теория ГАМКергического дефицита при депрессии

tudies of depressed patients indicate that MDDs are accompanied by reduced brain concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and by alterations in the subunit composition of the principal receptors (GABAA receptors) mediating GABAergic inhibition. In addition, there is abundant evidence that suggests that GABA has a prominent role in the brain control of stress, the most important vulnerability factor in mood disorders. Furthermore, preclinical evidence suggests that currently used antidepressant drugs (ADs) designed to alter monoaminergic transmission and nonpharmacological therapies may ultimately act to counteract GABAergic deficits. In particular, GABAergic transmission has an important role in the control of hippocampal neurogenesis and neural maturation, which are now established as cellular substrates of most if not all antidepressant therapies. Finally, comparatively modest deficits in GABAergic transmission in GABAA receptor-deficient mice are sufficient to cause behavioral, cognitive, neuroanatomical and neuroendocrine phenotypes, as well as AD response characteristics expected of an animal model of MDD. The GABAergic hypothesis of MDD suggests that alterations in GABAergic transmission represent fundamentally important aspects of the etiological sequelae of MDDs that are reversed by monoaminergic AD action.

The GABAergic deficit hypothesis of major depressive disorder

Случай улучшения в обсессивно-компульсивной симптоматике после инсульта

Within weeks of her stroke, she realized that her obsessive and intrusive thoughts, fears, rituals, and impulsive behavior had completely resolved. In addition, there was some improvement in her temperament. There was no improvement in attention or concentration. Owing to her improvement in neuropsychiatric symptoms, she strongly felt that her stroke was beneficial. These benefits have persisted for 24 months.

A Stroke Of Good Fortune Cures OCD?

стратегии аугментации l-метилфолатом при резистентной депрессии

Significant Benefit

In the TRD-1 study, 148 patients were randomized in a 2:3:3 design to receive either L-methylfolate for 60 days (7.5 mg/d in phase 1 and 15 mg/d in phase 2), placebo for 30 days followed by L-methylfolate for 30 days (7.5 mg/d), or placebo for 60 days.

The 75-patient TRD-2 was identical in design to TRD-1 except for a target dose of 15 mg/d of L-methylfolate throughout both phases.

The coprimary endpoints for both studies were the differences in response rates and in degree of improvement in the Hamilton Depression Rating Scale (HDRS-17) between treatment groups. An HDRS-17 response was defined asa 50% or greater reduction in HDRS-17 scale scores during treatment or a final score of 7 or less.

The TRD-1 study found no difference in outcome between the treatment groups.

The TRD-2 study showed greater efficacy for adjunctive 15 mg/d of L-methylfolate administered for up to 30 days vs placebo when added to continued SSRI therapy plus placebo on both primary outcome measures (degree of change and response rates according to the HDRS, P = .05 and .04, respectively).

There was no difference in the rates of treatment withdrawal due to adverse events in the L-methylfolate 15 mg/d/antidepressant and the placebo/antidepressant groups.

Finally, the number of patients needed to treat (NNT) for a response in the TRD-2 study was between 5 and 6 patients in favor of adjunctive 15 mg/dof L-methylfolate vs placebo. "This is on a par with NNTs reported for other augmentation strategies in MDD," Dr. Papakostas said.

Adjunctive L-Methylfolate May Help in Treatment-Resistant Depression

Ранние признаки шизофрении, длительность нелеченного психоза, предупреждение первого психоза

Early Antecedents and Detection of Schizophrenia

Болезнь Фабри и шизофреноформный психоз

A 21-year-old female with Fabry’s disease (FD) presented acute psychotic symptoms such as delusions, auditory hallucinations and formal thought disorders. Since the age of 14, she had suffered from various psychiatric symptoms increasing in frequency and intensity. We considered the differential diagnoses of prodromal symptoms of schizophrenia and organic schizophrenia-like disorder. Routine examinations including cognitive testing, electroencephalography and structural magnetic resonance imaging revealed no pathological findings. Additional structural and functional imaging demonstrated a minor CNS involvement of FD, yet without functional limitations. In summary our examination results support the thesis that in the case of our patient a mere coincidence of FD and psychotic symptoms is more likely than a causal connection.

Fabry’s Disease and Psychosis: Causality or Coincidence?

