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

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

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

Механизм действия ТГК на когнитивные функции

The star-shaped astrocytes have long been considered nothing more than support cells that protect neurons. “Our study provides compelling evidence that astrocytes control neurons and memory,” says Zhang. “The supporting actor has become the leading actor.”
The psychoactive ingredient of marijuana is tetrahydrocannabinol (THC). Using microelectrodes implanted into the brains of anaesthetized rats, the researchers found that the compound weakens the connections, or synapses, between neurons in the hippocampus, a structure that is crucial for memory formation.

How marijuana makes you forget

Мета-анализ: каннабиноиды и риск психоза

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

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

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

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

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

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

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

Cannabis Use and Earlier Onset of Psychosis

Эндоканнабиноиды и бег

Recent findings show that exercise increases serum
concentrations of endocannabinoids, a result suggestive of a
new possible explanation for a number of these changes.
Further research is necessary to characterise the precise
nature of this endocannabinoid response to exercise, speci-
fically the relative importance of factors such as the nature of
the activity, exercise duration, exercise intensity, sex, and
age. In addition, animal models can be used to identify the
production and binding sites of endocannabinoids as well as
their functional role in exercise.
The cannabinoids produce psychological states that closely
parallel several experiences described as being related to the
runner’s high. Compared with the opioid analgesics, the
analgesia produced by the endocannabinoid system is more
consistent with exercise induced analgesia. Activation of the
endocannabinoid system also produces sedation, anxiolysis, a
sense of wellbeing, reduced attentional capacity, impaired
working memory ability, and difficulty in time estimation.
This behavioural profile is similar to the psychological
experiences reported by long distance runners. Considerable
research is needed to clarify to what extent the endocanna-
binoid system might be responsible for the exercise induced
changes in mental status. Nevertheless, a significant upre-
gulation of serum concentrations of endocannabinoids has
recently been reported in endurance athletes, and studies are
underway to explore this further in laboratory animals.
The close interaction of endocannabinoids with dopamine
shows that they have a function in the brain’s reward system
and therefore possibly addiction. The endocannabinoid
system is also implicated in the control of motor activity
mediated through the basal ganglia, and central activation of
anandamide in freely moving rats has been demonstrated.
Finally, the endocannabinoid system mediates peripheral
effects such as vasodilation and bronchodilation that may
play a contributory role in the body’s response to exercise.

Endocannabinoids and exercise

Глутаматергические механизмы ОКР

Glutamatergic Dysfunction in Obsessive-Compulsive Disorder and the Potential Clinical Utility of Glutamate-Modulating Agents

Каннабиноиды и аппетит

In addition, research published in the Proceedings of the National Academy of Sciences, and blogged about by Neuroskeptic, showed that CB1 cannabinoid receptors on the tongue selectively boost our pleasurable responses to sweet-tasting food. Conversely, drugs that block cannabinoid receptors have been actively pursued as appetite suppressants. One such drug, trade name rimonabant, was disallowed by the FDA on the grounds that it worked so well in the guise of anandamide’s opposite number that it frequently caused debilitating depression in users. But it did appear to reduce appetites.

Addiction Inbox

Болезнь Хантингтона и каннабиноидная система

The biology of Huntington's is only partially understood. It's caused by mutations in the huntingtin gene, which lead to the build-up of damaging proteins in brain cells, especially in the striatum. But exactly how this produces symptoms is unclear.

The two new papers show that cannabinoids play an important role. First off, Van Laere et al used PET imaging to measure levels of CB1 receptors in the brain of patients in various stages of Huntington's. CB1 is the main cannabinoid receptor in the brain; it responds to natural endocannabinoid neurotransmitters, and also to THC, the active ingredient in marijuana.

They found serious reductions in all areas of the brain compared to healthy people, and interestingly, the loss of CB1 receptors occurred early in the course of the disease:

If so, drugs that activate CB1 - like THC - might be able to slow down the progression of the disease, and indeed it did: Huntington's mice given THC injections stayed healthier for longer, although they eventually succumbed to the disease. Further experiments showed that mutant huntingtin switches off expression of the CB1 receptor gene, explaining the loss of CB1.

Cannabinoids in Huntington's Disease