Mechanistic/mammalian target of rapamycin and side effects of antipsychotics: insights into mechanisms and implications for therapy

Antipsychotic pharmacotherapy has been widely recommended as the standard of care for the treatment of acute schizophrenia and psychotic symptoms of other psychiatric disorders. However, there are growing concerns regarding antipsychotic-induced side effects, including weight gain, metabolic syndrome (MetS), and extrapyramidal motor disorders, which not only decrease patient compliance, but also predispose to diabetes and cardiovascular diseases. To date, most studies and reviews on the mechanisms of antipsychotic-induced metabolic side effects have focused on central nervous system mediation of appetite and food intake. However, disturbance in glucose and lipid metabolism, and hepatic steatosis induced by antipsychotic drugs might precede weight gain and MetS. Recent studies have demonstrated that the mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical regulatory role in the pathophysiology of antipsychotic drug-induced disorders of hepatic glucose and lipid metabolism. Furthermore, antipsychotic drugs promote striatal mTOR pathway activation that contributes to extrapyramidal motor side effects. Although recent findings have advanced the understanding of the role of the mTOR pathway in antipsychotic-induced side effects, few reviews have been conducted on this emerging topic. In this review, we synthesize key findings by focusing on the roles of the hepatic and striatal mTOR pathways in the pathogenesis of metabolic and extrapyramidal side effects, respectively. We further discuss the potential therapeutic benefits of normalizing excessive mTOR pathway activation with mTOR specific inhibitors. A deeper understanding of pathogenesis may inform future intervention strategies using the pharmacological or genetic inhibitors of mTOR to prevent and manage antipsychotic-induced side effects.

Poussin's sign

V. Dosuzkova and Th. Dosuzkov (Revue V. neurologii i psychiatrii, 1928, no. 4). In contrast to Babinsky, Leshchenko and Nemlicher (Proceedings of the Ukrainian psychoneur. Inst., 1927, III), the authors do not consider this reflex part of the fan sign, just as they do not find definite connections of this reflex with the setting and defense reflexes. Poussin occurs with the simultaneous defeat of the pyramidal and extrapyramidal motor pathways and disinhibition of the reflex arc of this reflex.

Reversal of Haloperidol-Induced Orofacial Dyskinesia and Neuroinflammation by Isoflavones

Schizophrenia is a serious mental illness, and its pharmacological treatment consists in the administration of antipsychotics, such as haloperidol. However, treatment with haloperidol often causes extrapyramidal motor disorders such as tardive dyskinesia (TD). TD is a movement disorder characterized by involuntary movements, which can be studied in animals. So far, there is no effective treatment for TD and alternatives have been sought. Thus, the objective was to evaluate the possible protective effect of isoflavones against the induction of involuntary movements induced by haloperidol in an animal model. Male Wistars rats were treated with haloperidol (1 mg/ kg/day) and/or isoflavones (80 mg/kg) for 28 days. Rats were submitted to behavioral evaluation to quantify vacuous chewing movements (VCM) and the locomotor activity. In addition, the levels of pro-inflammatory cytokines were measured in the striatum. Haloperidol treatment reduced the locomotor activity and increased the number of VCM in rats. Co-treatment with isoflavones was able to reverse hypolocomotion and reduce the number of VCM to the levels of the control group. Besides, haloperidol caused significant increase in the proinflammatory cytokines (interleukin-1β:IL-1β, tumor necrosis factor-α:TNF-a and IL-6 and the co-treatment with isoflavones was able to reduce the levels of IL-1β and TNF-α, but not IL-6. It is believed that the beneficial effect found with this treatment is related to their anti-inflammatory potential and also to the action on estrogen receptors (based on findings in the scientific literature). Finally, further studies are needed to elucidate the mechanisms of isoflavones in reducing motor disorders induced by antipsychotic.

