Случай злоупотребления кока-колой в рамках депрессии

BACKGROUND: Cola is an extremely popular caffeinated soft drink. The media have recently cited a poll in which 16% of the respondents considered themselves to be addicted to cola soft drinks. We find the contrast between the apparent prevalence of cola addiction and the lack of scientific literature on the subject remarkable. To our knowledge, this is the first case of cola dependency described in the scientific literature.
CASE PRESENTATION:
The patient is a 40-year-old woman, who when feeling down used cola to give her an energy boost and feel better about herself. During the past seven years her symptoms increased, and she was prescribed antidepressant medication by her family doctor. Due to worsening of symptoms she was hospitalised and later referred to a specialised outpatient clinic for affective disorders. At entry to the clinic she suffered from constant tiredness, lack of energy, failing concentration, problems falling asleep as well as interrupted sleep. She drank about three litres of cola daily, and she had developed a metabolic syndrome.The patient fulfilled the ICD-10 criteria for dependency, and on the Yale Food Addiction Scale (YFAS) she scored 40 points. Her clinical mental status was at baseline assessed by the Major Depression Inventory (MDI) = 41, Hamilton Depression - 17 item Scale (HAMD-17) = 14, Young Mania Rating Scale (YMRS) = 2 and the Global Assessment of Functioning (GAF) Scale = 45.During cognitive therapy sessions she was guided to stop drinking cola and was able to moderate her use to an average daily consumption of 200 ml of cola Her concentration improved and she felt mentally and physically better. At discharge one year after entry her YFAS was zero. She was mentally stable (MDI =1, HAMD-17 = 0, YMRS = 0 and GAF = 85) and without antidepressant medication. She had lost 7.2 kg, her waistline was reduced by 13 cm and the metabolic syndrome disappeared.
CONCLUSION:
This case serves as an example of how the overconsumption of a caffeinated soft drink likely was causing or accentuating the patient's symptoms of mental disorder. When diagnosing and treating depression, health professionals should pay attention to potential overuse of cola or other caffeinated beverages.

 A case of cola dependency in a woman with recurrent depression.

Полиморфизм CYP2D6 и приверженность лечению антидепрессантами

Early discontinuation of antidepressant drugs (ADPs) therapy is common, occurring in about 30% of patients by week 6.1, 2 Among the most relevant reasons for ADP discontinuation are adverse drug reactions and lack of improvement,3 which can be explained by interindividual variability in drug metabolism. Thus, discontinuation of amitriptyline or fluoxetine, two of the most commonly used ADPs worldwide, which are mainly metabolized by CYP2D6, could be related to CYP2D6 genetic polymorphism.

...

Despite the limitations of the present study (naturalistic observation, non-fixed dose, lack of evaluation of drug plasma concentrations and efficacy), a relationship between CYP2D6 polymorphism and early discontinuation of fluoxetine or amitriptyline monotherapy treatment was observed. There were differences across CYP2D6 groups in the rate of ADP discontinuation at week 4 (P < 0.01;Table 1). Overall, the rates of ADP discontinuation were 25, 36 and 46% at weeks 4, 8 and 12, respectively; no patient returned after dropout. All UMs discontinued treatment within the first 4 weeks, whereas no PM did so within 12 weeks.

 CYP2D6 ultrarapid metabolism and early dropout from fluoxetine or amitriptyline monotherapy treatment in major depressive patients

Экспериментальные антидепрессанты AZD6765 и GLYX-13

A small, randomized crossover study conducted by investigators at the National Institute of Mental Health Health (NIMH) showed that after a single infusion of AZD6765, almost 32% of the patients with treatment-resistant major depressive disorder (MDD) had a significant decrease in symptom scores 80 minutes later vs 15% of the patients after they had received matching placebo.

Although after receiving the experimental drug, the total decrease in scores lasted only for 30 minutes, some of the patients did experience residual antidepressant effects up to 2 days later.

 Experimental Drug May Help Depression 'in Minutes'

In clinical trials administered at 12 sites across the country, a single dose of GLYX-13 resulted in significant reductions in depression symptoms among subjects who had shown little improvement with previous drugs. (Subjects had failed treatment with one or more antidepressant agents.)

The positive effects of GLYX-13 were evident within 24 hours and lasted an average of seven days. Side effects of GLYX-13 were mild to moderate and were consistent with those observed in subjects receiving a placebo.

New Fast-Acting Antidepressant, GLYX-13, Shows Promise in Clinical Trials

Количество значительно взаимодействующих с фуранокумаринами лекарственных средств растёт

"The number of drugs on the market with the potential to produce serious adverse and in many cases life-threatening effects when combined with grapefruit has markedly increased over the past few years from 17 to 43 in four years," said lead researcher David Bailey, from the Lawson Health Research Institute in London, Ontario.

Citrus fruits such as limes and Seville oranges, often used in marmalade, also contain the active ingredients -- called furanocoumarins -- that cause the dangerous interactions, the researchers said. The chemicals apparently inhibit an enzyme that normally deactivates about half the effects of medication.

More New Drugs a Bad Fit With Grapefruit, Study Finds

Допаминовая система больных шизофренией резистентных к лечению

The authors conclude: 'Our findings suggest that there may be a different molecular mechanism leading to schizophrenia in patients who do not respond to anti-psychotic medication. Identifying the precise molecular pathway particularly in these patients is of utmost importance and will help inform the development of much-needed novel treatments.'
Researchers used PET scan imaging to investigate dopamine synthesis capacity in 12 patients with schizophrenia who did not respond to treatment, 12 who did, and 12 healthy controls. They found that schizophrenia patients whose illness was resistant to antipsychotic treatment have relatively normal levels of dopamine synthesis capacity which would explain why the dopamine blocking anti-psychotic medication was not effective in this group.

 Research may explain why some people with schizophrenia do not respond to treatment

Психофармакологические тесты в диагностике аффективных расстройств

Таким образом, для выбора адекватной терапии приступов аффективных психозов необходимо понять структуру состояния больного, отражающую механизмы образования его синдрома. Для этой цели клинический метод успешно дополняется психофармакологическими тестами. Лечение аффективных и аффектив­но-бредовых больных (кроме маниакальных) целесообразно начи­нать с пробного терапевтического курса анксиолитиками (феназепамом, лепонексом) или с диазепамового теста. В зависимости от трансформации клинической картины, указывающей на основ­ное биологическое расстройство, на «блок», являющийся основой патологического состояния, в дальнейшем назначаются антиде­прессивные или энергизирующие препараты. Создается впечатление,  что сфера применения нейролептиков в терапии аффективных приступов должна быть весьма ограниченной рамками маниакаль­ных и маниакально-параноидных состояний, в комбинации с нормотимиками.

 Точилов В.А. - ОБ ИССЛЕДОВАНИИ СТРУКТУРЫ И ЛЕЧЕНИИ АФФЕКТИВНЫХ ПРИСТУПОВ

Скополамин и циталопрам в терапии депрессии

Evidence is accumulating that cholinergic pathways in the brain help to regulate mood, and researchers have shown that intravenous scopolamine (an anticholinergic) is effective for moderate-to-severe depression (JW Psychiatry Mar 29 2010). This 6-week, Iranian, double-blind study tested whether oral scopolamine (0.5 mg twice daily), added to citalopram as an initial treatment produces greater antidepressant effects than citalopram plus placebo. Participants were 40 patients with moderate-to-severe major depression (baseline score on the 17-item Hamilton Rating Scale for Depression, 22).
At days 4, 28, and 42, patients receiving scopolamine augmentation had significantly greater reduction in symptoms than patients taking add-on placebo, with an overall large effect size (0.9). Response rates were higher with scopolamine than placebo at week 4 (65% vs. 30%) but not at week 6. Remission rates for scopolamine-treated patients were higher at week 6 (65% vs. 20%). Dry mouth, dizziness, and blurred vision were each noted by at least 40% of scopolamine recipients.
Comment: This study shows that scopolamine given orally (a much preferable route of administration for routine clinical practice) adds significantly to the effect of a selective serotonin reuptake inhibitor for initial treatment of moderate-to-severe depression, although whether it is worth the side effect burden is unclear. Unfortunately, we also do not know whether scopolamine would benefit patients with treatment-resistant depression, although this study's effects in relatively severe depression suggest that such a trial might be pursued. The study's high rate of placebo response (but not remission) and the absence of formal cognitive testing compromise the generalizability of the findings.

