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