Механизм неврологических побочных эффектов сульфаниламидов

The team drew from previous research showing that blocking the activity of a certain enzyme (sepiapterin reductase) affects the levels of an important molecule called tetrahydrobiopterin (BH4) in cells. BH4 is critical for the production of neurotransmitters like serotonin and dopamine, and BH4 deficiency causes similar neurological problems to those associated with sulfonamide side effects. 

The EPFL scientists showed for the first time that sulfonamides actually bind to the part of the enzyme that makes BH4. Using a high-throughput drug screening system, the researchers identified ten sulfonamides that strongly inhibit the enzyme. Taking advantage of the expertise of Florence Pojer at EPFL's Global Health Institute, the scientists were able to solve the enzyme's molecular structure and determine how sulfonamides bind to it.

 New Understanding Of The Neurological Side Effects Of Sulfonamide Antibiotics

Галлюцинации

Hallucinations: Common features and causes

Транскраниальная стимуляция постоянным током в терапии вербального галлюциноза при шизофрении

In February 2011, a 44-year-old man with schizophrenia was referred to our hospital for the treatment of auditory verbal hallucinations. He had undergone outpatient treatment with adequate dosages of antipsychotic medications for several months, but he still heard a real-sounding voice that ordered him to commit suicide. We introduced transcranial direct current stimulation (tDCS) as a novel therapeutic approach. Cathodal stimulation diminishes cortical excitability at a circumscribed region (1), and Wernicke's area has been described as an appropriate target region for cathodal stimulation in previous transcranial magnetic stimulation (TMS) studies (2–4). The anodal electrode was placed over the right supraorbital area.

Transcranial direct current stimulation was applied for 15 minutes on 10 consecutive days by using a 1 mA current and 7 cm x 5 cm electrodes, resulting in a current density of 0.029 mA/cm2. The medication doses (5 mg of haloperidol and 20 mg of olanzapine) remained the same 4 weeks before and during the patient's intervention. Before and after tDCS, we measured arterial spin labeling, a noninvasive MR technique that provides a direct quantitative measure of cerebral blood flow (CBF). Arterial spin labeling has been successfully used to measure the difference and changes in regional CBF between healthy individuals and schizophrenia patients experiencing formal thought disorders (5). Clinical assessments showed improvements in our patient's scores on the Hallucination Change Scale (pre-tDCS score=10; post-tDCS score=4), the Positive and Negative Syndrome Scale (pre-tDCS score=61; post-tDCS score=50), and the Psychotic Symptom Rating Scale (pre-tDCS score=51; post-tDCS score=43). The decrease in regional CBF indicated that the intervention had a specific neurobiological effect (Figure 1). At follow-up investigation 6 weeks after the tDCS intervention, our patient's clinical improvement was maintained.

Muting the Voice: A Case of Arterial Spin Labeling-Monitored Transcranial Direct Current Stimulation Treatment of Auditory Verbal Hallucinations

Серотониновая система и шизофрения

Specifically, the study revealed that serotonin signals through the serotonin 2A receptor by recruiting a regulatory protein called β-arrestin2. The actions of serotonin at the receptor were found to be far different than those produced by hallucinogenic N-methyltryptamines, a class of naturally occurring substances found in several plants and in minute amounts in the human body.

These substances are also found in the abused drug DMT.

The N-methyltryptamines activate the serotonin 2A receptor independently of β-arrestin2, researchers said.

The serotonin and the N-methyltryptamines both produce what is known as a head twitch response in animal models. Researchers determined that any interruption in the exclusive serotonin pathway prevents that response to serotonin but has no effect on N-methyltryptamine-induced head twitches.

This difference in response points to a distinct divergence in the signaling pathways utilized by these two neurotransmitters.

“Despite the fact that they activate the same receptor, serotonin leads to the assembly of a number of proteins associated with the receptor that the metabolites of serotonin do not produce,” Bohn said. “But whether the lack of this complex formation is why compounds like DMT lead to hallucinations is not clear.”

Serotonin Discovery Points to New Therapies for Schizophrenia, Depression

Ингибиторы ацетилхолинэстеразы при зрительных галлюцинациях

Background

Visual hallucinations occur in various neurological diseases, but are most prominent in Lewy body dementia, Parkinson's disease and schizophrenia. The lifetime prevalence of visual hallucinations in patients with schizophrenia is much more common than conventionally thought and ranges from 24% to 72%. Cortical acetylcholine (ACh) depletion has been associated with visual hallucinations; the level of depletion being related directly to the severity of the symptoms. Current understanding of neurobiological visual processing and research in diseases with reduced cholinergic function, suggests that AChEI's may prove beneficial in treating visual hallucinations. This offers the potential for targeted drug therapy of clinically symptomatic visual hallucinations in patients with schizophrenia using acetylcholinesterase inhibition.
Methods

A systematic review was carried out investigating the evidence for the effects of AChEI's in treating visual hallucinations in Schizophrenia.
Results

No evidence was found relating to the specific role of AChEI's in treating visual hallucinations in this patient group.
Discussion

Given the use of AChEI's in targeted, symptom specific treatment in other neuropsychiatric disorders, it is surprising to find no related literature in schizophrenia patients. The use of AChEI's in schizophrenia has investigated effects on cognition primarily with non cognitive effects measured more broadly.
Conclusions

We would suggest that more focused research into the effects of AChEI's on positive symptoms of schizophrenia, specifically visual hallucinations, is needed.

