.76-1.14, p=0.49). Sub group analysis showed a significant standardized mean difference favouring OROS methylphenidate (SMD=0.32, 95% CI 0.12-0.53 (Z=3.05, p<0.002). Immediate release methylphenidate was not superior to atomoxetine (SMD= -0.04, 95% CI -0.19-0.12) (Z=0.46, p=0.64). Excluding open label trials did not significantly alter the effect size (SMD=0.08, 95% CI -0.04-0.21) (Z=1.27, p=0.20). All-cause discontinuation was used as a measure of acceptability. There was no significant difference in all cause discontinuation between atomoxetine and methylphenidate (RR 1.22, 95% CI 0.87-1.71). There was significant heterogeneity among the studies (p=0.002, I2=67%). Subgroup analysis demonstrated the heterogeneity to be due to the open label trials (p=0.001, I2=81%).
Conclusions
In general atomoxetine and methylphenidate have comparable efficacy and equal acceptability in treatment of ADHD in children and adolescents. However OROS methylphenidate is more effective than atomoxetine and may be considered as first line treatment in treatment of ADHD in children and adolescents.

Comparative efficacy and acceptability of methylphenidate and atomoxetine in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis

Результаты исследования антидепрессанта тройного действия

A paper just out reveals that the snappily-named GSK372475 doesn't work and has lots of side effects. It's a report of two clinicals trials in which Glaxo's contender was pitched against placebo and against older antidepressants in the treatment of depression.

Another Antidepressant Bites The Dust

Антидепрессивная активность клавулановой кислоты не подтвердилась

The randomized, double-blind, placebo-controlled study compared two doses of Serdaxin, 0.5 mg and 5 mg, to placebo over an 8-week treatment period. Results from the study did not demonstrate Serdaxin's efficacy compared to placebo measured by the Montgomery-Asberg Depression Rating Scale (MADRS).

Rexahn Pharmaceuticals Announces Phase II Results for Serdaxin as Treatment for Major Depressive Disorder

ИАХЭ и холинолитики взаимно снижают эффективность друг друга

Many patients with Alzheimer's disease are simultaneously prescribed cholinesterase inhibitors (ChIs) and anticholinergics (AChs), 2 drug classes that have the potential to cancel each other out.

Meds Prescribed for Alzheimer's May Cancel Each Other Out

Влияние физической активности на фармакокинетику лекарственных средств

Physical activity produces many positive physiological changes. Some of these physiological changes, however, can adversely affect the absorption, distribution, metabolism, and/or excretion of certain medications when taken concurrently. Blood flow distribution is fundamental to the study of pharmacokinetics and can vary dramatically during rest compared with exercise. The liver and the kidney play significant roles in calculating the pharmacokinetic parameters of medications. Blood flow to these organs is significant at rest but decreases during exercise. These changes in blood flow, as well as other physiological changes during exercise, have shown to alter the pharmacokinetics of some drugs. Medications that require extra therapeutic monitoring may be affected by this drug-exercise interaction. Health care professionals and patients should be aware of these potential drug-exercise interactions.

Pharmacokinetic Drug Interactions with Physical Activity

Воспалительная теория шизофрении

Of great interest are findings that microglial cells—the macrophages of the brain—are activated during psychosis.6 Cells visualized with a positron emission tomography tracer (PK11195) that binds to peripheral benzodiazepine receptors, an indicator of microglia activation, were found to have greater receptor expression in patients with recent-onset schizophrenia.7 Activated microg-lia stimulate astrocytes to produce S100B, a marker of inflammation that is considered to be the equivalent of C-reactive protein in the brain.8 Serum S100B levels are elevated in patients with schizophrenia, and antipsychotics such as haloperidol (Drug information on haloperidol) and clozapine (Drug information on clozapine) have been shown to decrease S100B release from glial cells.

The Link Between Immune System Dysregulation and Schizophrenia

Метиленовый синий как нормотимик

The investigators administered methylene blue to 37 subjects meeting criteria for bipolar disorder, while maintaining lamotrigine(Drug information on lamotrigine) as their primary mood stabilizer. Patients were randomized to receive 13 weeks treatment with either 195 mg methylene blue daily, or 15 mg as a putative subtherapeutic dose in lieu of a placebo that mimics the color in urine; with groups switching the regimen for an additional 13 weeks.

Alda reported that the active dose was associated with statistically significantly improved mood symptom scores from baseline on multiple measures, including the Montgomery-Asberg Depression Rating Scale (MADRS). There was no therapeutic effect apparent on cognitive performance, but no decrement observed with its use.

Methylene Blue Studied for Bipolar as FDA Issues Warning

Случай нейропсихиатрической манифестации анти-NMDA-рецепторного энцефалита

A 52-year-old Chinese man was admitted to the inpatient psychiatric unit of an academic teaching hospital with an admitting diagnosis of major depressive disorder (MDD) with psychotic features. His chief complaint was "I do not feel happy." The patient endorsed insomnia, hopelessness, passive suicidal ideation, and increased anxiety, especially at bedtime. He was disheveled, guarded, demonstrated poor eye contact, slurred and decreased speech output, psychomotor retardation, poor cognition, flat affect, and vague auditory and visual hallucinations of seeing and hearing people. The patient had a past psychiatric history of MDD with psychotic features diagnosed when he was in his early 30s, and suicidal gestures. He had two previous inpatient admissions while in China in 2008, for psychotic features described then as robotic speech, flat affect, and minimal verbal responsiveness. At the time of his current admission, he was being followed in the psychiatry outpatient clinic. He denied past or current substance abuse. The patient's past medical history was significant for one observed tonic–clonic seizure in December 2009, which was managed with phenytoin 300 mg daily. At that time, neurologic evaluation was unrevealing, and no etiology of the seizure was identified.
After initial evaluation in the hospital, the patient was started on escitalopram 15 mg daily and paliperidone 3 mg daily, and his phenytoin 300 mg daily was continued. ECT had been considered while he was being followed as an outpatient. Upon admission, he was started on a course of ECT. Despite numerous medication trials including paliperidone, olanzapine, and clozapine, as well as a series of 12 ECT treatments, the patient's condition did not improve, and he began to show signs of cognitive decline. A neurology consult was requested for continued agitated and bizarre behavior. An EEG showed diffuse slowing, and a magnetic resonance (MRI) scan showed only small-vessel ischemic microvascular disease.
After 2 months, while still on the psychiatry inpatient unit, he developed symptoms of extreme agitation, aggressiveness, and unusual behavior, and was verbally unresponsive. His agitation was treated with lorazepam. Vital signs at that time revealed tachycardia to a heart rate of 120 bpm, a blood pressure of 90/50 mmHg, and O2 saturation of 90% at room air. His temperature was 102.3°F. The patient was transferred to the medical intensive care unit (MICU) and intubated for airway protection. Laboratory data at transfer revealed a white cell count of 11.2 K/µl, BUN 32 mg/dl, Cr 1.2 mg/dl, and creatine kinase 2,361 u. Neuroleptic malignant syndrome was suspected but ruled out, as the patient's temperature and creatine kinase trended down in the subsequent days without any active intervention. After 11 days, he was extubated. He displayed echopraxia, but no focal findings were documented.
Because of his unusual course, failure to respond to standard treatments for depression and psychosis, and the presence of a documented seizure 1 month before admission, a work-up for possible anti-NMDA receptor antibody encephalitis was started. Lumbar puncture yielded clear, colorless fluid which was acellular, with a glucose of 76 mg/dl and protein of 21 mg/dl. VDRL and oligoclonal bands were negative. CSF and serum sample was also sent for anti-NMDA receptor antibody testing. The patient had an EEG performed, which revealed bilateral independent temporal lobe discharges more prominent in the left hemisphere than the right, but no active seizures were seen. CSF and serum results confirmed the patient's diagnosis of anti-NMDA antibody encephalitis by the presence of antibodies against NRI-NR2 heteromers of the NMDA receptor. The patient was transferred to another hospital and lost to follow-up.