Oral Scopolamine Augmentation for Major Depression

Связь вируса простого герпеса первого типа со снижением когнитивных функций у больных шизофренией

Latent infection with neurotropic herpes viruses, such as herpes simplex virus, type 1 (HSV1), has been generally considered benign in most immunocompetent individuals except for rare cases of encephalitis. However, several recent studies have shown impaired cognitive functions among individuals with schizophrenia exposed to HSV1 compared with schizophrenia patients not exposed to HSV1. Such impairments are robust and are prominently observed in working memory, verbal memory, and executive functions. Brain regions that play a key role in the regulation of these domains have shown smaller volumes, along with correlation between these morphometric changes and cognitive impairments in schizophrenia. One study noted temporal decline in executive function and gray matter loss among HSV1-exposed first-episode antipsychotic-naïve schizophrenia patients. Furthermore, a proof-of-concept double-blind placebo-controlled trial indicated improvement in cognitive performance following supplemental anti-herpes–specific medication among HSV1 seropositive schizophrenia patients. Cross-sectional studies have also identified an association between HSV1 exposure and lesser degrees of cognitive impairment among healthy control individuals and patients with bipolar disorder. These studies fulfill several Bradford-Hill criteria, suggesting etiological links between HSV1 exposure and cognitive impairment. Exposure to other human herpes viruses such as cytomegalovirus and herpes simplex virus type 2 (HSV2) may also be associated with cognitive impairment, but the data are less consistent. These studies are reviewed critically and further lines of enquiry recommended. The results are important from a public health perspective, as HSV1 exposure is highly prevalent in many populations.

 Exposure to Herpes Simplex Virus Type 1 and Cognitive Impairments in Individuals With Schizophrenia

Употребление витамина D3 не проявило эффективности в предупреждении депрессии у людей с низким уровнем 25-гидроксивитамина D

Aims

To compare depressive symptoms in participants with low and high serum 25-hydroxyvitamin D (25(OH)D) levels and to examine whether supplementation with vitamin D3 would improve symptoms in those with low serum 25(OH)D levels.

Method

Participants with low 25(OH)D levels were randomised to either placebo or 40 000 IU vitamin D3 per week for 6 months. Individuals with high serum 25(OH)D levels were used as nested controls. Depressive symptoms were evaluated with the Beck Depression Inventory, Hospital Anxiety and Depression Scale, Seasonal Pattern Assessment Scale and Montgomery–Åsberg Depression Rating Scale. The study was registered at ClinicalTrials.gov(NCT00960232).

Results

Participants with low 25(OH)D levels (n = 230) at baseline were more depressed (P < 0.05) than participants with high 25(OH)D levels (n = 114). In the intervention study no significant effect of high-dose vitamin D was found on depressive symptom scores when compared with placebo.

Conclusions

Low levels of serum 25(OH)D are associated with depressive symptoms, but no effect was found with vitamin D supplementation.

 Effect of vitamin D supplement on depression scores in people with low levels of serum 25-hydroxyvitamin D: nested case–control study and randomised clinical trial

Антидепрессивные свойства оланзапина

Background

Atypical antipsychotics are widely used in bipolar mania. However, the efficacy of atypical antipsychotics in bipolar depression has not been comprehensively explored.

Aims

To evaluate olanzapine monotherapy in patients with bipolar depression.

Method

Patients with bipolar depression received olanzapine (5–20 mg/day, n = 343) or placebo (n = 171) for 6 weeks. The primary outcome was change from baseline to end-point in Montgomery–Åsberg Depression Rating Scale (MADRS) total score. Secondary outcomes included: Clinical Global Impression – Bipolar Version (CGI-BP) scale, 17-item Hamilton Rating Scale for Depression (HRSD-17) and Young Mania Rating Scale (YMRS) scores, and the rate of response (50% reduction in MADRS at end-point), recovery (MADRS 12 for 4 weeks plus treatment completion) and remission (MADRS 8). The trial was registered with ClinicalTrials.gov (NCT00510146).

Results

Olanzapine demonstrated: significantly greater (P < 0.04) improvements on MADRS (least-squares mean change –13.82 v. –11.67), HRSD-17 and YMRS total scores and all CGI-BP subscale scores v. placebo; significantly (P⩽0.05) more response and remission, but not recovery; significantly (P < 0.01) greater mean increases in weight, fasting cholesterol and triglycerides; and significantly more (P < 0.001) patients gained ⩾7% body weight.

Conclusions

Olanzapine monotherapy appears to be efficacious in bipolar depression. Additional long-term studies are warranted to confirm these results. Safety findings were consistent with the known safety profile of olanzapine.

 Randomised, double-blind, placebo-controlled study of olanzapine in patients with bipolar I depression*

Аспирин снижает риск депрессии у людей с повышенным уровнем гомоцистеина

High total plasma homocysteine (tHcy) is associated with increased risk of cardiovascular events and depression. Consumption of B-vitamins (B6, B9 and B12) reduces tHcy by about 15%, but has equivocal effects on these health outcomes, suggesting that this relationship is either not causal or is confounded by other factors. The results of recent randomized trials suggest that antiplatelet therapy may confound these associations. This cross-sectional study assessed 3687 men aged 69–87 years for history of clinically significant depression (Geriatric Depression Scale 15 items 7) or a recorded diagnosis of depression in the Western Australian Data Linkage System, and collected information on the use of aspirin, B-vitamins and antidepressant medication, along with age, education, living arrangements, smoking history and medical comorbidity as assessed by the Charlson index. Participants donated a blood sample for the measurement of tHcy, and concentrations15 μmol l−1 were considered high. Five hundred and thirteen (13.9%) men showed evidence of depression, and of those 31.4% had high tHcy, 41.5% were using aspirin, 6.8% were consuming B-vitamins. Multivariate logistic regression showed that high tHcy was associated with increased odds of depression (odds ratio (OR)=1.60, 95% confidence interval (CI)=1.20–2.14), as was the use of B-vitamins (OR=1.95, 95% CI=1.21–3.13). There was a significant interaction between high tHcy and aspirin use (OR=0.57, 95% CI=0.36–0.91), but not between high tHcy and B-vitamin use (OR=0.80, 95% CI=0.26–2.46). The analyses were adjusted for smoking status, Charlson index and use of antidepressants. The results of this study indicate that older men with high tHcy who use aspirin have lower risk of depression, and suggest that antiplatelet therapy may be an effective preventive or management strategy for these cases. Randomized trials are required to confirm the antidepressant effect of aspirin in people with high tHcy.

Aspirin decreases the risk of depression in older men with high plasma homocysteine

Допамин и шизофрения

In this meta-analysis, Howes and colleagues studied the nature of dopaminergic dysfunction in schizophrenia. Data were gathered in vivo in 618 patients with schizophrenia and 606 controls using PET or single-photon emission CT. A highly significant elevation in presynaptic dopaminergic function was observed in patients with schizophrenia, with a large effect size but no alterations in dopamine transporter availability. There was a small elevation in D(2/3) receptor availability, but this was not evident in drug-naive patients and was influenced by the imaging approach used.

 The Nature of Dopamine Dysfunction in Schizophrenia and What This Means for Treatment

In the current study, Demjaha and colleagues examined striatal dopamine synthesis capacity in 12 treatment-resistant and 12 treatment-responsive schizophrenia subjects, as well as in 12 healthy controls. They found that dopamine synthesis capacity was elevated in the treatment-responsive subjects, but not in the treatment-resistant subjects or in healthy controls. The elevation was most prominent in the associative and limbic striatal subdivisions.

 News Brief: Normal Dopamine Synthesis Capacity in Treatment-Resistant Schizophrenia

Редкая генетическая аномалия как фактор риска развития шизофрении

Approximately 30 percent of people with a genetic disorder known as 22q11 deletion syndrome develop schizophrenia, making it one of the strongest risk factors for the disease.

 Rare genetic disorder points to molecules that may play role in schizophrenia

Современные лекарственные стратегии лечения алкоголизма

γ-Hydroxybutyrate (GHB), anticonvulsants, and α2-agonists have been studied as stand-alone or adjunctive agents in the treatment of alcohol withdrawal syndrome. Although these medications are promising for mild to moderate alcohol withdrawal syndrome, there is a dearth of information about their ability to prevent or treat complicated alcohol withdrawal.

Alcohol Disorders: Practical Tips From New Research

Целесообразность применения монотерапии кветиапином для лечения депрессии

Background

Schizophrenia and bipolar depression trials suggest that quetiapine may have an antidepressant effect.

Objectives

This meta-analysis aimed to determine the efficacy, acceptability and tolerability of quetiapine treatment for major depressive disorder (MDD). Only the randomized controlled trials (RCTs) comparison between quetiapine and placebo were included. The authors searched such clinical trials carried out between 1991 and February 2012.

Data sources

MEDLINE, EMBASE, CINHL, PsycINFO and Cochrane Controlled Trials Register were searched in February 2012. Study populations comprised adults with MDD or major depression.

Study eligible criteria, participants and interventions

Eligible studies were randomized, placebo-controlled trials of quetiapine monotherapy carried out in adults with MDD and presenting endpoint outcomes relevant to: i) depression severity, ii) response rate, iii) overall discontinuation rate, or iv) discontinuation rate due to adverse events. No language restriction was applied.

