Случай нейропсихиатрической манифестации анти-NMDA-рецепторного энцефалита

A 52-year-old Chinese man was admitted to the inpatient psychiatric unit of an academic teaching hospital with an admitting diagnosis of major depressive disorder (MDD) with psychotic features. His chief complaint was "I do not feel happy." The patient endorsed insomnia, hopelessness, passive suicidal ideation, and increased anxiety, especially at bedtime. He was disheveled, guarded, demonstrated poor eye contact, slurred and decreased speech output, psychomotor retardation, poor cognition, flat affect, and vague auditory and visual hallucinations of seeing and hearing people. The patient had a past psychiatric history of MDD with psychotic features diagnosed when he was in his early 30s, and suicidal gestures. He had two previous inpatient admissions while in China in 2008, for psychotic features described then as robotic speech, flat affect, and minimal verbal responsiveness. At the time of his current admission, he was being followed in the psychiatry outpatient clinic. He denied past or current substance abuse. The patient's past medical history was significant for one observed tonic–clonic seizure in December 2009, which was managed with phenytoin 300 mg daily. At that time, neurologic evaluation was unrevealing, and no etiology of the seizure was identified.
After initial evaluation in the hospital, the patient was started on escitalopram 15 mg daily and paliperidone 3 mg daily, and his phenytoin 300 mg daily was continued. ECT had been considered while he was being followed as an outpatient. Upon admission, he was started on a course of ECT. Despite numerous medication trials including paliperidone, olanzapine, and clozapine, as well as a series of 12 ECT treatments, the patient's condition did not improve, and he began to show signs of cognitive decline. A neurology consult was requested for continued agitated and bizarre behavior. An EEG showed diffuse slowing, and a magnetic resonance (MRI) scan showed only small-vessel ischemic microvascular disease.
After 2 months, while still on the psychiatry inpatient unit, he developed symptoms of extreme agitation, aggressiveness, and unusual behavior, and was verbally unresponsive. His agitation was treated with lorazepam. Vital signs at that time revealed tachycardia to a heart rate of 120 bpm, a blood pressure of 90/50 mmHg, and O2 saturation of 90% at room air. His temperature was 102.3°F. The patient was transferred to the medical intensive care unit (MICU) and intubated for airway protection. Laboratory data at transfer revealed a white cell count of 11.2 K/µl, BUN 32 mg/dl, Cr 1.2 mg/dl, and creatine kinase 2,361 u. Neuroleptic malignant syndrome was suspected but ruled out, as the patient's temperature and creatine kinase trended down in the subsequent days without any active intervention. After 11 days, he was extubated. He displayed echopraxia, but no focal findings were documented.
Because of his unusual course, failure to respond to standard treatments for depression and psychosis, and the presence of a documented seizure 1 month before admission, a work-up for possible anti-NMDA receptor antibody encephalitis was started. Lumbar puncture yielded clear, colorless fluid which was acellular, with a glucose of 76 mg/dl and protein of 21 mg/dl. VDRL and oligoclonal bands were negative. CSF and serum sample was also sent for anti-NMDA receptor antibody testing. The patient had an EEG performed, which revealed bilateral independent temporal lobe discharges more prominent in the left hemisphere than the right, but no active seizures were seen. CSF and serum results confirmed the patient's diagnosis of anti-NMDA antibody encephalitis by the presence of antibodies against NRI-NR2 heteromers of the NMDA receptor. The patient was transferred to another hospital and lost to follow-up.

An Unusual Case of Anti-NMDA-Receptor Encephalitis in the Psychiatry Inpatient Unit

Предупреждение нежелательных эффектов лекарственных препаратов в психиатрии

How to prevent adverse drug events

Антихолинэстеразные свойства шалфея и влияние на когнитивные функции

Extracts of sage (Salvia officinalis/lavandulaefolia) with terpenoid constituents have previously been shown to inhibit cholinesterase and improve cognitive function. The current study combined an in vitro investigation of the cholinesterase inhibitory properties and phytochemical constituents of a S. lavandulaefolia essential oil, with a double-blind, placebo-controlled, balanced crossover study assessing the effects of a single dose on cognitive performance and mood. In this latter investigation 36 healthy participants received capsules containing either 50 µL of the essential oil or placebo on separate occasions, 7 days apart. Cognitive function was assessed using a selection of computerized memory and attention tasks and the Cognitive Demand Battery before the treatment and 1-h and 4-h post-dose. The essential oil was a potent inhibitor of human acetylcholinesterase (AChE) and consisted almost exclusively of monoterpenoids. Oral consumption lead to improved performance of secondary memory and attention tasks, most notably at the 1-h post-dose testing session, and reduced mental fatigue and increased alertness which were more pronounced 4-h post-dose. These results extend previous observations of improved cognitive performance and mood following AChE inhibitory sage extracts and suggest that the ability of well-tolerated terpenoid-containing extracts to beneficially modulate cholinergic function and cognitive performance deserves further attention.