Применение эсциталопрама в дозах превышающих максимальные у больных с резистентной депрессией

Methods

This open-label, pilot study was designed to investigate the efficacy, safety and tolerability of escitalopram in doses up to 50 mg in Major Depressive Disorder (MDD). It was conducted in 60 primary care patients with MDD who had not responded to adequate treatment with citalopram. Patients were treated with escalating doses of escitalopram up to 50 mg for up to 32 weeks until they achieved remission (Montgomery-Asberg Depression Rating Scale [MADRS] (less than or equal to 8) or failed to tolerate the dose.
Results

Forty-two patients (70%) completed the study. Twenty-one patients (35%) achieved remission with 8 of the 21 patients (38%) needing the 50 mg dose to achieve remission. Median time to remission was 24 weeks and median dose in remission was 30 mg. No significant safety issues were identified although tolerability appeared to decline above a dose of 40 mg with 26% of patients unable to tolerate 50 mg. Twelve (20%) patients had adverse events leading to discontinuation. The most common adverse events were headache (35%), nausea, diarrhoea and nasopharyngitis (all 25%). Minor mean weight gain was found during the study, which did not appear to be dose-related. Half of the patients who completed the study chose to continue treatment with escitalopram rather than taper down the dose at 32 weeks.

Efficacy, safety and tolerability of escitalopram in doses up to 50 mg in Major Depressive Disorder (MDD): an open-label, pilot study

Перинатальные инфекции и риск шизофрении

These studies have yielded a series of intriguing associations (reviewed in Brown and Derkits)[2] and are briefly summarized here. Our group demonstrated that prenatal exposure to rubella was related to a greater than 5-fold increased risk of nonaffective psychosis during young adulthood[12] and in midadulthood over 20% of subjects who were exposed in utero to rubella were diagnosed with schizophrenia or a schizophrenia spectrum disorder.[13] Influenza exposure documented by quantification of maternal antibody titers during pregnancy was associated with a 3-fold increased risk of schizophrenia for exposure in mid to late gestation and a 7-fold elevation in risk of the disorder following first trimester exposure.[14] Elevated maternal IgG antibodies to Toxoplasma gondii, an intracellular parasite and a well-known infectious cause of central nervous system (CNS) congenital anomalies,[1,15] was related to greater than 2-fold increased risk of schizophrenia,[16] a finding which was essentially replicated in a Danish sample that capitalized on filter paper blood spots taken from the infant within the first week of birth.[17] In 3 studies, elevated maternal IgG antibody to (HSV-2) was related to an increased risk of psychotic disorders, including schizophrenia,[18,19,20] while the finding was not replicated in a different birth cohort.[21] Maternal genital/reproductive infections, broadly defined, were, however, associated with a 5-fold increased risk of schizophrenia when the exposure occurred during the periconceptional period.[22] Exposure to maternal respiratory infection was related to a 2-fold elevated schizophrenia risk,[23] as well as bacterial infections broadly defined.[24]

In summary, birth cohort studies have provided several key methodological advantages that have allowed for more rigorous testing of relationships between maternal infection and schizophrenia. Birth cohort studies conducted to date have provided further support for the hypothesis that maternal viral, protozoal, and bacterial infections increase the risk for schizophrenia in adult offspring.

Although cytokines represent a leading candidate agent for the effect of infection on schizophrenia risk, other possible mediators include hyperthermia, which is teratogenic to animals;[32] fetal hypoxia, which has been associated with schizophrenia;[33,34] and over the counter remedies taken for influenza such as aspirin, which has been associated with anomalies of the CNS.

Maternal Infection and Schizophrenia

Фолаты могут ослаблять негативную симптоматику у некоторых больных шизофренией

Folate supplementation appears to improve negative symptoms in schizophrenia patients, but only among those with a genetic variant of a folate-metabolizing enzyme, study results show.

It follows an earlier study by the same group showing that schizophrenia patients with low serum folate levels who were also homozygous for the 677C>T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene had severe negative symptoms.