Study appraisal and synthesis methods

All abstracts identified by the electronic searches were examined. The full reports of relevant studies were assessed, and the data of interest were extracted. Based on the Cochrane methods of bias assessment, risks of bias were determined. The studies with two risks or less were included. The efficacy outcomes were the mean change scores of depression rating scales, the overall response rate, and the overall remission rates. The overall discontinuation rate was considered as a measure of acceptability. The discontinuation rate due to adverse events was a measure of tolerability. Relative risks (RRs) and weighted mean differences (WMDs) with 95% confidence intervals (CIs) were computed by using a random effect model.

Results

A total of 1497 participants in three RCTs were included. All trials examined the quetiapine extended-release (XR). The pooled mean change scores of the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale (HAM-D) of the quetiapine-treated group were higher than those of the placebo-treated group with the WMDs (95%CI) of -3.37 (-3.95, -2.79) and -2.46 (-3.47, -1.45), respectively. All studies defined the response and remission as >= 50% reduction of the MADRS total score and the MADRS total score of <=8 at endpoint, respectively. The overall response and remission rates were significantly greater in the quetiapine-treated group with RRs (95%CIs) of 1.44 (1.26, 1.64) and 1.37 (1.12, 1.68), respectively. The pooled discontinuation rate was not significantly different between groups with an RR (95%CI) of 1.16 (0.97, 1.39). The pooled discontinuation rate due to adverse event was greater in the quetiapine group with an RR (95%CI) of 2.90 (1.87, 4.48). With respect to sleep time, the pooled mean change Pittsburgh Sleep Quality Index (PSQI) scores of the quetiapine-treated group was also significantly higher than that of the placebo-treated group [WMD (95%CI) of -1.21 (-1.81, -0.61)].

Limitations

Variety of quetiapine XR doses and the small number of RCTs were key limitations of this meta-analysis.

Conclusions

Based on the limited evidence obtained from three RCTs, quetiapine XR is effective for adult patients with MDD. The high dropout rate due to adverse events suggests that some MDD patients may not be able to tolerate quetiapine XR. Due to the balance of its efficacy benefit and risk of side effects, as the overall discontinuation rate shown, the acceptability of this agent is not more than placebo. These results should be viewed as the very preliminary one. Further studies in this area are warranted.

Quetiapine monotherapy in acute phase for major depressive disorder: a meta-analysis of randomized, placebo-controlled trials

 

Отсутствие долгосрочной противотревожной эффективности потенцирования кветиапином в предварительном исследовании

Background

Comorbid anxiety symptoms,in patients with a primary anxiety disorder or a mood disorder, leads to poor patient outcomes and burdens the healthcare system. This pilot study evaluated the feasibility of extended-release quetiapine fumarate (quetiapine XR) for the treatment of patients with either a primary anxiety disorder or a mood disorder with comorbid anxiety symptoms compared to a placebo, as an adjunct to antidepressant therapy.

Methods

Thirty-nine patients with a diagnosis of a primary anxiety disorder or a mood disorder with comorbid anxiety symptoms were enrolled in this study. Patients with a stable dose of antidepressant therapy were randomized according to a 2:1 probability of receiving either quetiapine XR or a placebo adjunctive treatment for 8 weeks. The efficacy was assessed by the Hamilton Anxiety Rating Scale (HAM-A) and the Clinical Global Impression of severity (CGI-S) score at baseline, week 1, 4, and 8.

Results

A total of 35 patients were included in this intention-to treat (ITT) population for the efficacy analysis (quetiapine XR: 22 patients; placebo: 13 patients). At week 4, statistically significant differences were observed on both the HAM-A score (p = 0.003) and the CGI-S score (p = 0.025), favouring the quetiapine XR (-13.00 +/- 4.14) compared to placebo (-6.63 +/- 5.42). However, no statistically significant difference was observed between the two groups with regard to changes from the baseline to week 8 on the HAM-A score (p = 0.332) or the CGI-S score (p = 0.833).

Conclusions

Augmentation of antidepressant treatment with quetiapine XR did not result in clinical improvement according to the outcome measure of anxiety using the HAM-A and CGI-S scores at week 8, among the patients with either a primary anxiety disorder or a mood disorder with comorbid anxiety symptoms. However, treatment with quetiapine XR as an adjunct to antidepressant therapy appeared to provide a short-term benefit at 4 weeks. Further study is needed with a larger sample size, randomized controlled design and control of the dosage prescribed.

 Quetiapine fumarate augmentation for patients with a primary anxiety disorder or a mood disorder: a pilot study

Исследование антагониста орексинных рецепторов в терапии инсомнии

Study Objectives:

To assess the acute effects of SB-649868 in male subjects with Primary Insomnia with regard to (1) objective and subjective sleep parameters, (2) safety and tolerability, (3) next-day residual effects.

Design:

Multicenter, randomized, double-blind, placebo-controlled crossover study using a complete set of Williams orthogonal Latin Squares

Setting:

9 sleep centers in Germany

Patients:

52 male subjects with a diagnosis of primary insomnia (difficulty in sleep initiation and maintenance) confirmed by polysomnography

Interventions:

SB-649868 (10, 30, 60 mg) and placebo administered after dinner 90 minutes before bedtime

Measurements and Results:

Sleep effects assessed by polysomnography during 2 consecutive nights and by sleep questionnaires completed by subjects after each night at the sleep laboratory. Safety and tolerability were assessed by adverse events collection, electrocardiogram (ECG), vital signs, laboratory tests. Next-day residual effects were assessed by Digit Symbol Substitution Test, and modified Verbal Learning Memory Test administered at “lights on” after night 2. SB-649868 significantly reduced latency to persistent sleep, wake after sleep onset (WASO), and increased total sleep time (TST) compared to placebo. A dose-dependent effect was observed. A dose-dependent increase in absolute and percent REM sleep and reduction in REM sleep latency was observed mainly at the 60-mg dose. SB-649868 was well tolerated with inconsistent next day residual effects. SB-649868 sleep effects were correlated with SB-649868 circulating levels.

Conclusion:

The data demonstrate the sleep-promoting properties of the orexin antagonist SB-649868 in male patients with insomnia.

The Orexin Antagonist SB-649868 Promotes and Maintains Sleep in Men with Primary Insomnia 

Исследования арбаклофена

The investigational γ-aminobutyric acid type B (GABA-B) agonist STX209 (arbaclofen, Seaside Therapeutics) may improve social function and behavior in patients with fragile X syndrome (FXS).

In a randomized, controlled phase 2 study of children and adults with FXS, investigators from Rush University Medical Center in Chicago found that treatment with arbaclofen was well tolerated and improved social avoidance and problem behaviors.

Drug Shows Promise in Fragile X and Possibly Autism 

Гинго билоба не эффективен в профилактике болезни Альгеймера

Another large trial shows no benefit from ginkgo biloba extract in preventing Alzheimer disease, researchers report in the Lancet Neurology.

Nearly 2900 older adults without dementia who spontaneously reported memory complaints to their physicians were randomized to consume standardized ginkgo biloba extract or placebo for 5 years. Overall, the rate of diagnosis with probable Alzheimer's did not differ significantly between the ginkgo and placebo groups (1.2 and 1.4 cases per 100 person-years).

The authors note that a lower-than-expected Alzheimer's rate in both groups reduced the study's power, while a Lancet Neurology editorialist concludes: "For adults aged 70 years or older with a memory complaint who might be mildly cognitively impaired, use of [ginkgo biloba extract] does not decrease the risk of Alzheimer's disease over 5 years.

 Ginkgo Biloba: No-Go for Alzheimer's Prevention

Позднее начало лечения депрессии ассоциировано с худшим ответом на терапию

Background

The duration of untreated illness has been considered a likely predictor of the course of psychotic disorders. However, there is only sparse data concerning the influence of treatment delay on the outcome of mood disorders. The present study aimed to assess the effect of prolonged untreated depression on the outcome of antidepressant treatment.

Method

Patients aged 18–70 years with recent onset of the first lifetime depressive episode were systematically recruited by the Danish Psychiatric Central Research Register during a 2-year period. A total number of 399 individuals out of 1006 potential participants in the Register were interviewed, and 270 fulfilled the inclusion criteria. The validity of the diagnosis, duration of untreated illness, remission on first-line antidepressant treatment and a number of covariates, including psychiatric co-morbidity, personality disorders and traits, stressful life events prior to onset, and family history of psychiatric illness, were assessed by structured interviews.

Results

The remission rate was significantly decreased among patients with six months or more of untreated depression as compared to patients who were treated with antidepressant medication earlier after onset (21.1% versus 33.7%, OR=0.5, 95% CI 0.3 to 0.9, p=0.03). The negative influence of a prolonged DUI on the outcome did not seem confounded by any of a wide range of demographic and clinical variables.

Limitations

The outcome was evaluated retrospectively. The findings cannot be generalized to patients outside hospital settings.

Conclusion

Initiation of antidepressant treatment more than six months after onset of first episode depression reduces the chance of obtaining remission. The results emphasize the importance of early recognition and treatment of patients suffering from depression.