Monoterpenoid extract of sage (Salvia lavandulaefolia) with cholinesterase inhibiting properties improves cognitive performance and mood in healthy adults

Drug-Resistant Epilepsy

Drug-Resistant Epilepsy

Запах шизофрении

They collected the sweat from 14 white male patients with schizophrenia and 14 comparable patients with ‘organic brain syndromes’ and found they could train rats to reliably distinguish the odours while a human panel of sweat sniffers seemed to be able to do the same.
Seemingly backed up by the nasal ninja skills of two different species, science attempted to determine the source of the ‘schizophrenic odour’.
Two years later researchers from Washington suggested the smell might be triggered by the bacteria Pseudomonas aeruginosa but an investigation found it was no more common in people with schizophrenia than those without the diagnosis.
But just before the end of the 60s, the original research team dropped a scientific bombshell. They claimed to have identified the schizophrenia specific scent and got their results published in glittery headline journalScience.
Using gas chromotography they identified the ‘odorous substance’ as trans-3-methyl-2-hexenoic acid, now known as TMHA.

Looking back, we now know that TMHA is genuinely an important component in sweat odour. Curiously, it turns out it is largely restricted to Caucasian populations but no link to mental illness or psychiatric disorder has ever been confirmed.
The theory seems like an curious anomaly in the history of psychiatry but it occasionally makes a reappearance. In 2005 study claimed that the odour exists but is “complex and cannot be limited to a single compound, but rather to a global variation of the body odor” but no replications or further investigations followed.

A whiff of madness

Депрессия, воспаление и сердечно-сосудистые заболевания

Led by Dr. Jesse Stewart, researchers found that depressive symptoms are associated with increases over time in interleukin-6, an inflammatory protein that predicts cardiovascular events.

On the other hand, levels of interleukin-6 were not linked to subsequent increases in depressive symptoms.

Depression leads to increased inflammatory protein linked to heart disease

Фармакогенетика СИОЗС, ассоциации между полиморфизмом CYP2D6 и CYP2C19 и ответом на терапию антидепрессантом

An investigation of MEDLINE and other database resources was carried out to summarize the research conducted between 1970 and 2003 in the role of CYP2D6 genetics on SSRI dose exposure.^[2] Area-under-the-concentration curve (AUC) values of 5 SSRIs in poor metabolizers, intermediate metabolizers, and extensive metabolizers as a measure of bioavailability were collected. Dose adjustments were then calculated to compensate for variability in CYP2D6 metabolizer status in white patients. On the basis of metabolizer phenotype, the following dose adjustments were extrapolated for extensive vs poor metabolizers: 33%-129% for fluvoxamine, 66%-114% for paroxetine, 56%-119% for fluoxetine (including the AUC of its active metabolite), 98%-101% for citalopram, and 99-100% for sertraline. A dose adjustment of 130% for paroxetine was extrapolated for ultrarapid metabolizers.

However, the study authors concluded that dose adjustments that are based on CYP2D6 could not be recommended for SSRIs for various reasons. They noted the limited data from multiple dosing, which more accurately reflects the clinical situation; the unknown effect of saturation kinetics of some SSRIs (eg, paroxetine and fluvoxamine); and the long-term effect of inhibition of CYP2D6 by some SSRIs (eg, fluoxetine, fluvoxamine, and paroxetine) when given in chronic treatment regimens. Thus, basic human pharmacokinetic data do not strongly support routine clinical use of CYP2D6 testing.

Another study scanning 1200 Web-based articles between 1966 and 2006 for treatment of major depression found no consistent association between CYP2D6 genotype and SSRI metabolism, efficacy, or risk for side effects.^[3]Although 2 studies showed greater nonresponse to SSRIs among ultrarapid metabolizers relative to the general population, the data were inconsistent across other studies. The study authors concluded that there is no established association between plasma drug concentration and SSRI drug response at standard doses.

Finally, a study of SSRI drug response and tolerability in 1953 patients enrolled in the Sequenced Treatment of Alternatives to Relieve Depression (STAR*D) study also showed no significant association between CYP2D6 variants and citalopram response, remission, or tolerability when comparing extensive metabolizers with poor metabolizers. However, the study design included numerous concomitant medications with unknown confounding effects.^[4]

The complexity derived from interaction between multiple CYP enzymes was highlighted in a study of the impact of extensive and poor metabolizer status for CYP2D6 and CYP2C19 on the SSRI citalopram. Researchers showed that the AUC for citalopram correlated with the combined CYP2D6/CYP2C19 metabolizer status.^[5] For example, individuals with CYP2D6 extensive metabolizer/CYP2C19 poor metabolizer status showed significantly higher citalopram AUC compared with extensive/extensive metabolizer or poor/extensive metabolizer carriers. Because citalopram metabolism is preferentially catalyzed by CYP2C19 over CYP2D6, consideration of more than 1 genetic variant may be necessary to guide medication dosing decisions.

