PharmGkb - Pharmacogenomics Knowledge Base

Our Mission: To collect, encode, and disseminate knowledge about the impact of human genetic variations on drug response. We curate primary genotype and phenotype data, annotate gene variants and gene-drug-disease relationships via literature review, and summarize important PGx genes and drug pathways.

Вилазодон: механизм действия и побочные эффекты

Vilazodone is the first approved drug that is both a combination selective serotonin reuptake inhibitor (SSRI) and a partial agonist of serotonergic (5HT1A) receptors. Its mechanism of action "is not fully understood but is thought to be related to its enhancement of serotonergic activity in the central nervous system through selective inhibition of serotonin reuptake," according to a press release from Clinical Data, which holds worldwide marketing rights for the drug.

In 2 randomized, double-blind trials in adults with MDD, vilazodone 40 mg once daily was shown to be significantly superior to placebo at improving depressive symptoms, as measured by a mean change in the Montgomery-Asberg Depression Rating Scale total score from baseline to week 8. Patients in the study were titrated up to the 40-mg dose over the course of 2 weeks.

In safety studies involving 2177 patients diagnosed with MDD, the most common adverse events were diarrhea, nausea, vomiting, and insomnia. In all, 7.1% of patients who received vilazodone discontinued treatment because of an adverse reaction compared with 3.2% of control patients. The drug was not associated with change in body weight over 8 weeks, and there were no reported drug-related abnormalities in hepatic or cardiac parameters or vital signs, the company says.

Коррекция метаболических побочных эффектов антипсихотиков

This systematic review and meta-analysis included 32 randomized, open and double-blind, placebo-controlled studies (mean duration: 13.1 weeks, range: 6-16 weeks) with a total of 1482 subjects and which tested the following 15 medications: amantadine, dextroamphatamine, d-fenfluramine, famotidine, fluoxetine, fluvoxamine, metformin, nizatidine, orlistat, phenylpropanolamine, reboxetine, rosiglitazone, sibutramine, topiramate, and metformin plus sibutramine).
Five of the agents assessed lead to significantly greater weight loss than placebo. The greatest weight loss was achieved with metformin (N = 7, n = 334, -2.94 kg [CI, -4.89, -0.99]), followed by d-fenfluramine (N = 1, n = 16, -2.60 kg [CI,-5.14, -0.06]), sibutramine (N = 2, n = 55, -2.56 kg [CI, -3.91, -1.22]), topiramate (N = 2, n = 133, -2.52, [CI, -4.87, -0.16]) and reboxetine (N = 2, n = 79, -1.90 kg [CI, -3.07, -0.72]). Nausea rates did not differ between treatment and placebo groups. Results on the secondary outcome measures of waist circumference and weight gain, carbohydrate metabolism and blood lipids as well as sensitivity analysis regarding prevention vs intervention trials were largely heterogeneous. No significant differences between treatment and placebo groups were found for the secondary outcome measures of psychiatric symptoms and adverse events.

The Year in Psychosis and Bipolar Disorder: Treating Antipsychotic-related Metabolic Abnormalities

Омега-3 ПНЖК в предупреждении развития психоза

Eighty-one putatively prodromal patients (16.4 years, 33.3% male) were included in this 12-month, randomized, double-blind, placebo-controlled trial comparing 1.2 g omega-3 PUFA (700 mg eicosapentaenoic acid [EPA] and 420 mg docosahexaenoic acid [DHEA]h) with placebo over 12 weeks with a follow-up of 40 weeks off medication/placebo. Randomization was stratified with regard to depressive symptoms (cut-off score on the Montgomery-Asberg Depression Rating Scale [MADRS]). Operationally defined conversion rates served as the outcome measure, with psychopathology ratings as secondary measures. Overall, this study had a very high 12-month completion rate (93.8%); adherence rates based on pill count and self-rating were as high as 81% and 75% in the active and placebo groups. The main result was that patients treated for 3 months with omega-3 PUFAs had significantly lower conversion rates to psychosis, at the end of the acute 3-month treatment phase and also after an additional 9 months off omega-3 PUFA (12-month conversion rate: 4.9% vs 27.5%). The number needed to treat (NNT) to prevent 1 additional patient with conversion to psychosis at 1 year was only 5. In addition, positive, negative, and general symptoms measured by the Positive and Negative Syndrome Scale (PANSS) were significantly more reduced in the active treatment group, whereas adverse events did not differ. Finally, the ratio of putatively beneficial omega-3 to omega-6 fatty acids increased significantly, linking the clinical effects to a proposed biological mechanism.