The effect of prolonged duration of untreated depression on antidepressant treatment outcome

Альтернативные методы коррекции СДВГ

Bacopa monnieri is an Ayurvedic medicinal herbal widely used as a tonic and memory enhancer. In a small 12-week double-blind RCT, 36 children with ADHD randomized to receive Bacopa, 50 mg BID, showed significant improvement over placebo in tests of sentence repetition, logical memory, and pair-associative learning.

A standardized extract of the bark from the French maritime pine (Pinus pinaster) may also help reduce symptoms of ADHD. A total of 61 children and adolescents randomized to a standardized extract of French maritime pine bark (Pycnogenol™), 1 mg/kg/d, for 1 month, experienced significant improvements in hyperactivity, inattention, and visual-motor coordination compared with placebo recipients; symptoms returned to pre-treatment baseline levels after a 1-month washout.

There is also promising evidence that zinc supplementation may mitigate ADHD symptoms. In a large 12-week double-blind placebo controlled trial (N = 400), children and adolescents randomized to a high dose of zinc, 150 mg/d, experienced significant improvement in hyperactivity and impulsivity but not inattention over placebo. In an augmentation study, the addition of zinc to methylphenidate resulted in greater improvement than methylphenidate alone.

 Alternative Medicine Therapies for ADHD

Изучение компульсивного поведения у собак

Researchers discovered a connection with stereotypic OCD behavior and vitamins and minerals. Dogs that received nutritional supplements, especially vitamins and minerals, with their food, chased their tails less.

“Our study does not prove an actual causal relationship between vitamins and lessened tail chasing, but interestingly similar preliminary results have been observed in human OCD,” said researcher Katriina Tiira, Ph.D.

 Study of Canine OCD May Help Humans

C-реактивный белок как предиктор резистентности к лечению депрессии, инфликсимаб в терапии резистентной депрессии

A new study suggests a drug used to treat autoimmune disorders and rheumatoid arthritis may help individuals with difficult-to-treat depression.

Prior studies have suggested that depressed people with evidence of high inflammation are less likely to respond to traditional treatments for the disorder, including anti-depressant medications and psychotherapy.

The study investigated the use of infliximab, a new biologic drug used to treat autoimmune and inflammatory diseases. Each participant was assigned either to infliximab or to a non-active placebo treatment.

A biologic drug copies the effects of substances naturally made by the body’s immune system. In this case, the drug was an antibody that blocks tumor necrosis factor (TNF), a key molecule in inflammation that has been shown to be elevated in some depressed individuals.

Study participants all had major depression and were moderately resistant to conventional antidepressant treatment.

When investigators looked at the results for the group as a whole, no significant differences were found in the improvement of depression symptoms between the drug and placebo groups.

However, when the subjects with high inflammation were examined separately, they exhibited a much better response to infliximab than to placebo.

Inflammation in this study was measured using a simple blood test that is readily available in most clinics and hospitals and measures C-reactive protein or CRP. The higher the CRP, the higher the inflammation, and the higher the likelihood of responding to the drug.

 Anti-Inflammatory Med May Ease Hard-to-Treat Depression

Стратегии потенцирования действия клозапина

Background. When schizophrenia patients have insufficient response to clozapine, pharmacological augmentation is often applied. This meta-analysis summarizes available evidence on efficacy of pharmacological augmentation of clozapine treatment in schizophrenia spectrum disorder.

Methods. Only double-blind randomized controlled studies were included. Primary outcome measure was total symptom severity, and secondary outcome measures were subscores for positive and negative symptoms. Effect sizes were calculated from individual studies and combined to standardized mean differences (Hedges's g). Results. Twenty-nine studies reporting on 15 different augmentations were included. Significant better efficacy than placebo on total symptom severity was observed for lamotrigine, citalopram, sulpiride, and CX516 (a glutamatergic agonist). The positive effect of lamotrigine disappeared after outlier removal. The other positive findings were based on single studies. Significantly better efficacy on positive symptom severity was observed for topiramate and sulpiride. The effect of topiramate disappeared after outlier removal.

Results for sulpiride were based on a single randomized controlled trial. Citalopram, sulpiride, and CX516 showed better efficacy for negative symptoms than placebo, all based on single studies.

Conclusions. Evidence for efficacy of clozapine augmentation is currently scarce. Efficacy of lamotrigine and topiramate were both dependent on single studies with deviating findings. The effect of citalopram, sulpiride, and CX516 were based on single studies. Thus, despite their popularity, pharmacological augmentations of clozapine are not (yet) demonstrated to be superior to placebo.

 Pharmacological Augmentation Strategies for Schizophrenia Patients With Insufficient Response to Clozapine: A Quantitative Literature Review

Противовирусные свойства флуоксетина

Surprisingly, fluoxetine stood out from the crowd. In a series of follow-up tests, the researchers found that fluoxetine interferes with the growth and replication of coxsackieviruses, a prominent subtype of enteroviruses.

The researchers repeated the experiment on several kinds of coxsackieviruses with recurring success. Without the ability to reproduce, these invading viruses simply would die off.

 Prozac May Have Antiviral Properties

Добавление креатина к СИОЗС

"There are some animal studies that show that this augmentation may be helpful, and there are older studies looking at enzymes in humans related to creatine that seem to be altered during episodes of depression, so there has been a sense that something may be going on here," he said.

"Creatine is a relatively harmless addition, so it's very testable, and would be very usable, and the fact that the American Journal of Psychiatry accepted the article signals genuine interest. It would be great to have a tool like this," he said.

 Dietary Supplement Speeds Clinical Efficacy of SSRIs

Генетические вариации эндоканнабиноидной системы и ответ на терапию циталопрамом

First line treatment of major depression is based on selective serotonin re-uptake inhibitors (SSRIs) that enhance serotonergic neurotransmission by blocking the serotonin transporter. However, clinical response is a complex phenomenon in which other systems such as the endocannabinoid system could be involved. Given the evidence for the role of the endocannabinoid system in the pathogenesis of depression as well as in the mediation of antidepressant drug effects, the aim of this study was to analyze genetic variability in the endocannabinoid system genes (CNR1, CNR2 and FAAH genes) and their role in clinical response (at week 4) and remission (at week 12) in SSRI (citalopram) treatment in a sample of 154 depressive outpatients, all of Spanish origin. All patients were treated with citalopram and followed over 12 weeks. Severity of depressive symptomatology was evaluated by means of the 21-item Hamilton Depression Rating Score (HDRS). No differences were found in any of the genotype distributions according to response or remission. The longitudinal study showed that (i) the CNR1 rs1049353-GG genotype conferred a better response to citalopram treatment in the subgroup of male patients and (ii) G allele carriers (CNR2 rs2501431) presented higher HDRS scores in the follow-up than AA homozygous allele carriers. Our results seem to suggest the involvement of CNR1 and CNR2 genes in clinical responses to citalopram treatment.

 Genetic variability in the endocannabinoid system and 12-week clinical response to citalopram treatment: the role of the CNR1, CNR2 and FAAH genes

Механизм резистентности к лечению шизофрении

Scientists have discovered a molecular mechanism for resistance to antipsychotic medications, a finding that may pave the way for the development of new drugs to treat a significant proportion of schizophrenia patients who do not respond to these medications.

Investigators led by Javier González-Maeso, PhD, assistant professor of psychiatry and neurology, Mount Sinai School of Medicine in New York City, found that long-term administration of atypical antipsychotic drugs selectively upregulates expression of the enzyme histone deacetylase 2 (HDAC2) in both mouse and human frontal cortex.

This epigenetic change, which is dependent on serotonin 5-hydroxytryptamine 2A (5-HT2A) upregulation, leads to lower expression of the metabotropic glutamate 2 receptor (mGlu2), thereby limiting the therapeutic effects of atypical antipsychotic therapy, often leading to a recurrence of psychotic symptoms.

According to investigators, blocking this cascade of events with HDAC inhibitors may improve responses to atypical antipsychotic drug therapy.

"Together, these data suggest that HDAC2 may be a new therapeutic target to augment the treatment of schizophrenia.... Specifically, our findings encourage the development and testing of HDAC2-selective inhibitors for schizophrenia," the investigators write.

 New Discovery Raises Hope for Drug-Resistant Schizophrenia

Исследования новых антипсихотиков: илоперидон, карипразин

Several trends dominated new research on antipsychotic medications presented at the 2012 American Psychiatric Association (APA) meeting and the 2012 New Clinical Drug Evaluation Unit (NCDEU) meeting sponsored by the American Society of Clinical Psychopharmacology. Data on the management of negative and cognitive symptoms of schizophrenia with antipsychotic depot injectables used either alone or with an adjunctive therapy are growing steadily, and a number of posters focused on that trend. In addition, long-term data were presented for several newer antipsychotics, both in schizophrenia and bipolar depression. Leslie Citrome, MD, MPH, commented on the data in an interview with Medscape shortly after the 2 meetings.