An Unusual Case of Anti-NMDA-Receptor Encephalitis in the Psychiatry Inpatient Unit

Предупреждение нежелательных эффектов лекарственных препаратов в психиатрии

How to prevent adverse drug events

Антихолинэстеразные свойства шалфея и влияние на когнитивные функции

Extracts of sage (Salvia officinalis/lavandulaefolia) with terpenoid constituents have previously been shown to inhibit cholinesterase and improve cognitive function. The current study combined an in vitro investigation of the cholinesterase inhibitory properties and phytochemical constituents of a S. lavandulaefolia essential oil, with a double-blind, placebo-controlled, balanced crossover study assessing the effects of a single dose on cognitive performance and mood. In this latter investigation 36 healthy participants received capsules containing either 50 µL of the essential oil or placebo on separate occasions, 7 days apart. Cognitive function was assessed using a selection of computerized memory and attention tasks and the Cognitive Demand Battery before the treatment and 1-h and 4-h post-dose. The essential oil was a potent inhibitor of human acetylcholinesterase (AChE) and consisted almost exclusively of monoterpenoids. Oral consumption lead to improved performance of secondary memory and attention tasks, most notably at the 1-h post-dose testing session, and reduced mental fatigue and increased alertness which were more pronounced 4-h post-dose. These results extend previous observations of improved cognitive performance and mood following AChE inhibitory sage extracts and suggest that the ability of well-tolerated terpenoid-containing extracts to beneficially modulate cholinergic function and cognitive performance deserves further attention.

Monoterpenoid extract of sage (Salvia lavandulaefolia) with cholinesterase inhibiting properties improves cognitive performance and mood in healthy adults

Drug-Resistant Epilepsy

Drug-Resistant Epilepsy

Запах шизофрении

They collected the sweat from 14 white male patients with schizophrenia and 14 comparable patients with ‘organic brain syndromes’ and found they could train rats to reliably distinguish the odours while a human panel of sweat sniffers seemed to be able to do the same.
Seemingly backed up by the nasal ninja skills of two different species, science attempted to determine the source of the ‘schizophrenic odour’.
Two years later researchers from Washington suggested the smell might be triggered by the bacteria Pseudomonas aeruginosa but an investigation found it was no more common in people with schizophrenia than those without the diagnosis.
But just before the end of the 60s, the original research team dropped a scientific bombshell. They claimed to have identified the schizophrenia specific scent and got their results published in glittery headline journalScience.
Using gas chromotography they identified the ‘odorous substance’ as trans-3-methyl-2-hexenoic acid, now known as TMHA.

Looking back, we now know that TMHA is genuinely an important component in sweat odour. Curiously, it turns out it is largely restricted to Caucasian populations but no link to mental illness or psychiatric disorder has ever been confirmed.
The theory seems like an curious anomaly in the history of psychiatry but it occasionally makes a reappearance. In 2005 study claimed that the odour exists but is “complex and cannot be limited to a single compound, but rather to a global variation of the body odor” but no replications or further investigations followed.

A whiff of madness

Депрессия, воспаление и сердечно-сосудистые заболевания

Led by Dr. Jesse Stewart, researchers found that depressive symptoms are associated with increases over time in interleukin-6, an inflammatory protein that predicts cardiovascular events.

On the other hand, levels of interleukin-6 were not linked to subsequent increases in depressive symptoms.

Depression leads to increased inflammatory protein linked to heart disease

Фармакогенетика СИОЗС, ассоциации между полиморфизмом CYP2D6 и CYP2C19 и ответом на терапию антидепрессантом

An investigation of MEDLINE and other database resources was carried out to summarize the research conducted between 1970 and 2003 in the role of CYP2D6 genetics on SSRI dose exposure.^[2] Area-under-the-concentration curve (AUC) values of 5 SSRIs in poor metabolizers, intermediate metabolizers, and extensive metabolizers as a measure of bioavailability were collected. Dose adjustments were then calculated to compensate for variability in CYP2D6 metabolizer status in white patients. On the basis of metabolizer phenotype, the following dose adjustments were extrapolated for extensive vs poor metabolizers: 33%-129% for fluvoxamine, 66%-114% for paroxetine, 56%-119% for fluoxetine (including the AUC of its active metabolite), 98%-101% for citalopram, and 99-100% for sertraline. A dose adjustment of 130% for paroxetine was extrapolated for ultrarapid metabolizers.

However, the study authors concluded that dose adjustments that are based on CYP2D6 could not be recommended for SSRIs for various reasons. They noted the limited data from multiple dosing, which more accurately reflects the clinical situation; the unknown effect of saturation kinetics of some SSRIs (eg, paroxetine and fluvoxamine); and the long-term effect of inhibition of CYP2D6 by some SSRIs (eg, fluoxetine, fluvoxamine, and paroxetine) when given in chronic treatment regimens. Thus, basic human pharmacokinetic data do not strongly support routine clinical use of CYP2D6 testing.

Another study scanning 1200 Web-based articles between 1966 and 2006 for treatment of major depression found no consistent association between CYP2D6 genotype and SSRI metabolism, efficacy, or risk for side effects.^[3]Although 2 studies showed greater nonresponse to SSRIs among ultrarapid metabolizers relative to the general population, the data were inconsistent across other studies. The study authors concluded that there is no established association between plasma drug concentration and SSRI drug response at standard doses.

Finally, a study of SSRI drug response and tolerability in 1953 patients enrolled in the Sequenced Treatment of Alternatives to Relieve Depression (STAR*D) study also showed no significant association between CYP2D6 variants and citalopram response, remission, or tolerability when comparing extensive metabolizers with poor metabolizers. However, the study design included numerous concomitant medications with unknown confounding effects.^[4]

The complexity derived from interaction between multiple CYP enzymes was highlighted in a study of the impact of extensive and poor metabolizer status for CYP2D6 and CYP2C19 on the SSRI citalopram. Researchers showed that the AUC for citalopram correlated with the combined CYP2D6/CYP2C19 metabolizer status.^[5] For example, individuals with CYP2D6 extensive metabolizer/CYP2C19 poor metabolizer status showed significantly higher citalopram AUC compared with extensive/extensive metabolizer or poor/extensive metabolizer carriers. Because citalopram metabolism is preferentially catalyzed by CYP2C19 over CYP2D6, consideration of more than 1 genetic variant may be necessary to guide medication dosing decisions.

Pharmacogenomics of SSRIs: Clinical Implications

Психические расстройства при гипотиреозе и гипертиреозе

The symptoms and signs of hyperthyroidism resemble those of primary mental disorders. Overactivity of the adrenergic system caused by hyperthyroidism may explain the similarity between the clinical presentations of hyperthyroidism and mania or anxiety, as well as the precipitating role of hyperthyroidism in the development of mania or anxiety disorder. It may also explain the increased sense of well being often experienced in the early stages of hyperthyroidism.[20,21]

The relationship between hyperthyroidism and depression is less clear. Depression is usually linked to hypothyroidism, not to hyperthyroidism. However, prolonged hyperthyroidism might exhaust noradrenergic transmission and thus contribute to depression. Noradrenergic exhaustion might well occur in patients with hyperthyroidism who have bipolar disorder. In the initial phase of hyperthyroidism, thyroid hormone stimulation of the noradrenergic system may cause mania; later, when noradrenergic neurotransmission is exhausted, it may contribute to depression.[21]

Mental symptoms and disorders secondary to hyperthyroidism should be treated first by restoring euthyroidism. Most mental symptoms, including depression, usually resolve once euthyroidism has been regained. Treatment with beta-adrenergic antagonists alone may quickly relieve many symptoms, including mental symptoms, even if euthyroidism is not restored,[22] providing evidence that overactivity of the adrenergic system is largely responsible for mental symptoms in hyperthyroidism.