The Year in Psychosis and Bipolar Disorder: Omega-3s and Psychosis Prevention

Влияние пищевых предпочтений на частоту тревожных и депрессивных расстройств

Thus, the present study used a composite dietary quality score as well as 3 dietary patterns ("traditional," "western," and "modern") derived by factor analysis to measure overall dietary intake and controlled for age, education, socioeconomic status, physical activity, alcohol and nicotine consumption, as well as body mass index as potential confounders. The "traditional" diet was mainly comprised of vegetables, fruit, beef, lamb, fish, and whole-grain foods; the "western" diet consisted mainly of meat pies, processed meats, pizza, chips, hamburgers, white bread, sugar, flavored milk drinks, and beer; and the "modern" diet comprised fruits and salad plus fish, tofu, beans, nuts, yogurt, and red wine. Psychopathology was assessed with the Structured Clinical Interview for DSM IV-TR, Non-patient Version (SCID I/NP) and the General Health Questionnaire (GHQ-12).

The results showed that, controlled for all potential confounders, a "traditional" diet was associated with significantly lower odds of depressive and anxiety disorders, while a "western" diet was significantly associated with higher general symptoms on the GHQ-12. The "western" diet was furthermore correlated with higher odds of depressive disorders before adjustment for confounders, while adjustment reduced it to a trend. The diet quality score was inversely related with general symptoms on the GHQ-12, also when controlled for confounders. Interestingly, the authors noted a positive correlation between a "modern" diet and depressive disorders after adjustment for confounders.

The Year in Psychosis and Bipolar Disorder: Association of Diet With Depression and Anxiety

Восприимчивость к глютену в норме, при шизофрении и при целиакии

Individuals with recent-onset psychosis and with multi-episode schizophrenia who have increased antibodies to gliadin may share some immunologic features of celiac disease, but their immune response to gliadin differs from that of celiac disease.

Markers of Gluten Sensitivity and Celiac Disease in Recent-Onset Psychosis and Multi-Episode Schizophrenia.

In contrast to previous reports, we found no evidence for celiac disease in patients with chronic schizophrenia as manifested by the presence of serum IgA anti-endomysial antibodies. It is unlikely that there is an association between gluten sensitivity and schizophrenia.

"Bread madness" revisited: screening for specific celiac antibodies among schizophrenia patients.

These findings indicate that the anti-gliadin immune response in schizophrenia has a different antigenic specificity from that in celiac disease and is independent of the action of transglutaminase enzyme and HLA-DQ2/DQ8.

Novel immune response to gluten in individuals with schizophrenia

We report the unexpected resolution of longstanding schizophrenic symptoms after starting a low-carbohydrate ketogenic diet. After a review of the literature, possible reasons for this include the metabolic consequences from the elimination of gluten from the diet, and the modulation of the disease of schizophrenia at the cellular level.

Schizophrenia, gluten, and low-carbohydrate, ketogenic diets: a case report and
review of the literature

There are several case reports of coexistence of coeliac sprue and depression, schizophrenia and anxiety. Coeliac disease should be taken into consideration in patients with psychiatric disorders, particularly if they are not responsive to psychopharmacological therapy, because withdrawal of gluten from the diet usually results in disappearance of symptoms.

Psychiatric symptoms and coeliac disease.

A double-blind control trial of gluten-free versus a gluten-containing diet was carried out in a ward of maximum security hospital: 24 patients were studied for 14 weeks. Most suffered from psychotic disorders, particularly schizophrenia. Various dimensions of behaviour were rated on the Psychotic In-Patient profile (PIP) at different stages. There were beneficial changes in the whole group of patients between pre-trial and gluten-free period in five dimensions of the PIP, maintained during the gluten challenge period; these changes could be attributed to the attention the patients received. Two patients improved during the gluten-free period and relapsed when the gluten diet was reintroduced.

A double-blind gluten-free/gluten-load controlled trial in a secure ward population.

Эффективность атипичных антипсихотиков при делирии

Haloperidol is the mainstay of delirium treatment.8 Compared with atypical antipsychotics in delirium treatment, haloperidol doses < 3.5 mg/d have not been associated with an increase in extrapyramidal symptoms (EPS).9

Although not devoid of side effects, atypical antipsychotics are an alternative to haloperidol.8,10 This article briefly summarizes the current evidence on the use of atypicals for treating delirium.