 Recent Research in Antipsychotics

Маркеры иммунного воспаления в прогнозе обострения при шизофрении

To get a better handle on how IL-6 levels correspond to disease status, they are looking at levels in blood samples taken multiple times over several years in 305 patients enrolled in a study comparing injectable to oral medication. They also are taking one-time measurements in 80 healthy controls and comparing those to levels in 240 patients who are acutely ill, stable outpatients or stable outpatients who smoke marijuana, a drug commonly abused by patients. While many previous studies have excluded drug abusers, marijuana may increase inflammation, so they want to explore the relationship between IL-6 levels and its use, Miller said.

Miller received a five-year, $920,000 National Institute of Mental Health Mentored Patient-Oriented Research Career Development Award to measure IL-6 levels as a potential indicator of how well treatment is working to control disease in these vulnerable patients and whether they are headed to relapse.

Amazingly the contributions of "immune disturbances" to schizophrenia have been debated for about 100 years yet anti-inflammatory drugs aren't routinely given to patients in addition to their antipsychotic medication, Miller said.

Part of the problem is physicians still have no idea what percentage of patients with this very heterogeneous disease have evidence of increased inflammation. In fact, no two patients have the exact constellation of symptoms considered disease hallmarks, such as hallucinations, delusions, disorganized speech and thinking, he said.

But mounting evidence suggests inflammation's impact in schizophrenia. A British study of 50 patients experiencing their first episode of schizophrenic behavior found a handful had indicators of an immune response to their brains, called autoantibodies, and no other conditions, such as a brain infection, to explain them. What amounts to a chronic low-grade flu has been found in some patients and rare immune system disorders such as Sjögren's syndrome, which attacks moisture-producing glands resulting in dry eyes and mouth, also tend to be more common in schizophrenics. Additionally, a handful of clinical trials has shown – not surprisingly – that patients with the highest levels of pro-inflammatory factors had the best response to anti-inflammatory drugs.

Researchers pursue red flag for schizophrenia relapse

Клозапин, нейтропения и гранулоцитарный фактор, стимулирующий рост клеток

Clozapine is the treatment of choice for treatment-resistant schizophrenia, but it is associated with a risk of neutropaenia and agranulocytosis. Clozapine use is regulated by mandatory blood monitoring in the UK, requiring cessation of treatment should the absolute neutrophil count (ANC) drop below specified values. Benign reductions in the ANC in non-white populations are common, and this can preclude a patient from receiving treatment with clozapine. A diagnosis of benign ethnic neutropaenia can reduce these treatment restrictions (UK specific), but the degree of neutropaenia can be significant enough to still prevent treatment. In this report, we show that response to granulocyte colony stimulating factor (G-CSF) may be quite variable and difficult to predict, but with careful monitoring it can be used to increase the ANC count and allow continued treatment with clozapine.

 Granulocyte Colony Stimulating Factor (G-CSF) can allow treatment with clozapine in a patient with severe Benign Ethnic Neutropaenia (BEN): a case report

Бетагистин как корректор увеличения массы тела при приёме оланзапина

Olanzapine is effective at treating multiple domains of schizophrenia symptoms. However, it induces serious metabolic side effects. Antipsychotic drug’s antagonistic affinity to histamine H1 receptors has been identified as a main contributor for weight gain/obesity side effects. This study therefore investigated whether a combined treatment of betahistine (a H1 receptor agonist and H3 receptor antagonist) could reduce the body weight/obesity induced by olanzapine. Female Sprague Dawley rats were treated orally with olanzapine (1 mg/kg, t.i.d.) and/or betahistine (2.67 mg/kg, t.i.d.), or vehicle for two weeks. Rats treated with olanzapine exhibited significant body weight gain and increased food intake. Co-treatment of olanzapine with betahistine significantly prevented (-45%) weight gain and reduced feeding efficiency compared to sole olanzapine treatment. Betahistine treatment alone had no effect on weight gain and food intake. Olanzapine reduced locomotor activity, but not betahistine. These findings demonstrate that olanzapine-induced body weight gain can partially be reduced by co-treatment with betahistine. Betahistine has H3 receptor antagonistic effects to increase histamine release, which may augment its direct agonistic effects on H1 receptors. These findings have important implications for clinical trials using betahistine to control antipsychotic-induced obesity side effects.

 Reducing olanzapine-induced weight gain side effect by using betahistine: a study in the rat model

РКИ миноциклина

The onset and early course of schizophrenia is associated with subtle loss of grey matter which may be responsible for the evolution and persistence of symptoms such as apathy, emotional blunting, and social withdrawal. Such ‘negative’ symptoms are unaffected by current antipsychotic therapies. There is evidence that the antibiotic minocycline has neuroprotective properties. We investigated whether the addition of minocycline to treatment as usual (TAU) for 1 year in early psychosis would reduce negative symptoms compared with placebo. In total, 144 participants within 5 years of first onset in Brazil and Pakistan were randomised to receive TAU plus placebo or minocycline. The primary outcome measures were the negative and positive syndrome ratings using the Positive and Negative Syndrome Scale. Some 94 patients completed the trial. The mean improvement in negative symptoms for the minocycline group was 9.2 and in the placebo group 4.7, an adjusted difference of 3.53 (s.e. 1.01) 95% CI: 1.55, 5.51; p < 0.001 in the intention-to-treat population. The effect was present in both countries. The addition of minocycline to TAU early in the course of schizophrenia predominantly improves negative symptoms. Whether this is mediated by neuroprotective, anti-inflammatory or others actions is under investigation.

Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment

Потенциальные механизмы лечения депрессии

EMERGING THERAPEUTIC TARGETS


Consider the following novel mechanisms that may become the basis for creating entirely new antidepressants in the foreseeable future, by design, not by serendipity:

• corticotropin-releasing factor (CRF) and glucocorticoids

         – CRF antagonists
           – vasopressin receptor antagonists
           – glucocorticoids as agonists or antagonists

• neurokinin system
• brain derived neurotropic factor (BDNF) and other neurotropins, such as fibroblast growth factor (FGF) or vascular endothelial growth factor (VEGF)
• phosphodiesterase inhibitors
• glutamate pathway modulators

        – ketamine (IV infusion with immediate efficacy)
          – α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor modulators
          – glycine

• hypothalamic feeding peptides
• circadian gene products
• other evolving antidepressants

        – K-opioid receptor antagonists
          – CB1 cannabinoid receptor agonists/antagonists
          – cytokines
          – melatonin receptor agonists
          – galanin
          – neuropeptide Y
          – histone deacetylase inhibitors
          – tissue plasminogen activator

 The hazards of serendipity

Нарушения дыхания во сне и психиатрические расстройства

The mechanism(s) underlying the connection between SDB and psychiatric symptoms is a matter of debate. From a psychiatric perspective, one can conceptualize the relationship as stemming from a direct physiological consequence of the general medical condition (in this case, sleep deprivation and nocturnal hypoxia/hypercapnia). Therefore, the increased prevalence of depression with SDB would not be surprising given that such a relationship is seen in other diseases that produce hypoxia and impair quality of life (eg, chronic obstructive pulmonary disease). On the other hand, excessive sleepiness and fatigue as a result of sleep apnea produce significant social and personal problems and result in depression. Ishman and colleagues showed that the daytime sleepiness is a strong predictor of depressive symptoms in patients with SDB.

Sleep apnea and depression can be bridged conceptually by vital exhaustion. Vital exhaustion refers to a state characterized by elevated somatic and cognitive symptoms of depression without affective symptoms. Our group as well as others demonstrated that vital exhaustion profiles were affected in patients with SDB. Therefore, depressive manifestations in patients with sleep apnea may reflect the patients’ vital exhaustion, which differs dramatically from melancholic affective mood changes observed in more typical forms of depression and dysthymia. As such, depressive phenomena in patients who have sleep apnea should be more akin to depression secondary to chronic medical illness.

The Correlation Between Sleep-Disordered Breathing and Psychiatry 

Профиль препарата JNJ-37822681

JNJ-37822681 is a novel, fast-dissociating dopamine D2 receptor antagonist, currently in development as an antipsychotic drug candidate. A previous first-in-human study demonstrated mild central nervous system effects of JNJ-37822681 in healthy male volunteers. Significant but transient serum prolactin elevations were demonstrated, whereas other neurophysiological effects were relatively small. To investigate striatal dopamine D2 receptor occupancy by variable single doses of JNJ-37822681, an open-label [11C]raclopride positron emission tomography study was performed in 12 healthy male volunteers, using the simplified reference tissue model with cerebellum as reference tissue. Oral administration of JNJ-37822681 resulted in dose-dependent dopamine D2 receptor occupancy. Receptor occupancy increased from 9–19% at 2 mg doses to 60–74% at 20 mg doses of JNJ-37822681. Therefore, single oral doses of JNJ-37822681 can produce occupancy levels that are generally associated with clinical efficacy for registered antipsychotic drugs.