Thyroid deficits are frequently observed in bipolar patients, especially in women with the rapid cycling form of the disease.[24] Both subclinical hypothyroidism and subclinical hyperthyroidism increase the risk for Alzheimer's disease, especially in women.[25] However, most hypothyroid patients do not meet the criteria for a mental disorder.

A recent study evaluated brain glucose metabolism during T4 treatment of hypothyroidism. A reduction in depression and cognitive symptoms was associated with restoration of metabolic activity in brain areas that are integral to the regulation of mood and cognition.[26••]

In hypothyroidism, replacement therapy with T4 remains the treatment of choice and resolves most physical and psychological signs and symptoms in most patients. However, some patients do not feel entirely well despite doses of T4 that are usually adequate.[27] In T4-treated patients, it was found that reduced psychological well being is associated with occurrence of polymorphism in the D2 gene,[28••] as well as in the OATP1c1 gene.[29]

Thyroid hormone replacement with a combination of T4 and T3, in comparison with T4 monotherapy, improves mental functioning in some but not all hypothyroid patients,[30,31•] and most of the patients subjectively prefer combined treatment.[32] Two studies have evaluated whether D2 polymorphism is associated with changes in psychological well being after combined T4 and T3 treatment. One underpowered study[33] reported a trend toward improvement. In a second study[28••] involving a very large sample, D2 polymorphism was associated with improvement in psychological well being after T4 and T3 treatment.

Thyroid Disease and Mental Disorders: Cause and Effect or Only comorbidity?

MDMA в психиатрии

The pharmacological effects of MDMA include serotonin release; serotonin type 2 receptor stimulation; and an increase in levels of the neurohormones oxytocin(Drug information on oxytocin), prolactin, and cortisol.24-29 Serotonin release plays an important role in producing the subjective effects of MDMA.30-33 Pretreatment with SSRIs reduces most acute subjective and physiological effects of MDMA, including effects on mood and perception. Serotonin release directly or indirectly leads to an elevation in oxytocin levels, possibly by stimulating serotonin type 1A receptors.24,28,34 Studies suggest that oxytocin plays an important role in stress response, reduces the fear response, and increases social affiliation and trust35-39; thus, elevated oxytocin levels might help patients form a therapeutic alliance and revisit traumatic experiences in an emotionally engaged state.
Elevation in oxytocin levels after MDMA administration has been associated with greater sociability and more gregarious behavior.24 MDMA has recently been shown to decrease perception of negative emotions in others and perception of threat-related signals, such as fear, which might increase social approach behavior.40 It has been postulated that prolactin release following MDMA administration may contribute to a postorgasmic-like sense of relaxation and receptivity.41 The neurocircuitry model of PTSD postulates a deficit in extinction of fear conditioning mediated by the amygdala and the ventromedial prefrontal cortex, a model supported by findings of reduced hippocampal activity and volume, increased activity in the amygdala, and decreased activation of the medial prefrontal cortex in persons with PTSD.42,43
Gamma and colleagues44 used positron emission tomography to measure cerebral blood flow 75 minutes after MDMA was given to healthy volunteers. Their findings showed increases in cerebral blood flow in the ventromedial frontal and occipital cortex and decreases in the left amygdala. MDMA may produce some of its effects through these acute changes in brain activity, which may reverse abnormalities associated with PTSD and thereby allow effective processing of traumatic memories. The nature of the effects is consistent with much of what we observed in our clinical trial.

Does MDMA Have a Role in Clinical Psychiatry?

Сравнение антидепрессивной эффективности антипсихотиков у психотических больных

There was no substantial difference in anti-depressive effectiveness among olanzapine, quetiapine, risperidone or ziprasidone in this clinically relevant sample of patients acutely admitted to hospital for symptoms of psychosis. Based on our findings we can make no recommendations concerning choice of any particular SGA for targeting symptoms of depression in a patient acutely admitted with psychosis.

Anti-depressive effectiveness of olanzapine, quetiapine, risperidone and ziprasidone: a pragmatic, randomized trial.

Progressive Gray Matter Loss and Changes in Cognitive Functioning Associated With Exposure to Herpes Simplex Virus 1 in Schizophrenia: A Longitudinal Study

Транскраниальная стимуляция постоянным током в терапии вербального галлюциноза при шизофрении

In February 2011, a 44-year-old man with schizophrenia was referred to our hospital for the treatment of auditory verbal hallucinations. He had undergone outpatient treatment with adequate dosages of antipsychotic medications for several months, but he still heard a real-sounding voice that ordered him to commit suicide. We introduced transcranial direct current stimulation (tDCS) as a novel therapeutic approach. Cathodal stimulation diminishes cortical excitability at a circumscribed region (1), and Wernicke's area has been described as an appropriate target region for cathodal stimulation in previous transcranial magnetic stimulation (TMS) studies (2–4). The anodal electrode was placed over the right supraorbital area.

Transcranial direct current stimulation was applied for 15 minutes on 10 consecutive days by using a 1 mA current and 7 cm x 5 cm electrodes, resulting in a current density of 0.029 mA/cm2. The medication doses (5 mg of haloperidol and 20 mg of olanzapine) remained the same 4 weeks before and during the patient's intervention. Before and after tDCS, we measured arterial spin labeling, a noninvasive MR technique that provides a direct quantitative measure of cerebral blood flow (CBF). Arterial spin labeling has been successfully used to measure the difference and changes in regional CBF between healthy individuals and schizophrenia patients experiencing formal thought disorders (5). Clinical assessments showed improvements in our patient's scores on the Hallucination Change Scale (pre-tDCS score=10; post-tDCS score=4), the Positive and Negative Syndrome Scale (pre-tDCS score=61; post-tDCS score=50), and the Psychotic Symptom Rating Scale (pre-tDCS score=51; post-tDCS score=43). The decrease in regional CBF indicated that the intervention had a specific neurobiological effect (Figure 1). At follow-up investigation 6 weeks after the tDCS intervention, our patient's clinical improvement was maintained.

Muting the Voice: A Case of Arterial Spin Labeling-Monitored Transcranial Direct Current Stimulation Treatment of Auditory Verbal Hallucinations

ЭЭГ-диагностика шизофрении

They used electroencephalography (EEG), which measures the brain’s electrical activity or “brain waves”, to study the brain’s response to commonly and rarely presented tones that differed in length.

When these rare “deviant” tones are presented to healthy people, the brain automatically generates a particular electrical wave called mismatch negativity, or MMN. People diagnosed with schizophrenia have reduced MMN.

In this new study, the researchers followed a group of people clinically at high risk for developing psychosis. They found that the individuals who went on to develop schizophrenia had smaller MMN than the subgroup who did not. This finding suggests that MMN might be useful in predicting the later development of schizophrenia.

A “Brain Wave” Test for Schizophrenia Risk?

