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?