Folate may improve negative symptoms in some schizophrenia patients

H2-блокаторы не снижают риск возникновения деменции и болезни Альгеймера

To examine whether histamine-2 receptor antagonist medications (H2RAs) are associated with a lower incidence of all-cause dementia or Alzheimer's disease (AD), as some studies have suggested.
Design: Prospective population-based cohort
Setting: Group Health, an integrated health maintenance organization, Seattle, Washington.
Participants: Two thousand nine hundred twenty-three participants aged 65 and older without dementia at baseline, with initial recruitment between 1994 and 1996.
Measurements: Follow-up occurred every 2 years to identify incident dementia and AD using standard criteria. Exposure to H2RAs was determined based on automated pharmacy data. Three aspects of exposure (time-varying) were examined based on standard daily dose (SDD): cumulative use, intensity of use (highest SDD in any prior 2-year window), and cumulative use stratified according to recency (1–3 years vs >3 years before).
Results: Over a mean follow-up of 6.7 years, 585 subjects developed dementia (453 developed AD). Total cumulative exposure was not associated with dementia (P=.35; omnibus test) or AD (P=.23). The adjusted hazard ratios for the highest exposure category (>1,080 SDDs) compared with light or no use were 1.28 (95% confidence interval (CI)=0.95–1.72) for dementia and 1.41 (95% CI=1.00–1.97) for AD. Intensity of use was not associated with dementia (P=.39) or AD (P=.63). Examining exposure according to recent and distant cumulative use also showed no association with dementia (P=.11) or AD (P=.30).
Conclusion: No association was found between H2RA use and risk of all-cause dementia or AD using more-detailed and -extensive information about past H2RA use than any prior study.

Histamine-2 Receptor Antagonist Use and Incident Dementia in an Older Cohort

Особенности воздействия пароксетина тревожную и депрессивную симптоматику

This is rather remarkable. Everyone calls paroxetine "an antidepressant", yet at least in one important sense it works better against OCD and social anxiety than it does against depression!

In fact, is paroxetine an antidepressant at all? It works better on MADRS and very poorly on the HAMD; is this because the HAMD is a better scale of depression, and the MADRS actually measures anxiety or OCD symptoms?

That's a lovely neat theory... but in fact the HAMD-17 has two questions about anxiety, scoring 0-4 points each, so you can score up to 8 (or 12 if you count "hypochondriasis", which is basically health anxiety, so you probably should), out of a total maximum of 52. The MADRS has one anxiety item with a max score of 6 on a total of 60. So the HAMD is more "anxious" than the MADRS.

This is more than just a curiosity. Paroxetine's antidepressant effect was tiny in those aged 25 or under on the HAMD - treatment just 9% of the placebo effect - but on the MADRS in the same age group, the benefit was 35%! So what is the HAMD measuring and why is it different to the MADRS?

Honestly, it's hard to tell because the Hamilton scale is so messy. It measures depression and the other distressing symptoms which commonly go along with it. The idea, I think, was that it was meant to be a scale of the patient's overall clinical severity - how seriously they were suffering - rather than a measure of depression per se.

Paxil: The Whole Truth?

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

Significant Weight Gain Associated with Post-Clozapine Antipsychotics

Significant Weight Gain* Associated with Post-Clozapine Antipsychotics
*≥7% body weight increase vs placebo; 4-8 week trials

Пролонгированная инъекционная форма рисперидона вызывает больше побочных эффектов

Long-acting, injectable risperidone, the first second-generation antipsychotic available in the United States in this formulation, is no better than oral antipsychotics for the treatment of unstable schizophrenia, a new study published in the March 3 issue of the New England Journal of Medicine suggests.

In a randomized study of more than 300 Veterans Affairs (VA) patients, investigators found injectable risperidone did not significantly decrease hospitalization rates or improve symptoms, social function, or quality of life compared with those treated with "clinicians' choice" of oral antipsychotics. The risperidone-treated group also reported more adverse effects.

No Benefit, More Side Effects With Injectable Risperidone

Фармакотерапия когнитивных нарушений при травмах головного мозга

Recommended treatments for mild TBI-related cognitive deficits

Deficit	First-line medication	Side effects	Contraindications	Other treatments
Memory	Donepezil (5 to 10 mg/d)	Diarrhea, nausea, vomiting, muscle cramps, fatigue, anorexia	Hypersensitivity to donepezil or piperidine derivatives	Rivastigmine, galantamine, physostigmine, CDP-choline
Speed of processing	Methylphenidate (0.3 mg/kg twice daily)	Headache, insomnia, decreased appetite, nausea, vomiting, anxiety, irritability	Hypersensitivity to methylphenidate, glaucoma, history of Tourette syndrome or tics, use of MAOI within 14 days	Dextroamphetamine
Executive function	Amantadine (200 to 400 mg/d)	CNS depression, orthostatic hypotension, peripheral edema, agitation, nausea, anorexia	Hypersensitivity to amantadine	Bromocriptine, pramipexole, carbidopa/levodopa
CDP-choline: cytidinediphosphocholine; MAOI: monoamine oxidase inhibitor
Source:Reference 8

Executive function responds to non-stimulant catecholaminergics. In a review, Writer and Schillerstrom5 found that TBI patients who received catecholaminergic augmentation showed improved function in 6 of 7 studies. In 2 randomized controlled trials (RCTs) and 4 nonrandomized, placebo-controlled trials, patients with mild to severe TBI showed improved executive function, attention, global cognitive function, memory, language, and/ or arousal with use of bromocriptine, pramipexole, carbidopa/levodopa, or amantadine.5 The greatest improvements were found in executive function. In 1 RCT, 10 patients with mild to severe TBI showed no functional improvement after 2 weeks of treatment.