Индивидуальная музыкальная терапия депрессии

Individual music therapy for depression: randomised controlled trial

Psychopathology of perpetrators of fabricated or induced illness in children: case series

Симптомы дефицита тестостерона

Symptoms and Signs Suggestive of Testosterone Deficiency in Men

More Specific Signs and Symptoms – Reduced libido – Erectile dysfunction (ED) – Reduced intensity of orgasm and genital sensation – Osteoporosis or low bone mineral density – Decreased spontaneous erection – Oligospermia or azoospermia – Very small or shrinking testes – Hot flushes, sweats – Breast discomfort, gynecomastia – Loss of pubic and axillary hair, reduced shaving Less Specific Signs and Symptoms – Decreased energy or vitality, increased fatigue – Depressed mood – Reduced muscle mass and strength – Poor concentration and memory – Sleep disturbance; increased sleepiness – Mild anemia – Increased body fat, body mass index – Diminished physical or work performance

Risks and Comorbid Illnesses Associated With Testosterone Deficiency

– Metabolic syndrome – Obesity – Hyperlipidemia – Hypertension – Elevated fasting plasma glucose and serum insulin – Elevated C-reactive protein – Diabetes mellitus (type 1 or 2) – Cardiovascular disease (including aortic atherosclerosis) – Chronic obstructive lung disease – Inflammatory arthritis – Low trauma fracture – End-stage renal disease – HIV-related weight loss – Hemochromatosis – Sellar mass, radiation to the sellar region, or other diseases of the sellar region – Chronic pain syndrome and treatment with opioids – Treatment with glucocorticoids – Radical prostatectomy

Low Testosterone Medscape CME Expert Column Series. Issue 1: Testosterone Deficiency in Men: Common and Under-recognized

Назначение антидепрессантов при депрессивной симптоматике в рамках деменций не целесообразно

Antidepressants may provide little benefit but appear to increase adverse side effects in individuals with dementia and comorbid depression, suggesting that clinicians should reconsider use of these agents in this population, new research suggests.

Antidepressants of Little Use in Dementia Patients

Психоиммунологические разработки в терапии депрессии

Для повышения эффективности лечения антидепрессантами, в том числе и сертралином, нами предложен комплекс средств патогенетической терапии больных с депрессивными расстройствами, целью применения которого является восстановление иммунного и метаболического гомеостаза.

На первой неделе лечения мы считаем весьма полезным назначение 1,5% соли янтарной кислоты как средства детоксикации и улучшения энергетического метаболизма, который у больных депрессиями существенно снижен. Соль янтарной кислоты обладает выраженным детоксицирующим, антигипоксическим, антиоксидантным, гепато-, нефро- и кардиопротекторным действиями, что обусловлено способностью препарата усиливать аэробный гликолиз, увеличивать внутриклеточный фонд макроэргических соединений — АТФ и креатинфосфата, а также активировать систему АОЗ, снижать выраженность процессов ПОЛ и оказывать мембраностабилизирующий эффект, в том числе в отношении клеток головного мозга. При умеренно выраженных депрессиях мы вводим по 400 мл 1,5% раствора соли янтарной кислоты 2–3 раза с интервалом 1–2 дня между инфузиями. При тяжелых депрессиях реамберин желательно назначать ежедневно по 400 мл на инфузию, а количество инфузий увеличить до 5–6. Клинический опыт показывает, что введение 1,5% раствора соли янтарной кислоты способствует улучшению самочувствия у больных депрессиями, уменьшению астенического компонента и чувства тревоги.

В комплексе лечебных средств у больных депрессиями с целью снижения выраженности СМИ мы широко используем положительно зарекомендовавший себя метод энтеросорбции. Пациенты с первого дня лечения получают современные кремнеземные энтеросорбенты отечественного производства (атоксил, энтеросгель, силлард П и др.) в виде 1–2% водной суспензии 2–3 раза в день в перерывах между приемами пищи и других лекарственных препаратов по 200–250 мл курсами по 10–12 дней с перерывами между ними 7–10 дней. При легкой степени депрессии обычно проводится 2 курса энтеросорбции, при умеренно выраженной — 2–3 курса, у больных с тяжелой депрессией назначают до 5–6 курсов энтеросорбции.

Для снижения активности ПОЛ и повышения антиоксидантных потенций крови у больных депрессиями применяют витамины с антиоксидантной активностью — аскорбиновую кислоту до 500 мг в сутки внутрь, а при тяжелых депрессиях также внутривенно в виде 10% раствора по 10 мл 2 раза в день на 40% глюкозе или изотоническом растворе хлорида натрия, токоферола ацетат по 0,2 мл 50% раствора внутрь в капсулах 2–3 раза в день, а при тяжелых депрессиях внутримышечно по 1 мл 10% раствора 1 раз в день в течение 20–40 дней. У больных с фоновой соматической патологией — при хронических гепатитах и начальной фазе цирроза печени — дополнительно назначаем внутрь современные препараты эссенциальных фосфолипидов: ливолин, ливенциале форте или эссенциале Н по 2 капсулы 3 раза в день курсами по 25–30 дней. При необходимости у больных с тяжелыми соматоформными депрессиями этот курс лечения эссенциальными фосфолипидами может быть повторен через 1–1,5 месяца.

Депрессивные расстройства: иммунные и метаболические нарушения и их коррекция

Монотерапия антидепрессантами (STAR*D vs CO-MED)

Perhaps the HAM-D as administered across the CO-MED sites did not adequately capture the element of symptom severity most relevant to the emergence of clear drug effects. The CO-MED study group contained far fewer subjects with melancholia than did either of the groups of Blier et al., and depressed patients with melancholic features have been shown to have higher severity ratings on global and other symptom-based measures in comparison to those without melancholia, despite having nearly identical HAM-D scores (9). Group differences were only somewhat larger in the CO-MED subset with melancholic features than in the patients without them. The performance of melancholia as a response predictor, though, varies considerably by how its components are defined and applied (10), and the CO-MED report does not state how melancholic symptoms were assessed. The relative scarcity of melancholia in the CO-MED patients nevertheless indicates a correspondingly lower severity level on some dimension.

A particularly striking feature of the CO-MED study group is the coexistence of the absence of treatment resistance, as specified by the entry criteria, and a high rate of chronicity. Although none of the participants had had an adequate monotherapy trial of an FDA-approved antidepressant within the current episode, over one-half of the group had a depressive episode that had been fully syndromal for at least the preceding 2 years. Why had they not undergone even one adequate antidepressant trial before the CO-MED effort came to pass? Whatever the answer, it seems likely that the average interval between episode onset and the receipt of first treatment was quite long. A number of prospective studies of major depressive disorder have shown the no-treatment interval to be as robust a predictor of poor outcome with treatment as neuroticism (11). Why this is so is a matter of speculation, but the measure's association with poorer treatment response generally may well have narrowed differences between the regimens applied here.

The Search for Improved Antidepressant Strategies: Is Bigger Better?

Treatment-resistant schizophrenia: What can we do about it?

Антиконвульсанты при тревожных расстройствах

Can Anticonvulsants Help Patients With Anxiety Disorders?

Lurasidone at 40 mg/day and 80 mg/day did not show a statistically significant improvement over placebo in PANSS total score change at the six-week study endpoint, despite a significant within-group reduction of the total PANSS score after treatment. This clinical trial is viewed as a failed study, as it was unsuccessful in establishing assay sensitivity. Despite the failure, company leaders believe they obtained useful data, which will assist with the design of future studies to support the registration of lurasidone in Japan.

Перспективные стратегии лечения когнитивной симптоматики шизофрении

A randomized, double-blind, placebo-controlled study demonstrated that members of a sarcosine (2 g/day) group showed greater reductions in their Positive and Negative Syndrome Scale (PANSS) total scores than members of a placebo group or D-serine (2 g/day) group, suggesting that sarcosine is superior to D-serine in that benefits both patients with long-term stable disease and also acutely ill persons with schizophrenia .

Furthermore, a randomized, double-blind study reported that sarcosine (2 g/day) alone was effective in the treatment of acutely symptomatic drugfree patients with schizophrenia.

Nonetheless, all these findings suggest that GlyT-1 inhibition could be a novel pharmacotherapeutic target for enhancing cognitive dysfunction in schizophrenia and several clinical trials are underway with very promising results.

Gaining a better understanding of the role of GlyT-1 in the treatment of cognition in schizophrenia is expected to provide new perspectives for treating this disorder. The pharmacological modulation of glycine modulatory sites on NMDA receptors by GlyT-1 inhibitors could be beneficial in the treatment of the cognitive deficits and psychosis associated with schizophrenia and other psychiatric conditions.