In vivo quantification of striatal dopamine D2 receptor occupancy by JNJ-37822681 using [11C]raclopride and positron emission tomography 

Using the rate of dissociation from the D2 receptor as a means to screen novel compounds for antipsychotic drug candidates, the centrally acting and fast-dissociating selective dopamine D2 receptor antagonist JNJ-37822681 was developed. In a blinded, placebo-controlled, randomized first-in-human study, JNJ-37822681 was administered orally to 27 healthy male volunteers at doses of 0.5, 2, 5, 10, 15 and 20 mg. Safety, pharmacokinetics and central nervous system effects were evaluated by measuring prolactin levels, eye movements, adaptive tracking, visual analogue scales, body sway, finger tapping and electroencephalography. JNJ-37822681 was well tolerated and somnolence was the most frequently reported adverse effect. Peak plasma concentrations increased more than proportional to dose, but increases in the area under curve (AUC) were dose-proportional. Prolactin elevations started at doses of 5 mg, whereas small decreases in adaptive tracking were demonstrated at 10 mg doses. At higher doses, JNJ-37822681 caused a small decrease in saccadic peak velocity, smooth pursuit, alertness, finger tapping and electroencephalography activity, and an increase in body sway. This effect profile is likely to be the result of the selectivity of JNJ-37822681 for the D2 receptor, leading to strong D2 receptor-mediated elevations in serum prolactin, but fewer effects on more complex central nervous system functions, which are likely to involve multiple neurotransmitters.

Pharmacokinetics and central nervous system effects of the novel dopamine D2 receptor antagonist JNJ-37822681 

Препарат LY2140023 не превзошел по эффективности плацебо

Eli Lilly (LLY) announced Wednesday that its schizophrenia drug candidate didn't do better than the placebo in a phase-two study.

The study in question looked at the drug, called pomaglumetad methionil, as the sole treatment for the mental disease, but another ongoing trial is still studying the compound as a supplemental treatment with other medicines. Lilly said that trial is complete, but it's still awaiting results.

 Lilly's Schizophrenia Drug Candidate Fails Trial

Сравнение CDSS и HAMD-17 у больных шизофренией

Background: The aim of this study was to compare two measures of depression in patients with schizophrenia and schizophrenia spectrum disorder, including patients with delusional and schizoaffective disorder, to conclude implications for their application.

Sampling and Methods: A total of 278 patients were assessed using the Calgary Depression Scale for Schizophrenia (CDSS) and the Hamilton Depression Rating Scale (HAMD-17). The Positive and Negative Syndrome Scale (PANSS) was also applied. At admission and discharge, a principal component analysis was performed with each depression scale. The two depression rating scales were furthermore compared using correlation and regression analyses. 

Results: Three factors were revealed for the CDSS and HAMD-17 factor component analysis. A very similar item loading was found for the CDSS at admission and discharge, whereas results of the loadings of the HAMD-17 items were less stable. The first two factors of the CDSS revealed correlations with positive, negative and general psychopathology. In contrast, multiple significant correlations were found for the HAMD-17 factors and the PANSS subscores. Multiple regression analyses demonstrated that the HAMD-17 accounted more for the positive and negative symptom domains than the CDSS.

Conclusions: The present results suggest that compared to the HAMD-17, the CDSS is a more specific instrument to measure depressive symptoms in schizophrenia and schizophrenia spectrum disorder, especially in acutely ill patients.

Evaluating Depressive Symptoms in Schizophrenia: A Psychometric Comparison of the Calgary Depression Scale for Schizophrenia and the Hamilton Depression Rating Scale

Пример неэффективности лечения шизофрении витаминно-минеральными комплексами и анализ доказательной базы БАДов Truehope

A B.C. Supreme Court judge will decide if a schizophrenic man who killed his father and injured his mother while taking multivitamins instead of his anti-psychotic medication is criminally responsible for the attack.

 Mentally ill killer tried vitamin therapy, court told

However, there is no doubt that vitamin deficiencies can produce neurological and psychiatric disturbances. For instance, a lack of B12 can damage the central nervous system via changes in cytokine and growth factor production (Scalabrino, 2009). Thiamine deficiency is well-known for causing Wernicke's encephalopathy and Korsakoff's syndrome, disorders characterized by severe memory impairments. Previous studies have suggested that vitamins and minerals do have an effect on mood and perhaps even antisocial behavior Kaplan et al., 2007; Bohannon, 2009). The question here is whether broad-spectrum micronutrient treatments (i.e., nutritional supplements) can improve or "cure" bipolar disorder.

Truehope lists 17 published studies on the effectiveness of EMPowerplus™ in treating bipolar, ADHD, autism, and OCD. However, none of these studies is a randomized controlled trial that compares placebo to EMPowerplus™ in a double-blind fashion. Thus, it cannot be established that any improvements are due to the supplement, rather than to expectation or placebo effects.

EMPowered to Kill

Did "Alternative Medicine" Lead to Murder?

Меланокортин и ангедония

The researchers report that chronic stress in mice leads to activation of the melanocortin 4 receptor, which decreases the strength of excitatory synapses on neurons expressing D1 dopamine receptor in the nucleus accumbens, the brain's pleasure center.

The research also shows that stress-elicited increases in behavioral measurements of anhedonia in the mice can be prevented by blocking melanocortin 4 receptor–mediated synaptic changes in the animals.

"By delineating the molecular mechanisms underlying the circuit modifications that mediate specific behavioural manifestations of psychiatric symptoms such as anhedonia, it should be possible to accelerate the development of efficacious therapies with new mechanisms of action," the investigators write.

Hormone a New Treatment Target for Depression, Schizophrenia?

Фармакодинамика антипсихотика SB-773812

The aim of this study was to assess human striatal dopamine receptor 2 (D2) and cortical 5-hydroxytryptamine receptor 2A (5-HT2A) occupancy of SB-773812 to demonstrate brain penetration and binding to the target receptors and assess the pharmacokinetics–receptor occupancy relationship over time to aid dose selection and dosage regimen, in preparation for the phase II trials.
Methods: D2 and 5-HT2A occupancy were measured over time (both at the time of maximum [Tmax; 6 6 2 h] and at the time of minimum [Ttrough; 24 6 4 h] plasma concentration after dosing) by means of 123I-iodobenzamide and 123I-4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide (123I-R91150) SPECT in 3 studies. Study A consisted of SB-773812 single doses in healthy volunteers—D2 occupancy measured at 48 (n 5 9) and 56 mg (n 5 9) and 5-HT2A occupancy at 56 mg (n 5 9); study B consisted of D2 and 5-HT2A occupancy measured in 12 stabilizedschizophrenia patients on stable doses (16–18 d of 56 mg/d) after washout of previous medication; and study C included D2 occupancy measured in a double-blind study of patients with acutely exacerbated schizophrenia (n 5 10) on stable doses (18–21 d) of SB-773812 (100 mg/d; n 5 7) or risperidone (6 mg/d; n 5 3).
Results: Study A showed less than 30% D2 occupancy at Tmax, maintained at Ttrough. 5-HT2A occupancy was 74%–97% and also maintained over time. Study B revealed that 8 of the 12 schizophrenia patients showed more than 40% D2 occupancy. 5-HT2A occupancy ranged from 91% to 100%. In study C, SB-773812–induced D2 occupancy was 60.3% 6 13.3% at Tmax and 55.1% 6 4.9% at Ttrough. The pharmacokinetics–receptor occupancy relationship was assessed in each study and strengthened, combining all data to yield a concentration associated with 50% occupancy (EC50) of 92.7 6 13.5 ng/mL for D2 and 2.11 6 0.50 ng/mL for 5-HT2A.
Conclusion: In all subjects, SB-773812 showed penetration into the brain, reaching its target receptors. In patients with schizophrenia, D2 occupancy levels induced by a single dose were maintained over time, indicating that once-daily dosing regimens are appropriate. Pharmacokinetics–receptor occupancy analysis provided guidance for the selection of a clinically effective dose, supporting progression in phase II.

 Contribution of SPECT Measurements of D2 and 5-HT2A Occupancy to the Clinical Development of the Antipsychotic SB-773812

Индивидуальные предпочтения в фармакотерапии среди врачей-психиатров

BACKGROUND:
Psychiatrists' preference for certain medications is not only determined by their efficacy and side effect profile but may also depend on the psychiatrists' beliefs about specific therapeutic effects based on their own observation and experience. We aimed to evaluate which antipsychotic or antidepressant drugs psychiatrists would prefer for themselves, their partners and children in case of a mental illness.
SUBJECTS AND METHODS:
The study was conducted among psychiatrists in Serbia. The sample consisted of 90 psychiatrists who were asked to complete the questionnaire about their drug selection in hypothetical situations of becoming ill with schizophrenia or depression or these conditions occurring in their partners and children.
RESULTS:
In case of schizophrenia, risperidone was the first choice made by most psychiatrists for themselves, their partners or children, followed by clozapine, haloperidol and olanzapine. In case of depression, SSRIs and SNRIs were generally favored, with sertraline and escitalopram being the preferred medications for psychiatrists, partners and their children. With regards to depression, 82.3% of participants would opt for an antidepressant as monotherapy or in combination, but 13.3% would opt for anxiolytic monotherapy. The preferred doses were slightly lower than the recommended ones, especially for antipsychotic agents.
CONCLUSIONS:
Most psychiatrists would take or administer atypical antipsychotics or SSRIs as the first choice for themselves, their partners or children. These preferences are mostly in accordance with current treatment guidelines, but there is still room to narrow the gap between guideline recommendations and psychiatrists' medication choices in personally meaningful situations.