Evidence for antipsychotics

Haloperidol has been the antipsychotic of choice for treating delirium symptoms. It is recommended by the Society of Critical Care Medicine7 and is regarded as safe, cost-effective, and efficacious for delirium5 despite a risk of dose-related EPS and potential cardiac conduction alterations.5,14

Risperidone is not indicated for treating delirium but is one of the most extensively studied atypical antipsychotic alternatives to haloperidol. Evidence consisting primarily of case reports has illustrated the potential efficacy of risperidone in treating delirium (Table 2).10,15-19

Clinical Point

In a small double-blind, randomized trial, risperidone was effective but not significantly more so than low-dose haloperidol

In 2004, Parellada et al17 observed significant mean improvements in all measures (Delirium Rating Scale [DRS], Mini-Mental State Exam [MMSE], positive subscale of the Positive and Negative Syndrome Scale [PANSS-P], and Clinical Global Impressions scale [CGI]) in 64 delirium patients treated with risperidone. In a 2004 double-blind trial of 28 delirium patients randomly assigned to risperidone or haloperidol, risperidone was effective but not significantly more efficacious than low-dose haloperidol for acute delirium treatment.18

Advantages of using risperidone include its lack of anticholinergic effects. Potential side effects include dose-related EPS and weight gain, which were observed in patients with schizophrenia and other psychotic disorders and dementia-related behavioral disorders.20,21

Olanzapine. Much like risperidone, olanzapine’s use in delirium is relatively well described in the literature (Table 3).22-24 In a randomized, placebo-controlled study comparing olanzapine with haloperidol, 175 patients were treated for 7 days with olanzapine, haloperidol, or placebo. Olanzapine and haloperidol showed significantly greater DRS score improvement than placebo.24 There was no difference between olanzapine and haloperidol outcomes; however, olanzapine showed significant improvement by days 2 and 3 compared with haloperidol. Haloperidol was associated with a significantly higher rate of dystonia compared with olanzapine.

Olanzapine carries a risk of anticholinergic effects. This can be a drawback, especially in patients such as Ms. B whose delirium has an anticholinergic component. Olanzapine is available in an IM formulation, which can be an advantage when addressing agitation and medical comorbidities of delirium.

Quetiapine. Case reports have suggested quetiapine is effective for delirium (Table 4).10,25-27 In a prospective, open-label trial, Sasaki et al26 treated 12 delirium patients with a single bedtime dose of quetiapine. All patients achieved remission within several days of beginning quetiapine, and the drug was well tolerated with no detected EPS or excessive sedation.

Clinical Point

Quetiapine reduced delirium duration and agitation in a small double-blind randomized trial of adult ICU patients

In 2010 Devlin et al27 reported on the efficacy and safety of quetiapine in a prospective double-blind, placebo-controlled study of 36 adult ICU patients. Compared with those receiving placebo, patients taking quetiapine had a statistically significant shorter time to first resolution of delirium, reduced duration of delirium, and less agitation as measured by the Sedation-Agitation Scale. Mortality, ICU length of stay, and incidence of QTc prolongation did not differ, but patients treated with quetiapine were more likely to be discharged home or to rehabilitation and to have more somnolence. Quetiapine’s side effect profile includes a low occurrence of EPS, sedation, and dose-related anticholinergic effects.25

Ziprasidone. The literature on ziprasidone for delirium so far is limited to a few anecdotal case reports (Table 5).28-31 In 2002, Leso and Schwartz28 successfully used ziprasidone to treat delirium in a patient with human immunodeficiency virus and cryptococcal meningitis. Ziprasidone was chosen for its lack of sedating effects and low EPS risk. The patient experienced significant clearing of his delirium and lowering of his DRS score. Ziprasidone eventually was discontinued because a fluctuating QTc interval associated with comorbid electrolyte imbalances—a potential drawback to ziprasidone.

In the case of Ms. B, ziprasidone appeared to be efficacious; however, improvement in her medical condition, rather than ziprasidone treatment, is the most likely explanation for the resolution of her delirium symptoms.