Galantamine, which acts as both a cholinesterase inhibitor and a nicotinic receptor modulator had the best result. The cognitive effects of galantamine may be accentuated by its nicotinic allosteric agonist action, which can improve attention and memory. Furthermore, galantamine appears to more powerfully elevate frontal cortical dopamine levels than cholinesterase inhibitors such as donepezil. This biological effect may be significant since frontal dopaminergic deficits have been proposed to underlie cognitive impairment in schizophrenia.

Importantly, significant improvement in attentional set shifting was seen. Modafinil may have potential as an important therapy for cognitive impairment in patients with schizophrenia, particularly because of its beneficial effects on attentional set shifting.

Patient with schizophrenia manifest signs of a dysregulation of the NPY system. Extensive preclinical studies suggest that the neuropeptide Y (NPY) counteracts the behavioral consequences of stress and anxiety to and maintain emotional homeostasis. Thus it is involved in stress regulation and coping.

Treatment of Cognition in Schizophrenia

Депо-формы классических антипсихотиков превосходят по эффективности пролонгированную форму рисперидона

In a large population-based cohort study, conventional depot antipsychotics turned out to be superior to risperidone long-acting injection, Danish researchers reported here at the New Clinical Drug Evaluation Unit (NCDEU) 51st Annual Meeting, sponsored by the American Society of Clinical Psychopharmacology.

Older Antipsychotics Trump Newer Agents for Schizophrenia

Blepharospasm as an Obsessive-Compulsive Phenomenon

Маниакальная симптоматика ассоциированная с приступами мигрени

This is a case report of a previously diagnosed "treatment-refractory bipolar" patient whose successful treatment of atypical migraine resulted in the questioning of any psychiatric diagnosis.

A 47-year-old man was referred to the Mood Disorders Clinic for severe migraine associated with mood, "psychic," and neurologic symptoms. He had first presented to Psychiatry 8 years earlier, for acute "mania" with agitation, extreme lability, intense anger, and religiosity necessitating hospitalization. Subsequently, he had recurrences of similar manic "crises" followed by a "depressive" states consisting of cognitive dysfunction, avolition, and anhedonia. He also experienced severe headache and nonspecific neurological symptoms. A diagnosis of migraine was suspected, and a thorough neurological work-up did not yield other diagnoses. Medical history revealed multiple recurrent migraine-equivalents since childhood (particularly, abdominal pain).

Each psychiatric "crisis" was preceded by weeks of increasingly frequent, severe, early morning migraine attacks, with subsequent sleep deprivation, and intensification of migraine symptoms, including aura, with disorganized speech and thinking and bizarre behavior. A prolonged period of complete rest would break the cycle of migraine, accompanied by complete resolution of psychiatric symptoms.

Previous treatments included lithium, buproprion, as well as nortriptyline, stemetil, valproic acid, and quetiapine, none of which were helpful. Family history was positive for migraine and negative for psychiatric disorders. On referral, his medications were propranolol 40 mg twice daily, valproic acid 500 mg twice daily, and lamotrigine 100 mg twice daily. Valproic acid level was therapeutic. A diagnosis of mood disorder, bipolar type secondary to severe migraine was made.

Discussion

This case illustrates the importance of inquiry of neurological symptoms, in particular headache, in patients with bipolar disorder. Patients with bipolar disorder have a greater-than-twofold risk of having migraine, as compared with the general population.1 Treatment for migraine, irrespective of mood disorder, includes amitriptyline, valproate, topiramate, and beta-blockers.2 In patients with bipolar disorder and migraine, judicious use of treatments for both disorders should be considered. Lamotrigine was used for this patient because valproate, although approved for both disorders,3 did not ameliorate the migraine symptoms. For bipolar disorder, lamotrigine is efficacious in the prevention of depressive episodes and, possibly, rapid-cycling type.4 Less evidence supports its use in acute depression or mania.4 For migraine, lamotrigine was not beneficial in a placebo-controlled trial, but had some effectiveness in two open pilot studies for the treatment and prevention of migraine aura.2

Lamotrigine is generally well tolerated, with an acceptable side-effects profile (mainly dizziness, nausea, and insomnia), and may be considered for a patient with aura nonresponsive to other medication. Slow and low dose increase is recommended for side-effects monitoring, especially for severe rashes and Steven's Johnson syndrome. In our patient, lamotrigine was increased to 200 mg twice daily. Use of lamotrigine with valproate may increase lamotrigine concentrations by up to 200% because of increased lamotrigine clearance inhibition,3,5 and valproate levels may also decrease.3 The patient's headache duration eventually decreased to 1 hour nightly, and he returned to work full-time with a 45-minute nap.

Atypical Migraine Manifesting as Mania

Случаи психиатрической манифестации рассеянного склероза

Psychiatric disturbances, such as psychosis, have been often described during the course of multiple sclerosis (MS),1 but rarely at onset of the disease.2 In our work, we present two patients with psychotic disorders at onset of relapsing-remitting MS.

The first patient, a 26-year-old woman, was diagnosed with schizoaffective disorder after the acute appearance of auditory hallucinations and confusion; she was treated with antipsychotic drugs, without significant results. One year later, the patient developed weakness in the left leg and widespread paraesthesia. MR images showed demyelinating lesions in the white matter of the left temporal horn and in the dorsal spine. We made a diagnosis of MS,3 and she started glatiramer acetate treatment to prevent further relapses. To date, after 12 months from the beginning of treatment, the patient shows no relevant neurological and psychiatric alterations.

The second patient, a 30-year-old man, presented (2 years before our observation) with an episode characterized by psychomotor agitation with identity disturbances diagnosed as borderline personality disorder, and he started treatment with olanzapine without results. After a few months, he was referred to our department because of the development of lower-limb weakness and urge-incontinence. An MRI showed several lesions in the subcortical white matter and in the periventricular regions. All findings supported the diagnosis of MS, and the patient started beta-interferon treatment, with progressive clinical improvement, both in neurological and then in psychiatric alterations.

The exact percentage of psychiatric onset of MS is still unknown, but the number of MS patients with psychiatric onset may exceed 1%: in our experience, 2 among a cohort of 148 MS subjects had a psychiatric onset, about 1.3%. In our two cases, only the presence of abnormalities at the neurological examination induced clinicians to consider MS as cause of psychiatric disturbance.

Several reports highlight the association of psychotic symptoms with the presence of demyelinating lesions in the left temporal lobe. In our patients, one had temporal lesions, and the other had periventricular plaques, without significant relationship with the temporal lobe. In our opinion, it is not possible to establish a direct relationship between the sites of cerebral lesions and the psychiatric manifestations observed in MS.

After the psychiatric episode, both patients started long-term treatment with glatiramer acetate or beta-interferon. As reported in literature, glatiramer acetate also results in relief of affective disorders,4 whereas beta-interferon increases anxiety and depression.5 Nevertheless, in our patient, the administration of beta-interferon probably contributed to stabilizing the clinical picture.

Although studies on the prevalence of psychiatric onset of MS are few, we conclude that it may occur in more than 1% (in our experience, about 1.3%) and that, in previously healthy people with acute psychotic disorders, even the presence of the slightest neurological abnormality justifies a cranial MRI examination. Further studies are necessary to evaluate the factors that influence the development of psychiatric disorders in MS and the relationship between disease-modifying drugs and psychiatric disorders.

Psychiatric Onset Of Multiple Sclerosis: Description Of Two Cases

Интраназальный окситоцин в дополнение к эсциталопраму в терапии депрессии

Oxytocin (OT) is, first, a hormone synthesized in the hypothalamus and released by the neurohypophysis, but OT is also involved in the regulation of emotions, and OT receptors are distributed in various brain regions, including the limbic system and amygdala. There is much data suggesting a role for OT as an endogenous antidepressant/anxiolytic hormone and there is support for the idea that stimulation of OT receptors inhibits the hypothalamo-pituitary-adrenal (HPA) axis. The pathophysiology of stress-related diseases, such as depression or anxiety disorders, includes both endogenous/genetic predisposing factors and a dysregulated response to stress, and efficiency of antidepressants involves normalization of HPA-axis abnormalities.