Acetylcholinesterase Inhibitors (AChEI's) for the treatment of visual hallucinations in schizophrenia: A review of the literature

Background

Visual hallucinations are commonly seen in various neurological and psychiatric disorders including schizophrenia. Current models of visual processing and studies in diseases including Parkinsons Disease and Lewy Body Dementia propose that Acetylcholine (Ach) plays a pivotal role in our ability to accurately interpret visual stimuli. Depletion of Ach is thought to be associated with visual hallucination generation. AchEI's have been used in the targeted treatment of visual hallucinations in dementia and Parkinson's Disease patients. In Schizophrenia, it is thought that a similar Ach depletion leads to visual hallucinations and may provide a target for drug treatment
Case presentation

We present a case of a patient with Schizophrenia presenting with treatment resistant and significantly distressing visual hallucinations. After optimising treatment for schizophrenia we used Rivastigmine, an AchEI, as an adjunct to treat her symptoms successfully.
Conclusions

This case is the first to illustrate this novel use of an AchEI in the targeted treatment of visual hallucinations in a patient with Schizophrenia. Targeted therapy of this kind can be considered in challenging cases although more evidence is required in this field.

Acetylcholinesterase Inhibitors (AChEI's) for the treatment of visual hallucinations in schizophrenia: A case report.

К казуистике синдрома Кандинского-Клерамбо

приведённом клиническом наблюдении даже такой значительный органический дефект как глухонемота не трансформировал вербальную псевдогаллюцинацию в зрительную, а только «перенёс» её в систему другого анализатора. Для синдрома Кандинского–Клерамбо обязательны вербальные псевдогаллюцинации и поэтому наша больная испытывала их в виде уникальных «жесто-речевых ложно-зрительных псевдогаллюцинаций».

К КАЗУИСТИКЕ СИНДРОМА КАНДИНСКОГО–КЛЕРАМБО

Механизмы действия галлюциногенов

The Neuropharmacology of Hallucinogens

Слуховые галлюцинации при психических заболеваниях

Auditory Hallucinations in Psychiatric Illness

психофизиология вербальных галлюцинаций

Hearing Voices – Underpinnings of Auditory Hallucinations

высокочастотная транскраниальная магнитная стимуляция уменьшает вербальный галлюциноз при шизофрении

High frequency rTMS reduces auditory hallucinations in schizophrenia

галлюцинаторный "взрыв в голове"

Case 1
A 48-year-old man was seen in December 2006. For the past several months about three to four times a month, he had been having attacks of a peculiar sensation in the head likened to the noise of an exploding bomb only at night while going off to sleep. The 'explosion' would wake him up and disappear completely the moment he woke up.

There was no headache and no associated symptoms such as nausea, vomiting or any visual sensation. For the past 3 months, the frequency of these sensations had increased and had been occurring nearly daily at the time of consultation. The noise occurred only once during every night, after which he could go off to sleep. His past medical history had been unremarkable and he had never suffered from any significant headache problem. General physical and neurological examination had been unremarkable. Magnetic resonance imaging (MRI) of brain with contrast had been normal. He was prescribed Flunarazine 10 mg daily. At 6 months' follow-up he had much improved and noticed the exploding head symptom only on two occasions.

Case 2
A 65-year-old man was seen in February 2007. He was hypertensive and diabetic (both well controlled on oral medication) and had been having infrequent attacks of International Headache Society migraine headache (every 2–4 months) without aura since the age of 15 years. For the past 4 months prior to consultation, every 2–3 weeks, he had been awakened while going off to sleep only during taking a daytime nap by a sudden exploding (like a bomb bursting) noise in his head lasting for only few moments.

This noise was always accompanied with jerky elevation of his right arm and a queer sensation in the right side of his chest (not arm) and again lasting only momentarily. He felt quite well on waking up and could go off to sleep again. These were never accompanied by any visual flashes and never occurred during sleep at night. These sensations were very different from his migraine headaches, which lasted for several hours and the noises were not accompanied by any nausea or vomiting.

Physical examination was normal and his blood presswure in the clinic was 136/80 mmHg. He had already had a MRI of brain with contrast, MR angiography of brain and two interictal sleep EEG recordings performed before consultation with the author, all of which were normal. A video EEG with daytime sleep recording was performed, but no event could be captured.