 Psychiatrists' psychotropic drug prescription preferences for themselves or their family members.

Агрессивность может быть связана со снижением функции дофаминергической системы

The neurobiology of aggression is not well understood, but scientists are aware of a relationship between the neurotransmitter serotonin and certain aggressive behaviors. The objective of this study was to explore whether higher levels of another brain chemical called dopamine, involved in pleasure and reward, increased aggressive response in its subjects. To scientists' surprise, it was not as they first theorized.

"The results of this study were astonishingly opposite of what was previously hypothesized," says Ingo Vernaleken, M.D., lead author of the study and research scientist for the department of psychiatry at RWTH Aachen University in Aachen, Germany. "Subjects with more functional dopaminergic reward-systems were not more aggressive in competitive situations and could concentrate even more on the game. Subjects with lower dopaminergic capacity were more likely to be distracted by the cheating behavior."

Molecular Imaging Finds Link Between Low Dopamine Levels and Aggression

Празозин как препарат выбора при ночных кошмарах в структуре ПТСР

Prazosin is an α1-adrenergic receptor antagonist with good CNS penetrability. The rationale for reducing adrenergic activity to address intrusive PTSD symptoms has been well documented. In open-label trials, a chart review, and placebo-controlled trials,prazosin reduced trauma nightmares and improved sleep quality and global clinical status more than placebo. In these studies, prazosin doses ranged from 1 to 20 mg/d, with an average of 3 mg at bedtime and a starting dose of 1 mg. Prazosin is the only agent recommended in the AASM’s Best Practice Guide for treating PTSD-related nightmares.

 PTSD nightmares: Prazosin and atypical antipsychotics

Влияние различных антидепрессантов на фазы сна

A clinical consequence of REM suppression can be a change in frequency and intensity of dreaming, as well as a pronounced exacerbation of intense, disturbing dreams related to “REM rebound” on discontinuation. Pulmonary specialists sometimes advocate use of an activating TCA such as protriptyline because it may help suppress REM sleep—when sleep apnea episodes may be accentuated—and also provide benefit for the daytime somnolence that many patients with sleep apnea experience.

The Effects of Antidepressants on Sleep

Тест шизофрении на основе нарушений координации движения глаз

MedWire News: Viewing tests that detect eye movement can accurately identify patients with schizophrenia, research shows.
Overall, schizophrenic patients had abnormal results on viewing tests that combined pursuit, scene viewing, and steady fixation tasks.
"Indeed, on this test no schizophrenia cases are misclassified as normal," report researcher Philip Benson (University of Aberdeen, UK) and colleagues.
Although abnormal eye movements have been documented in unmedicated psychotic patients, there has been almost no success in identifying marker traits associated with schizophrenia that can separate cases from healthy controls.
In the present study, published in Biological Psychiatry, 88 schizophrenia patients were presented with visual stimuli. Smooth pursuit involved tracking a circular target as it moved around the display screen. The ability to scan scenes of everyday objects and fixate on specific images was also assessed.
The free-viewing scanpaths were abnormally restricted in schizophrenic patients, report the researchers, and this was the single biggest discriminator of cases from healthy controls.
They also observed that these patients had impaired scores on the fixation-stability test. This test is a measure of saccade inhibition and can be used to "interpret aberrant patterns in picture viewing, saccade, and pursuit tasks," explain Benson and colleagues.
Additionally, horizontal and "Lissajous" pursuit of the moving images was abnormal compared with controls.
The differential effects were stable over time, and independent of gender, medication usage, and cigarette smoking.
In terms of the predictive validity of the eye-movement tests, re-test assessments and testing on patients with newly diagnosed schizophrenia showed the viewing test predicted schizophrenia in 87.8% of patients. Use of a probability model showed the test could achieve 98% discrimination between schizophrenics and control cases.
"This is a remarkable level of discrimination and well beyond that of other potential trait markers previously reported in schizophrenia," state the researchers.
Other benefits of the eye-viewing test include its low cost, ease of use, and that it can be used in the hospital or clinic on nearly all schizophrenic patients.

Eye-viewing tests identify schizophrenic patients

Амисульприд-индуцированная акатизия как маркер нарушения взаимоотношений серотонина и дофамина при ОКР

We report about a clinical observation in a well-characterized group of patients with obsessive–compulsive disorder (OCD) during an experimental medicine study in which a single dose of amisulpride (a selective D2/3 antagonist) was administered. Almost half of the OCD patients, in particular those with less severe obsessive–compulsive symptoms, experienced acute akathisia in response to the amisulpride challenge. This unexpectedly high incidence of akathisia in the selective serotonin reuptake inhibitor (SSRI)-treated patients with OCD suggests that individual differences in dopamine–serotonin interactions underlie the clinical heterogeneity of OCD, and may thus explain the insufficiency of SSRI monotherapy in those patients not experiencing a satisfactory outcome in symptom reduction. We further speculate about the neuropathology possibly underlying this clinical observation and outline a testable hypothesis for future molecular imaging studies.

 Amisulpride-induced acute akathisia in OCD: an example of dysfunctional dopamine–serotonin interactions?

Антипсихотические свойства каннабидола

A certain marijuana compound known as cannabidiol (CBD) can treat schizophrenia as well as antipsychotic drugs, with far fewer side effects, according to a preliminary clinical trial.

The research team, led by Markus Leweke of the University of Cologne in Germany, studied 39 people with schizophrenia who were hospitalized for a psychotic episode. Nineteen patients were treated with amisulpride, an antipsychotic medication that is not approved in the U.S., but is similar to other approved drugs.

The remaining 20 patients were given CBD, a substance found in marijuana that is considered responsible for the mellowing or anxiety-reducing effects. Unlike the main ingredient in marijuana, THC, which can trigger psychotic episodes and worsen schizophrenia, CBD has antipsychotic effects, according to prior research in both animals and humans.

Neither the patients nor the scientists knew who was receiving which drug. At the end of the four-week trial, both groups made significant clinical improvements in their schizophrenic symptoms, and there was no difference between those getting CBD or amisulpride.

 Marijuana Compound May Beat Antipsychotics at Treating Schizophrenia

Шизофрения и курение

The self-medication hypothesis of smoking in schizophrenia

There is a discrepancy in the literature, with numerous animal studies suggesting that nicotine should help negative symptoms but scarce clinical data suggesting that this may be true in those with schizophrenia (Hughes, 2000). Two main sub-hypotheses are usually included in the self-medication hypothesis: smoking reduces the side-effects of antipsychotics; and nicotine may improve schizophrenic symptoms, particularly the negative, cognitive and/or depressive symptoms (Taiminen et al, 1998).

Two mechanisms have been implicated in the reduction of antipsychotic side-effects: a release of dopamine resulting from the administration of nicotine, a notion supported by both acute administration of nicotine in animal models (Drew et al, 2000) and in vivo human studies (Salokangas et al, 2000); and a decrease in antipsychotic blood levels through enzymatic induction. Individuals with schizophrenia who smoke tend to receive consistently higher doses of antipsychotics than non-smokers (Ziedonis et al, 1994; de Leon et al,1995, 2002a). The inductive effect of smoking in antipsychotic metabolism therefore is inadvertently corrected by psychiatrists, because smokers tend to be treated with higher daily doses of antipsychotics than non-smokers. When compared with others with severe mental illness in three epidemiological studies in psychiatric hospitals, the effect of antipsychotic medication did not explain the association between schizophrenia and smoking (de Leon et al,1995, 2002a; Llerena et al, 2003). Some cross-sectional studies have suggested that smoking reduces antipsychotic side-effects and others have not (Dalack et al, 1998); yet all of these studies are hampered by the lack of control for confounding factors. Longitudinal studies with small samples suggest that, when compared with atypical antipsychotics, typical antipsychotics are associated with increased smoking in some individuals (McEvoy et al, 1995) and with a greater difficulty for quitting smoking (Georgeet al, 2000). Anticholinergic medication was not associated significantly with smoking in this or in previous studies (de Leon et al, 1995, 2002a, b).

In spite of the hypothesis from animal studies (Drew et al, 2000), very limited clinical data support an association between smoking and a reduction in negative symptoms (Dalack et al, 1998). Data indicating that nicotine may improve sensory gating abnormalities and smooth pursuit eye movements in schizophrenia or cognitive abnormalities induced by antipsychotics are somewhat stronger. Nicotine may have antidepressant qualities in individuals with depression (Salin-Pascual et al, 1996), but this is not well established in those with schizophrenia.