Case Report

RX is a 38-year-old man with a 15-year history of major depressive disorder without psychotic features. His depression severely worsened over a 5-year period despite various antidepressant treatments (tricyclics, serotonin reuptake inhibitors, and serotonin-noradrenaline reuptake inhibitors). He also received benzodiazepines and amisulpride without clinical success. His current treatment involves escitalopram 20 mg. After he gave full informed consent, intranasal synthetic OT (Syntocinon®, 1 puff per nostril each with 4 U.I., twice daily; Novartis Pharmaceuticals Corporation, Switzerland) was added. Initial severity of depression was scored at 17 on the Hamilton Rating Scale for Depression (Ham-D), and anxiety reached 57 on the Spielberger State-Anxiety Inventory (STAI–A). One week after OT initiation, his Ham-D score decreased to 11, and the STAI–A score to 49. At this time, the patient bought a car after several months of hesitancy. He contracted a loan and explained that he was offered good buying conditions. One week later, the patient was very much improved; his HAM-D score dropped to 2, and his STAI–A to 37. Unfortunately, Syntocinon® was stopped after 1 week because the patient missed the visit. After this period, the patient was much worse. Intranasal OT was then delivered at the dose of 36 UI per day in addition to escitalopram, 20 mg. His symptoms improved after 7 days (Ham-D: 5; STAI–A: 48). At the same time, he was very affected by the [bankruptcy] of his [step-]father, who raised him. One week later, he offered to install hardware [electronic equipment] in his parent's house. On The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), he scored at higher levels, going from 1 to 4 by the end of the study.

Discussion

This is the first trial of OT as an adjunct to antidepressant in major depression. Our case report suggests that OT instillation significantly improves mood and anxiety. OT was already shown to reduce responses to social stress,1 to increase trust,2 and improve "mind-reading" in humans.3 It is possible that the efficacy of SSRIs in restoring interest in social interactions is due, in part, to their action on the reward circuit via the OT system.4 Further studies are needed to investigate the effects of OT or OT-receptor selective agonists in additional clinical models to promote the development of psychopharmacology targeting central OT receptors.

Intranasal Oxytocin as an Adjunct to Escitalopram in Major Depression

Акатизия при отмене габапентина

OBJECTIVE: To report a case of akathisia in a patient with type 2 diabetes after abrupt discontinuation of gabapentin.

CASE SUMMARY: A 76-year-old female with type 2 diabetes was admitted for change in mental status, agitation, and restless limb movements. She had been taking gabapentin 3600 mg daily for approximately 1 month for diabetic neuropathy. Her other home medications were glyburide 10 mg twice daily, oxycodone/acetaminophen 5 mg/325 mg every 6 hours as needed for leg pain, and zolpidem 5 mg at bedtime. She had taken none of these drugs for 4 days prior to admission because she was unable to have the prescriptions refilled. Subsequently, the patient exhibited repeated arm and leg motions in response to an inner restlessness. Upon admission to the emergency department, she was agitated and restless; all vital signs and results of laboratory studies were within normal limits. Gabapentin was restarted at the original dosage and the symptoms resolved within 8 hours. Because the patient developed lethargy, the gabapentin dosage was reduced and titrated to the original level over 2 days. After 3 days, the patient was well oriented and experienced no further symptoms. She was discharged on the original dosage of gabapentin.

DISCUSSION: To our knowledge, this is the first reported cases of akathisia induced by gabapentin withdrawal. Available case reports suggest that gabapentin withdrawal can occur at doses ranging from 400-8000 mg/day. Patients experienced symptoms similar to those that develop with benzodiazepine withdrawal and were taking gabapentin for as little as 3 weeks to as long as 5 years. This is the first case report to describe akathisia induced by gabapentin withdrawal. The Naranjo probability scale revealed a probable relationship between akathisia and gabapentin withdrawal.

CONCLUSIONS: If gabapentin discontinuation is desired, it is prudent to gradually taper the dose to avoid withdrawal symptoms, which may occur after as little as 1 month of treatment. Should the patient experience withdrawal symptoms, the optimal treatment is to restart gabapentin.

Akathisia Induced by Gabapentin Withdrawal

Пропранолол в профилактике рецидивов зависимостей

However, the research also suggests that treatment with the β-blocker propranolol can block stress-induced impairment in decision-making in these individuals, potentially reducing the risk for stress-related relapse.

Beta-Blocker May Prevent Stress-Related Relapse in Addicts

Мета-анализ: структурные изменения в мозге больных шизофренией

Background

It is well established that schizophrenia is associated with structural brain abnormalities, but whether these are static or progress over time remains controversial.

Methods

A systematic review of longitudinal volumetric studies using region-of-interest structural magnetic resonance imaging in patients with schizophrenia and healthy control subjects. The percentage change in volume between scans for each brain region of interest was obtained, and data were combined using random effects meta-analysis.

Results

Twenty-seven studies were included in the meta-analysis, with 928 patients and 867 control subjects, and 32 different brain regions of interest. Subjects with schizophrenia showed significantly greater decreases over time in whole brain volume, whole brain gray matter, frontal gray and white matter, parietal white matter, and temporal white matter volume, as well as larger increases in lateral ventricular volume, than healthy control subjects. The time between baseline and follow-up magnetic resonance imaging scans ranged from 1 to 10 years. The differences between patients and control subjects in annualized percentage volume change were −.07% for whole brain volume, −.59% for whole brain gray matter, −.32% for frontal white matter, −.32% for parietal white matter, −.39% for temporal white matter, and +.36% for bilateral lateral ventricles.

Conclusions

These findings suggest that schizophrenia is associated with progressive structural brain abnormalities, affecting both gray and white matter. We found no evidence to suggest progressive medial temporal lobe involvement but did find evidence that this may be partly explained by heterogeneity between studies in patient age and illness duration. The causes and clinical correlates of these progressive brain changes should now be the focus of investigation.

Are There Progressive Brain Changes in Schizophrenia? A Meta-Analysis of Structural Magnetic Resonance Imaging Studies

Добавление N-ацетилцистеина может облегчать симптоматику депрессии при БАР

In an open-label study from Australian researchers presented here at the Ninth International Conference on Bipolar Disorder (ICBD), patients diagnosed with bipolar disorder and given 2000 mg of NAC in addition to their "treatment as usual" showed significantly lower symptom severity scores and increased functioning and quality-of-life scores.

Adjunctive N-Acetyl Cysteine Effective for Bipolar Depression

Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence

Когнитивная дисфункция при злоупотреблении психоактивными веществами

Novel Therapies for Cognitive Dysfunction Secondary to Substance Abuse

Перспективы лечения БАР

Excitotoxicity
Several lines of evidence suggest that glutamatergic system dysfunction (eg, N-methyl d-aspartate [NMDA] receptor complex) may play a critical role in the pathophysiology of bipolar disorder. In keeping with this view, the use of glutamatergic modulators may be predicted to alleviate symptoms and modify the disease process. Postmortem studies indicate that altered NMDA receptor complexes are observed in the brain tissue of patients with bipolar disorder. Moreover, genetic polymorphisms for genes implicated in the glutamate receptor complex have been associated with this disorder.6
Riluzole, an inhibitor of glutamate release, is approved by the FDA for the treatment of amyotrophic lateral sclerosis. This agent, at a dosage of 50 to 200 mg/d, was evaluated in an 8-week add-on study in combination with lithium in 14 adults with bipolar depression, 6 of whom had bipolar I disorder, and 8 of whom had bipolar II disorder. Eight patients completed the 8-week trial.6 Significant improvement in depressive symptoms was noted in weeks 5 through 8 as measured by the Montgomery Asberg Depression Rating Scale (MADRS).
Ketamine is a noncompetitive NMDA antagonist that has been evaluated in subanesthetic doses in persons with bipolar disorder.7 Results from a double-blind, randomized, placebo-controlled, crossover study indicate that a single intravenous infusion of ketamine(Drug information on ketamine) combined with lithium or valproate(Drug information on valproate) was capable of alleviating depressive symptoms within 40 minutes of administration when compared with placebo.7 The benefit of ketamine was sustained through day 3. Overall, 71% of patients responded to ketamine and 6% responded to placebo at some point during the trial. Ketamine was not associated with significant increases in hypomania or mania but was associated with dissociative symptoms.