Pharmacogenomics of SSRIs: Clinical Implications

Психические расстройства при гипотиреозе и гипертиреозе

The symptoms and signs of hyperthyroidism resemble those of primary mental disorders. Overactivity of the adrenergic system caused by hyperthyroidism may explain the similarity between the clinical presentations of hyperthyroidism and mania or anxiety, as well as the precipitating role of hyperthyroidism in the development of mania or anxiety disorder. It may also explain the increased sense of well being often experienced in the early stages of hyperthyroidism.[20,21]

The relationship between hyperthyroidism and depression is less clear. Depression is usually linked to hypothyroidism, not to hyperthyroidism. However, prolonged hyperthyroidism might exhaust noradrenergic transmission and thus contribute to depression. Noradrenergic exhaustion might well occur in patients with hyperthyroidism who have bipolar disorder. In the initial phase of hyperthyroidism, thyroid hormone stimulation of the noradrenergic system may cause mania; later, when noradrenergic neurotransmission is exhausted, it may contribute to depression.[21]

Mental symptoms and disorders secondary to hyperthyroidism should be treated first by restoring euthyroidism. Most mental symptoms, including depression, usually resolve once euthyroidism has been regained. Treatment with beta-adrenergic antagonists alone may quickly relieve many symptoms, including mental symptoms, even if euthyroidism is not restored,[22] providing evidence that overactivity of the adrenergic system is largely responsible for mental symptoms in hyperthyroidism.

Thyroid deficits are frequently observed in bipolar patients, especially in women with the rapid cycling form of the disease.[24] Both subclinical hypothyroidism and subclinical hyperthyroidism increase the risk for Alzheimer's disease, especially in women.[25] However, most hypothyroid patients do not meet the criteria for a mental disorder.

A recent study evaluated brain glucose metabolism during T4 treatment of hypothyroidism. A reduction in depression and cognitive symptoms was associated with restoration of metabolic activity in brain areas that are integral to the regulation of mood and cognition.[26••]

In hypothyroidism, replacement therapy with T4 remains the treatment of choice and resolves most physical and psychological signs and symptoms in most patients. However, some patients do not feel entirely well despite doses of T4 that are usually adequate.[27] In T4-treated patients, it was found that reduced psychological well being is associated with occurrence of polymorphism in the D2 gene,[28••] as well as in the OATP1c1 gene.[29]

Thyroid hormone replacement with a combination of T4 and T3, in comparison with T4 monotherapy, improves mental functioning in some but not all hypothyroid patients,[30,31•] and most of the patients subjectively prefer combined treatment.[32] Two studies have evaluated whether D2 polymorphism is associated with changes in psychological well being after combined T4 and T3 treatment. One underpowered study[33] reported a trend toward improvement. In a second study[28••] involving a very large sample, D2 polymorphism was associated with improvement in psychological well being after T4 and T3 treatment.

Thyroid Disease and Mental Disorders: Cause and Effect or Only comorbidity?

MDMA в психиатрии

The pharmacological effects of MDMA include serotonin release; serotonin type 2 receptor stimulation; and an increase in levels of the neurohormones oxytocin(Drug information on oxytocin), prolactin, and cortisol.24-29 Serotonin release plays an important role in producing the subjective effects of MDMA.30-33 Pretreatment with SSRIs reduces most acute subjective and physiological effects of MDMA, including effects on mood and perception. Serotonin release directly or indirectly leads to an elevation in oxytocin levels, possibly by stimulating serotonin type 1A receptors.24,28,34 Studies suggest that oxytocin plays an important role in stress response, reduces the fear response, and increases social affiliation and trust35-39; thus, elevated oxytocin levels might help patients form a therapeutic alliance and revisit traumatic experiences in an emotionally engaged state.
Elevation in oxytocin levels after MDMA administration has been associated with greater sociability and more gregarious behavior.24 MDMA has recently been shown to decrease perception of negative emotions in others and perception of threat-related signals, such as fear, which might increase social approach behavior.40 It has been postulated that prolactin release following MDMA administration may contribute to a postorgasmic-like sense of relaxation and receptivity.41 The neurocircuitry model of PTSD postulates a deficit in extinction of fear conditioning mediated by the amygdala and the ventromedial prefrontal cortex, a model supported by findings of reduced hippocampal activity and volume, increased activity in the amygdala, and decreased activation of the medial prefrontal cortex in persons with PTSD.42,43
Gamma and colleagues44 used positron emission tomography to measure cerebral blood flow 75 minutes after MDMA was given to healthy volunteers. Their findings showed increases in cerebral blood flow in the ventromedial frontal and occipital cortex and decreases in the left amygdala. MDMA may produce some of its effects through these acute changes in brain activity, which may reverse abnormalities associated with PTSD and thereby allow effective processing of traumatic memories. The nature of the effects is consistent with much of what we observed in our clinical trial.

Does MDMA Have a Role in Clinical Psychiatry?

Сравнение антидепрессивной эффективности антипсихотиков у психотических больных

There was no substantial difference in anti-depressive effectiveness among olanzapine, quetiapine, risperidone or ziprasidone in this clinically relevant sample of patients acutely admitted to hospital for symptoms of psychosis. Based on our findings we can make no recommendations concerning choice of any particular SGA for targeting symptoms of depression in a patient acutely admitted with psychosis.

Anti-depressive effectiveness of olanzapine, quetiapine, risperidone and ziprasidone: a pragmatic, randomized trial.