The literature appears to suggest that those with severe forms of schizophrenia may smoke more frequently, and more heavily, than those with less severe forms (Lohr & Flynn, 1992). The possible beneficial effect of nicotine (and smoking) on schizophrenic symptoms and antipsychotic side-effects may be obscured by this association between smoking and severe forms of schizophrenia. In summary, a critical reading of the literature lends very limited support to the self-medication hypothesis, but this effect may be obscured by the association between severe forms of schizophrenia and heavy smoking.

Nicotine dependence and symptoms in schizophrenia 

Литий-индуцированный гиперпаратиреоз

Approximately 15% to 20% of patients receiving long-term lithium treatment show elevated calcium levels, although only a few of these patients also have significant elevations of PTH levels and clinical symptoms of hyperparathyroidism. Interestingly, lithium-associated clinical hyperparathyroidism is almost always caused by a single parathyroid adenoma rather than 4-gland hyperplasia.
...
Neuropsychiatric symptoms associated with primary hyperparathyroidism include anxiety as well as cognitive and psychotic presentations. However, the most common presentation is depression with associated apathy. In a prospective study of 34 patients with hyperparathyroidism, Velasco and colleagues6 found that approximately one-third of participants had no psychiatric symptoms, one-third had affective symptoms (with or without paranoia), and one-third had cognitive impairment. Affective symptoms were most common in patients with modest elevations in electrolyte levels, while cognitive deficits were more often related to higher calcium concentrations.

 Hyperparathyroidism Resulting From Lithium Treatment Remains Underrecognized

Арипиразол, кветиапин и оланзапин в терапии биполярной депрессии

Seven published papers were identified on the use of aripiprazole, olanzapine and quetiapine. Internal validity of the trials was fairly good, external validity only moderate. Different outcome measures of efficacy and safety were assessed. When the individual trials were looked at, quetiapine and to a lesser extent olanzapine demonstrated significant improvement in MADRS (Montgomery–Åsberg Depression Rating Scale) total scores. This was not demonstrated for aripiprazole. Efficacy was hampered by adverse events, such as weight gain, akathisia and somnolence/sedation. Both clinical heterogeneity of the included trials and statistical heterogeneity of the meta-analytic data were considerable. The number of quetiapine trials was disproportionate to the number of trials of aripiprazole and olanzapine. Further research is needed to assess differential efficacy of the different SGAs and their use in clinical practice.

Second generation antipsychotics in the treatment of bipolar depression: a systematic review and meta-analysis

Роль минеральных веществ в патогенезе психических расстройств

Early studies showed that women affected by chronic depression sometimes have copper, zinc, and cesium deficiencies [37,38]. Later studies suggest that the presence of depression and other neuropsychiatric symptoms is due to the deposit of copper in the central nervous system [39]. Eggers et al. [40] used SPECT to demonstrate a reduction in thalamichypothalamic presynaptic dopamine and serotonin transporters due to the accumulation of copper. There was a negative correlation between the density of presynaptic dopamine transporters and the severity of depression as assessed using the Hamilton Rating Scale for Depression.

It was recently hypothesized that trace elements play an important role in the pathogenesis of

bipolar disorders by causing neurodegeneration [41]. Moreover, essential elements like vanadium have been implicated as a causative factor for bipolar mood disorder, while elevated vanadium and molybdenum levels have been reported in serum samples from bipolar mood disorder patients [41]. This latter study showed, using DSM-IV standard diagnostic criteria and classification into types I, II, and V according to the concept of Young and Klerman, that Na, K, P, Cu, Al, and Mn were elevated significantly in Bipolar I (Mania) (P < 0.001). In Bipolar II hypomania, Na, S, Al, and Mn were increased significantly (P < 0.02), while in Bipolar II depression, Na, K, Cu, and Al were increased significantly (P < 0.001). Finally, in Bipolar V, Na, Mg, P, Cu, and Al were increased significantly (P < 0.002) compared to a control group [41]. A recent study by Gonzales-Estecha and colleagues [21] found higher serum copper and zinc, blood lead and cadmium, and urine lead, cadmium, and thallium concentrations in patients diagnosed with bipolar disorders compared to a control group.

Increased neuronal oxidative stress (OxS) induces deleterious effects on signal transduction, structural plasticity and cellular resilience, mostly by inducing lipid peroxidation in membranes, proteins and genes [42]. It has been hypothesized that these pathological processes occur in critical brain circuits that regulate affective functioning, emotions, motoric behavior and pleasure involved in bipolar disorder (BD) [43,44].

The brain is particularly vulnerable to oxidative damage since it contains large amounts of polysaturated fatty acids and possesses low antioxidant capacity [45]. Several studies have demonstrated altered OxS parameters in the pathophysiology and therapeutics of BD, including changes in the levels of enzymes superoxide dismutase (SOD), catalase (CAT) and thiobarbituric acid reactive substances (TBARS) [46]. The well-known stabilizing agent Lithium was found to limit the enzyme activity, potentially lowering hydrogen peroxide and hydroxyl radical formation. Similarly, lithium was also shown to reverse increased OxS parameters in BD [43,47]. For instance, a decline in lipid peroxidation and an increase in CAT levels were observed in valproate and lithium-treated rats [42,48]. Accumulation of copper was shown to increase oxidative stress in bivalve species [49]. In skeletal muscle of Broilers Under Heat Stress, copper decreases because of dietary Selenium, Vitamin E, and their combination with an increase in antioxidant defense [50]. In humans accumulation of copper was associated with oxidative stress in allergic asthma patients, and introduction of nutritional supplement therapy accompanies improved oxidative stress, immune response, pulmonary function, and decrease in copper plasma levels [51]. On the other hands copper levels were elevated in several brain areas in a degenerative disease such as Niemann-Pick C [52]. Interestingly, Nieman-Pick C disease was specifically indicated to be associated with Bipolar Disorders [53]. If the results of our study are further confirmed, it will lend significant support to the hypothesis that minerals such as copper play an etiological role in psychiatric disorders, and WD may serve as a pathogenic model for the bipolar disorder. 

Bipolar disorders and Wilson’s disease

Ботулотоксин и эмоции

This small, controlled study suggests that paralysis of the "frowning" muscle might be effective.
Several classic studies demonstrate that activation of specific facial muscles (e.g., clenching a pencil between one's teeth to activate the smiling muscles) can alter mood. These researchers examined whether clinical improvement is associated with decreased depressive facial expression through the use of botulinum toxin type A in the glabellar region.
Inclusion criteria were ongoing major depressive disorder, Hamilton Rating Scale for Depression (HRSD) score of 15 or higher, and a moderate-to-severe vertical glabellar line during maximum frowning. Patients were taking one or two antidepressants or had not responded to at least one previous antidepressant. The investigators assessed 263 patients for eligibility and accepted 30 (23 women; average age, 51; mean HRSD, 20; illness duration, 16 years; current episode, 29 months). Patients received injections of botulinum toxin or placebo and were assessed biweekly.
To mask treatment assignment, patients wore caps covering the affected area during assessments. HRSD scores significantly improved at 6 weeks in the active group (HRSD change, –10.07 vs. –1.73 with placebo; response rate [50% decrease in HRSD], 60% vs. 13%). The treatment was identified by 60% of raters and 90% of subjects. Opinion about the cosmetic change was not linked to response.
Comment: These thought-provoking results raise a skeptical eyebrow. Very few screened subjects were enrolled, and group assignment was obvious. The authors claim that exclusion rates were high because of psychiatric comorbidity, medication history, and patient refusal (recruitment information did not identify the protocol). Still, in these subjects with moderate and chronic major depressive disorder unresponsive to at least one medication, botulinum toxin demonstrated an effect similar to medication and greater than transcranial magnetic stimulation. The results appear to confirm the connection between facial expression and feelings. Botulinum toxin may have a therapeutic role in depression, although larger clinical trials are necessary to confirm this initial finding.

Put On a Happy Face: Botulinum Toxin for Depression?

Тиоридазин и онкология

By testing hundreds of compounds, they identified nearly 20 potential cancer stem cell specific drugs.
The one that appeared most promising is an antipsychotic drug, thioridazine, which combats the symptoms of schizophrenia by targeting dopamine receptors in the brain. But concerns about side effects of the drug, brand name Mellaril, have meant that far fewer people with schizophrenia are prescribed the drug than newer antipsychotic medications.
Researchers say thioridazine doesn’t appear to kill cancer stem cells, but rather encourages them to differentiate, thus exhausting the pool of self-renewing cells.
Investigators discovered thioridazine kills leukemia stem cells without affecting normal blood stem cells by comparing the proteins in leukemia versus normal blood cells.
Furthermore, leukemia cells, but not normal blood stem cells, express a dopamine receptor on their surfaces. This finding is supported by the discovery of dopamine receptors on some breast cancer stem cells.
“This gives us some explanation,” Bhatia said. It also suggests that dopamine receptors might serve as a biomarker for rare, tumor-initiating cells.
In light of the findings, Bhatia’s team is already planning for a clinical trial of the FDA-approved thioridazine in combination with standard anti-cancer drugs for adult acute myeloid leukemia.

 Drug Used for Schizophrenia May Check Cancer