Amantadine, 200 to 400 mg/d, has been shown to safely improve arousal and cognitive function in patients with moderate to severe TBI when started 3 days to 5 months after injury.9 Amantadine, 400 mg/d, also improves executive function measures without significant benefit in attention or memory in patients with mild to severe TBI 6 months post-injury.10

Memory responds to cholinesterase inhibitors. Memory deficits secondary to TBI affect immediate and delayed memory. The cholinesterase inhibitor donepezil is approved for treating Alzheimer’s disease (AD) in the United States and Canada, and research suggests memory deficits after TBI may be similar to those seen in AD.11 This includes deficits in long-term memory storage, which likely is associated with the cholinergic system.11 Post-mortem studies have found similarities in traumatically injured brains and those of AD patients.11

Three small prospective studies of done-pezil have shown improved memory and attention in TBI patients when cognition is the primary outcome, with 1 small negative open-label trial.7 In a study of 53 patients, Whelan et al12 found that donepezil improved patients’ intelligence quotient and clinician-based assessment of cognition over 2 years. Taverni et al13 found memory improvement in 2 TBI patients within 3 weeks of starting donepezil. These results suggest that donepezil may be used in acute and late phases of memory deficits following mild, moderate, or severe TBI.6 All studies titrated donepezil from 5 to 10 mg/d over several weeks. Dosing guidelines for donepezil in AD suggest 5 mg/d for 4 to 6 weeks, which may be increased to 10 mg/d if needed.8

Rivastigmine (3 to 6 mg/d) has been shown to be effective in mild TBI when started 1 year after injury and safe for 12 to 38 weeks of treatment.14,15 One retrospective cohort study of 111 patients with chronic TBI found no difference among donepezil, rivastigmine, or galantamine, with mean doses of 7.2 mg/d, 10 mg/d, and 2.3 mg/d, respectively.16 Sixty-one percent of patients showed improvement and the remainder had modest or no response. This study suggests that positive response on cognition may be similar among cholinesterase inhibitors. In case reports, physostigmine has offered some benefit17,18; however, cardiovascular and autonomic side effects restrict its use.11 Tacrine is associated with problematic gastrointestinal and hepatic side effects.

Processing speed responds to stimulant catecholaminergics. Although the incidence of psychiatric illness is not correlated with TBI severity, evidence suggests that speed of processing mediates the relationship between injury severity and functional decline.19 Therefore, aggressively treating these deficits may help improve function.

Methylphenidate improves attention and processing speed after TBI. A review of 7 randomized trials and 2 nonrandomized trials indicated that patients with mild to severe, chronic TBI experienced significantly improved cognitive function after methylphenidate treatment.5 Willmott and Ponsford20 found significant enhancement in information processing speed within 2 weeks of methylphenidate treatment in 40 patients with moderate or severe TBI. Methylphenidate increased the rate of recovery and led to improvement in acute21 and post-acute phases.22 In addition, methylphenidate may improve processing speed even in the absence of significant changes in attention.23

The standard methylphenidate dose used in most studies, 0.3 mg/kg twice daily, is safe and effective. Dosing usually is started at 5 mg/d and titrated to symptomatic relief. Because methylphenidate does not lower the seizure threshold, it is safe for patients at high risk for seizure.24 Methylphenidate also significantly improves attention and speed of processing in pediatric head trauma.25,26

Dextroamphetamine also is used to treat speed of processing dysfunction after TBI, but is less studied than methylphenidate. Dextroamphetamine, 5 to 30 mg/d, was found to effectively treat attention problems that interfered with rehabilitation in patients with severe TBI.

Traumatic brain injury: Pharmacotherapy options for cognitive deficits

Механизмы действия новейших антипсихотиков

Early pharmacotherapeutic agents used for schizophrenia targeted neuronal pathways related to psychosis. One of the first pharmacologic agents used in the treatment of patients with schizophrenia was the antihypertensive agent reserpine. The antipsychotic effects of this drug result from reduction of synaptic dopamine release.