Aripiprazole. Alao et al30 reported on 2 delirium patients treated with 30 mg and 15 mg aripiprazole; improvement was monitored using the MMSE and DRS (Table 5).28-31 In both cases, confusion, disorientation, and agitation improved within 7 days of treatment. In the first case, the patient’s MMSE score improved from 5 to 28 and his DRS score decreased from 28 to 6. The second patient’s MMSE score improved from 7 to 27 and her DRS score went from 18 to 6.

Straker et al31 reported on 14 delirium patients treated with aripiprazole. Twelve patients had a ≥50% reduction in DRS, Revised-98 scores, and 13 showed improvement on CGI scores. The rate of adverse side effects was low. Three patients had prolonged QTc interval, but no patients developed arrhythmia or discontinued aripiprazole.

Atypical antipsychotics for delirium: A reasonable alternative to haloperidol?

Двигательные расстройства после прививки от гриппа

After a routine flu shot last fall, Jennings said she began experiencing fever and painful body aches. The symptoms quickly progressed until she could only walk with a twisted, halting gait, and had trouble reading, doing simple math -- even remembering things. Her condition put a halt on her once-frenetic lifestyle.

Jennings developed another odd symptom -- a strange foreign accent; the Midwestern woman suddenly sounded British. "It sounds like an accent, but it's not. I just can't pronounce words anymore," she said.

Miraculously, Jennings could run. She also found out she could walk backwards, and even sideways, and that while doing so, her speech returned to normal.

Traditional medicine having failed her, Jennings said she decided to do something "outside the box," and ended up at a North Carolina clinic run by Dr. Rashid Buttar.

Buttar uses an unproven, alternative treatment for almost every medical condition, from autism to cancer. It's called "chelation," the chemical removal of metals from the body.

Within less than two weeks, Jennings' condition seemed to improve: she walked again, and her stutter disappeared.

But just as she was leaving Dr. Buttar's clinic on her last visit in December 2009 -- with "20/20's" cameras rolling -- it all seemed to fall apart. Jennings was in distress again. She could no longer walk forward, and had to be taken out in a wheelchair.

Novella is confident whatever she has was not caused by mercury in a flu shot.

Other experts consulted by "20/20" agree. Dr. Charles McKay, a board member of the American College of Medical Toxicology, said Jennings would have been exposed to far less mercury in a flu shot than in a tuna steak.

When asked by "20/20" about the effectiveness of his chelation treatments, Buttar claimed he gets results and pointed to patient testimonials on his website. But when pressed by Jim Avila that "anecdotal stories on the Internet are not science," Buttar responded: "Nobody said it was science."

"It's a psychogenic disorder rather than a neurological disorder," Novella said.

Novella feels the temporary improvements Jennings experienced while undergoing Buttar's treatment were also in her mind: she got better because she thought she would. He called it "the placebo effect on steroids."

Medical Mystery or Hoax: Did Cheerleader Fake a Muscle Disorder?

Антидепрессанты малоэффективны при невыраженных депрессивных расстройствах

To review systematically the evidence of efficacy and acceptability of antidepressant and benzodiazepine treatments for patients with minor depression.

Method

A systematic review and meta-analysis of double-blind randomised controlled trials comparing antidepressants or benzodiazepines v. placebo in adults with minor depression. Data were obtained from MEDLINE, CINAHL, EMBASE, PsycInfo, Cochrane Controlled Trials Register and pharmaceutical company websites. Risk of bias was assessed for the generation of the allocation sequence, allocation concealment, masking, incomplete outcome data, and sponsorship bias.

Results

Six studies met inclusion criteria. Three studies compared paroxetine with placebo; fluoxetine, amitriptyline and isocarboxazid were studied in one study each. No studies compared benzodiazepines with placebo. In terms of failures to respond to treatment (6 studies, 234 patients treated with antidepressants and 234 with placebo) no significant difference between antidepressants and placebo was found (relative risk (RR) 0.94, 95% CI 0.81–1.08). In terms of acceptability, data extracted from two studies (93 patients treated with antidepressants and 93 with placebo) showed no statistically significant difference between antidepressants and placebo (RR = 1.06, 95% CI 0.65–1.73). There was no statistically significant between-study heterogeneity for any of the reported analyses.

Conclusions

There is evidence showing there is unlikely to be a clinically important advantage for antidepressants over placebo in individuals with minor depression. For benzodiazepines, no evidence is available, and thus it is not possible to determine their potential therapeutic role in this condition.

Efficacy of antidepressants and benzodiazepines in minor depression: systematic review and meta-analysis