Cyclooxygenase-2 (COX-2) inhibitors have been shown to protect against glutamate-induced neurotoxicity; to prevent normal aging-related increases of cytokines, prostaglandins, and TNF in neurons; and to modulate the hypothalamic adrenal axis.10 The COX-2 inhibitor celecoxib(Drug information on celecoxib) was evaluated as a potential antidepressant in adults with bipolar I/II depression (N = 28).10 This drug was administered at a dosage of 400 mg daily in combination with a mood stabilizer or antipsychotic medication as part of a 6-week, randomized, double-blind, placebo-controlled study. Depressive symptoms in both the treatment group and the placebo group improved, with a statistically significant (P = .01) advantage at week 1 in patients treated with celecoxib compared with patients who received placebo. Although there was an advantage in favor of the treatment group at week 1, both the active-treatment and placebo groups had similar reductions for each of the remaining observation points.

Several case reports and case series suggest that insulin sensitizers (eg, rosiglitazone(Drug information on rosiglitazone)) may offer an antidepressant effect in persons with major depressive disorder. Studies are currently under way in bipolar disorder. For example, several studies are evaluating the antidepressant effects of intranasal insulin and insulin secretagogues (eg, incretins) in bipolar disorder. Moreover, there is ongoing research to determine whether weight loss, bariatric surgery, and dietary modification (eg, ketogenic diet) improve depressive symptoms in persons with bipolar disorder.

Results from a randomized, double-blind, multicenter, placebo-controlled study of adults with bipolar disorder (N = 75) indicate that N-acetylcysteine (1 g bid) adjunctive to usual medications was capable of alleviating depressive symptoms as measured by the MADRS.14 The benefit on depressive symptoms was noted at week 20 as part of this 24-week study. Benefits were noted by week 8 on the Global Assessment of Functioning Scale and Social and Occupational Functioning Assessment Scale. N-acetylcysteine did not induce hypomania or mania and was well tolerated. Adverse events reported in more than 15% of the N-acetylcysteine group included change in energy, headaches, heartburn, and increased joint pain.

Armodafinil is the longer-lasting isomer of modafinil, and its therapeutic indications are similar to those of the racemic agent modafinil. Armodafinil at a dosage of 150 mg/d was evaluated as an antidepressant in adults with bipolar disorder who received either olanzapine, lithium, or valproic acid as part of an 8-week double-blind placebo-controlled study.

Novel Treatment Avenues for Bipolar Depression

MDMA в психиатрии

The pharmacological effects of MDMA include serotonin release; serotonin type 2 receptor stimulation; and an increase in levels of the neurohormones oxytocin(Drug information on oxytocin), prolactin, and cortisol.24-29 Serotonin release plays an important role in producing the subjective effects of MDMA.30-33 Pretreatment with SSRIs reduces most acute subjective and physiological effects of MDMA, including effects on mood and perception. Serotonin release directly or indirectly leads to an elevation in oxytocin levels, possibly by stimulating serotonin type 1A receptors.24,28,34 Studies suggest that oxytocin plays an important role in stress response, reduces the fear response, and increases social affiliation and trust35-39; thus, elevated oxytocin levels might help patients form a therapeutic alliance and revisit traumatic experiences in an emotionally engaged state.
Elevation in oxytocin levels after MDMA administration has been associated with greater sociability and more gregarious behavior.24 MDMA has recently been shown to decrease perception of negative emotions in others and perception of threat-related signals, such as fear, which might increase social approach behavior.40 It has been postulated that prolactin release following MDMA administration may contribute to a postorgasmic-like sense of relaxation and receptivity.41 The neurocircuitry model of PTSD postulates a deficit in extinction of fear conditioning mediated by the amygdala and the ventromedial prefrontal cortex, a model supported by findings of reduced hippocampal activity and volume, increased activity in the amygdala, and decreased activation of the medial prefrontal cortex in persons with PTSD.42,43
Gamma and colleagues44 used positron emission tomography to measure cerebral blood flow 75 minutes after MDMA was given to healthy volunteers. Their findings showed increases in cerebral blood flow in the ventromedial frontal and occipital cortex and decreases in the left amygdala. MDMA may produce some of its effects through these acute changes in brain activity, which may reverse abnormalities associated with PTSD and thereby allow effective processing of traumatic memories. The nature of the effects is consistent with much of what we observed in our clinical trial.

Does MDMA Have a Role in Clinical Psychiatry?

Координация при БАР

Problems with postural control may be a core feature of bipolar disorder (BD) and not just a random symptom, new research suggests.

In a small comparison study of 32 patients, those with BD showed a "greater sway magnitude" compared to healthy controls, especially when asked to close their eyes.

Off Balance? Postural Problems May Point to Bipolar Disorder

Мета-анализ: каннабиноиды и риск психоза

Context A number of studies have found that the use of cannabis and other psychoactive substances is associated with an earlier onset of psychotic illness.

Objective To establish the extent to which use of cannabis, alcohol, and other psychoactive substances affects the age at onset of psychosis by meta-analysis.

Data Sources Peer-reviewed publications in English reporting age at onset of psychotic illness in substance-using and non–substance-using groups were located using searches of CINAHL, EMBASE, MEDLINE, PsycINFO, and ISI Web of Science.

Study Selection Studies in English comparing the age at onset of psychosis in cohorts of patients who use substances with age at onset of psychosis in non–substance-using patients. The searches yielded 443 articles, from which 83 studies met the inclusion criteria.

Data Extraction Information on study design, study population, and effect size were extracted independently by 2 of us.

Data Synthesis Meta-analysis found that the age at onset of psychosis for cannabis users was 2.70 years younger (standardized mean difference = –0.414) than for nonusers; for those with broadly defined substance use, the age at onset of psychosis was 2.00 years younger (standardized mean difference = –0.315) than for nonusers. Alcohol use was not associated with a significantly earlier age at onset of psychosis. Differences in the proportion of cannabis users in the substance-using group made a significant contribution to the heterogeneity in the effect sizes between studies, confirming an association between cannabis use and earlier mean age at onset of psychotic illness.

Conclusions The results of meta-analysis provide evidence for a relationship between cannabis use and earlier onset of psychotic illness, and they support the hypothesis that cannabis use plays a causal role in the development of psychosis in some patients. The results suggest the need for renewed warnings about the potentially harmful effects of cannabis.

Cannabis Use and Earlier Onset of Psychosis

Плацебо часто работает лучше лекарства

Плацебо часто работает лучше лекарства

Депо-формы антипсихотиков при первом эпизоде шизофрении

OBJECTIVE: Data on the effectiveness of antipsychotics in the early phase of schizophrenia are limited. The authors examined the risk of rehospitalization and drug discontinuation in a nationwide cohort of 2,588 consecutive patients hospitalized for the first time with a diagnosis of schizophrenia between 2000 and 2007 in Finland.

METHOD: The authors linked national databases of hospitalization, mortality, and antipsychotic prescriptions and computed hazard ratios, adjusting for the effects of sociodemographic and clinical variables, the temporal sequence of the antipsychotics used, and the choice of the initial antipsychotic for each patient.