For those who believe that focusing on these variations in neuropharmacologic binding effects is of minor importance, recall that the first effective antiobsessive, the tricyclic antidepressant chlomipramine, differs from imipramine by only 1 chloride atom substitution.31 It was hard to believe that chlomipramine would be effective for obsessive-compulsive disorder (OCD) when imipramine was not, but that is, in fact, what happened.

Iloperidone is an antipsychotic that was approved in May 2009 for the acute treatment of schizophrenia in adults. The mechanism of action, which involves antagonism of serotonin-2A (5HT-2A) and dopamine 2 receptors with a high 5HT-2A/D2 ratio, is similar to other atypical antipsychotics. Its efficacy appears to be similar to haloperidol, risperidone, and ziprasidone. It also has a very low EPS and akathisia profile, for reasons that are not well understood. It has strong alpha-adrenergic antagonism effects, and therefore requires a cautious dosing and titration schedule to reduce the potential for orthostatic hypotension and dizziness. The lack of affinity of iloperidone for other receptors (e.g., histamine, muscarinic) results in a low antihistaminic and anticholinergic side effect profile.37

Asenapine, approved for acute and maintenance treatment of schizophrenia, has a unique human receptor signature with binding affinities and antagonistic properties that are substantially different from other available schizophrenia treatments. Asenapine, which is administered sublingually, is a potent antagonist at several serotonin receptors38 and also has high affinity for alpha-adrenergic and dopaminergic receptors, which suggests potential for both antipsychotic and cognitive-enhancing properties.39 Clinical trial data demonstrate strong efficacy for positive symptoms, and there is some evidence of beneficial effects on negative and cognitive symptoms.

Expanding the Treatment Paradigm in Patients With Schizophrenia: Beyond Psychotic Symptoms

Стратегии лечения тиков при синдроме Туретта

The majority of treatment options for tics are pharmacological. The most commonly prescribed drugs are primarily dopamine antagonists, such as neuroleptics (e.g. haloperidol), benzamides (e.g. sulpiride) or atypical antipsychotics (e.g. risperidone). Other agents that may be efficacious include drugs which modulate noradrenaline (e.g. clonidine), GABA (e.g. benzodiazepines) and acetylcholine (e.g. nicotine). Nonpharmacological interventions include behavioural approaches such as habit reversal training and exposure response prevention therapy. Surgical techniques involving deep brain stimulation (DBS) of the thalamus or globus pallidus may also be considered for severe, treatment refractory patients. Some of the more recent treatments that have been trialled include electroconvulsive therapy and repetitive transcranial magnetic stimulation.

.
Treatment Strategies for Tics in Tourette Syndrome

Оксибутинин в качестве корректора гипергидроза вызванного приёмом антидепрессантов

Patient A is a 59-year-old man with a history of recurrent episodes of panic disorder, for which he had used paroxetine, venlafaxine, and escitalopram as well as high doses of oxazepam in the past. He was admitted to the hospital because of a severe depressive episode with suicidal ideation. The depression was successfully treated with clomipramine, 100 mg/day, which was effective for the treatment of panic attacks as well. Although he sweated all over his body, he was willing to continue clomipramine monotherapy after discharge. Lowering the dosage did not change the situation, nor did treatment with cognitive-behavioral therapy. Finally, a trial with oxybutynin, 2.5 mg b.i.d., relieved the hyperhidrosis completely, without any side effects.

Patient B is a 60-year-old man with recurrent severe depressive episodes with psychotic symptoms and agitation. Typical for his disorder are the rapid onset of relapse and the severity of agitation, which in the past required hospitalization and seclusion. In the latest episode he was treated with clomipramine, 75 mg/day, and olanzapine, 15 mg/day, but he suffered from severe hyperhidrosis. A switch from olanzapine to haloperidol did not change the hyperhidrosis. Later, 800 mg/day of lithium was successfully added for the treatment of his depressive symptoms. Oxybutynin, 5 mg t.i.d., was added to his treatment and relieved his hyperhidrosis without side effects.

There are several preferential strategies to treat hyperhidrosis, such as lowering the dosage or altering the dosing schedule, changing clothing or food habits, or regulating anxiety (2). In the present two cases, these strategies were unsuccessful and oxybutynin maintenance treatment was introduced. With its rapid, short-term effect (within an hour), oxybutynin could also be considered "as needed" in specific social situations. One should be careful in dosing to avoid anticholinergic side effects such as constipation, urinary retention, and blurred vision. Although placebo-controlled research is necessary, the cases reported here suggest that adding oxybutynin to antidepressants can be a simple and effective treatment option for hyperhidrosis.

Oxybutynin for Antidepressant-Induced Hyperhidrosis