RESULTS: Of 2,588 patients, 1,507 (58.2%) collected a prescription for an antipsychotic during the first 30 days after hospital discharge, and 1,182 (45.7%, 95% confidence interval [CI]=43.7–47.6) continued their initial treatment for 30 days or longer. In a pairwise comparison between depot injections and their equivalent oral formulations, the risk of rehospitalization for patients receiving depot medications was about one-third of that for patients receiving oral medications (adjusted hazard ratio=0.36, 95% CI=0.17–0.75). Compared with oral risperidone, clozapine (adjusted hazard ratio=0.48, 95% CI=0.31–0.76) and olanzapine (adjusted hazard ratio=0.54, 95% CI=0.40–0.73) were each associated with a significantly lower rehospitalization risk. Use of any antipsychotic compared with no antipsychotic was associated with lower mortality (adjusted hazard ratio=0.45, 95% CI=0.31–0.67).

CONCLUSIONS: In Finland, only a minority of patients adhere to their initial antipsychotic during the first 60 days after discharge from their first hospitalization for schizophrenia. Use of depot antipsychotics was associated with a significantly lower risk of rehospitalization than use of oral formulations of the same compounds. Among oral antipsychotics, clozapine and olanzapine were associated with more favorable outcomes. Use of any antipsychotic was associated with lower mortality.

A Nationwide Cohort Study of Oral and Depot Antipsychotics After First Hospitalization for Schizophrenia

Риски и преимущества перехода на терапию одним антипсихотическим препаратом

The study did find that treatment discontinuation was more common in the group that switched to monotherapy than in the polypharmacy group, but the symptom control and weight loss associated with the switch to monotherapy suggests that monotherapy may be an option worth trying for patients who are relatively stable.

Monotherapy After Polypharmacy Effective for Some Patients

Метирапон и психотравмирующие воспоминания

“Metyrapone is a drug that significantly decreases the levels of cortisol, a stress hormone that is involved in memory recall,” explained lead author Marie-France Marin, a doctoral student.

Manipulating cortisol close to the time of forming new memories can decrease the negative emotions that may be associated with them, the researchers said.

“The results show that when we decrease stress hormone levels at the time of recall of a negative event, we can impair the memory for this negative event with a long-lasting effect,” said Sonia Lupien, Ph.D., who directed the research.

The Drug Metyrapone to Erase Bad Memories?

Индивидуальные различия в ответе на терапию оланзапином

The antipsychotic drug, olanzapine, one of the most widely used drugs in clinical medicine, has a high rate of discontinuation due to inefficacy and/or adverse effects. We identified a single nucleotide polymorphism in the drug metabolizing enzyme, cytochrome P450 3A43 (CYP3A43; rs472660), that highly significantly predicted olanzapine clearance in the Clinical Antipsychotic Trials of Intervention Effectiveness trial (P=5.9e−7). Moreover, at standard antipsychotic doses, 50% of individuals with the high clearance genotype (AA) have trough blood levels below the therapeutic range. Interestingly, a much higher proportion of African Americans carry the A allele compared with Caucasians (allele frequency 67 vs 14%). After accounting for CYP3A43 genotype, race is no longer a significant predictor of olanzapine clearance. Olanzapine clearance was associated with measures of clinical response. Patients with greater clearance had higher symptom ratings and were more likely to discontinue treatment due to an inadequate response. Our data identify a genetic mechanism for variation in olanzapine response and demonstrate that blood level monitoring of olanzapine treatment is advisable.

Genetic variation in CYP3A43 explains racial difference in olanzapine clearance

Диагностика и лечение смешанных состояний при БАР

Identifying and Managing Patients With Mixed States in Bipolar Disorder

Лекарственные средства вызывающие депрессию

Interferons are powerful antivirals but they have the dubious honor of being one of the few medical drugs clearly implicated in causing depression. Others include reserpine, an anti-hypertensive and rimonabant, a weight-loss drug (it got banned for this reason).

The anti-malarial mefloquine can cause a range of neuropsychiatric symptoms including depression but also hallucinations and nightmares, as can the HIV drug efavirenz which I covered recently.

Most people who take each of these drugs don't experience problems but in a non-trivial minority it happens. It obviously poses a serious problem for doctors, but it's also very interesting for people researching mood and depression. Work out why these drugs cause depression, and it might help work out why people get "normal" clinical depression.

For example, just recently it was shown that mefloquine has a unique and unusual effect on cells in the dopamine system of the brain, responsible for motivation and pleasure. Whether this explains the side-effects is an open question but without mefloquine we wouldn't even be able to ask it.

As for interferons, which are actually not drugs as such but rather molecules produced by the immune system during infections, it's given rise to the inflammation theory of depression. There's always a risk, though, that by focussing too much on just one class of depressing drug, you'll end up with a narrow theory that can't account for the others.

Antivirals and Suicide

Социальное функционирование при долгосрочном приёме антипсихотиков, преимущества оланзапина

Background
When treating schizophrenia, improving patients' productivity level is a major goal considering schizophrenia is a leading cause of functional disability. Productivity level has been identified as the most preferred treatment outcome by patients with schizophrenia. However, little has been done to systematically investigate productivity levels in schizophrenia. We set out to better understand the change in productivity level among chronically ill patients with schizophrenia treated with olanzapine compared with other antipsychotic medications. We also assessed the links between productivity level and other clinical outcomes.

Methods
This post hoc analysis used data from 6 randomized, double-blind clinical trials of patients with schizophrenia or schizoaffective disorder, with each trial being of approximately 6 months duration. Change in productivity level was compared between olanzapine-treated patients (HGBG, n=172; HGHJ, n=277; HGJB, n=171; HGLB, n=281; HGGN, n=159; HGDH, n=131) and patients treated with other antipsychotic medications (separately vs. haloperidol [HGGN, n=97; HGDH, n=132], risperidone [HGBG, n=167; HGGN, n=158], quetiapine [HGJB, n=175], ziprasidone [HGHJ, n=271] and aripiprazole [HGLB, n=285]). Productivity was defined as functional activities/work including working for pay, studying, housekeeping and volunteer work. Productivity level in the prior 3 months was assessed on a 5-point scale ranging from no useful functioning to functional activity/work 75% to 100% of the time.

Results
Chronically ill patients treated with olanzapine (OLZ) experienced significantly greater improvement in productivity when compared to patients treated with risperidone (RISP) (OLZ= 0.22+/-1.19, RISP=-0.03+/-1.17, p=0.033) or ziprasidone (ZIP) (OLZ=0.50+/-1.38, ZIP=0.25+/-1.27, p=0.026), but did not significantly differ from the ziprasidone, quetiapine, aripiprazole or haloperidol treatment groups. Among first episode patients, OLZ therapy was associated with greater improvements in productivity levels compared to haloperidol (HAL), during the acute phase (OLZ=-0.31+/-1.59, HAL=-0.69+/-1.56, p=0.011) and over the long-term (OLZ=0.10+/-1.50, HAL=-0.32+/-1.91, p=0.008). Significantly more chronically ill and first episode patients treated with olanzapine showed moderately high (>50%-75% of the time) and high levels of productivity (>75%-100% of the time) at endpoint, when compared to risperidone- or haloperidol-treated patients (p<.05), respectively. Higher productivity level was associated with significantly higher study completion rates and better scores on the positive, negative, disorganized thoughts, hostility and depression subscales of the Positive and Negative Symptom Scale (PANSS).

Conclusions
Some antipsychotic medications significantly differed in beneficial impact on productivity level in the long-term treatment of patients with schizophrenia. Findings further highlight the link between clinical and functional outcomes, showing significant associations between higher productivity, lower symptom severity and better persistence on therapy. TRIAL REGISTRATION: clinicaltrials.gov identifier NCT00088049; NCT00036088

Change in Level of Productivity in the Treatment of Schizophrenia with Olanzapine or Other Antipsychotics