Clinical Findings of Type 3 Spinocerebellar Ataxia

Background: Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of progressive autosomal disorders of dominant inheritance with a gradual degeneration of the cerebellum and related pathways [1]. This leads to a movement disorder, loss of balance and coordination, accompanied by slurred speech [2]. Among the approximately 40 types of SCA, the spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most clinically heterogeneous [3]. It involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems [2]. Objectives: Understand the clinical findings of SCA3. Methods: The review was based on papers from SciELO and LILACS databases. Articles presented in full, written in English or Portuguese, were researched. Results: SCA3 is a consequence of the ATXN3 gene modification, which generates pathogenic repeated expansions of trinucleotides CAG, leading to polyglutamine coding. The common clinical phenotype includes the presentation of symptoms such as cerebellar ataxia, ophthalmoplegia, spasticity, basal ganglia symptoms, sensory symptoms, amyotrophy, including facial atrophy and fasciculations [4]. In addition, atrophy of the cerebellar vermis, hemispheres, brainstem and medial cerebellar peduncle are visualized on MRI in the early stages, resulting in an enlargement of the fourth ventricle. Furthermore, changes also occur in the caudate nucleus, putamen and upper cerebellar peduncle [5]. Conclusion: Through data analysis, there is a necessity to know the clinical and pathological characteristics of SCA3. This neurological disorder causes suffering for the patients, since it is a highly debilitating serious condition.

The mammalian target of rapamycin (mTOR) kinase mediates haloperidol-induced cataleptic behavior

The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine/threonine kinase protein complex (mTORC1 or mTORC2) that orchestrates diverse functions ranging from embryonic development to aging. However, its brain tissue-specific roles remain less explored. Here, we have identified that the depletion of the mTOR gene in the mice striatum completely prevented the extrapyramidal motor side effects (catalepsy) induced by the dopamine 2 receptor (D2R) antagonist haloperidol, which is the most widely used typical antipsychotic drug. Conversely, a lack of striatal mTOR in mice did not affect catalepsy triggered by the dopamine 1 receptor (D1R) antagonist SCH23390. Along with the lack of cataleptic effects, the administration of haloperidol in mTOR mutants failed to increase striatal phosphorylation levels of ribosomal protein pS6 (S235/236) as seen in control animals. To confirm the observations of the genetic approach, we used a pharmacological method and determined that the mTORC1 inhibitor rapamycin has a profound influence upon post-synaptic D2R-dependent functions. We consistently found that pretreatment with rapamycin entirely prevented (in a time-dependent manner) the haloperidol-induced catalepsy, and pS6K (T389) and pS6 (S235/236) signaling upregulation, in wild-type mice. Collectively, our data indicate that striatal mTORC1 blockade may offer therapeutic benefits with regard to the prevention of D2R-dependent extrapyramidal motor side effects of haloperidol in psychiatric illness.

Teaching NeuroImages: All hemiparesis are not contralateral

A 56-yr-old hypertensive male presented with left-sided weakness of 2-h duration. He made complete recovery from right hemiparesis due to left parietal infarct. Examination showed dysarthria and left hemiparesis (NIHSS 8/42). MR-brain showed both left parietal acute infarct and gliosis from old infarct (Figure-1). He was successfully thrombolysed with intravenous alteplase. Present stroke was diagnosed as ipsilateral hemiparesis, confirmed by DTI (Figure-2). Ipsilateral hemiparesis, mostly seen with posterior fossa malformations and remote infarctions, results from injury to uncrossed corticospinal tract (CST) in patients of remote brain injury or with no decussation of CST or injury to ipsilateral extrapyramidal motor pathway.

The Mammalian Target of Rapamycin (mTOR) Kinase Mediates Haloperidol-Induced Cataleptic Behavior

ABSTRACTThe mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine/threonine kinase protein complex (mTORC1 or mTORC2) that orchestrates diverse functions ranging from embryonic development to aging. However, its brain tissue-specific roles remain less explored. Here, we have identified that the depletion of the mTOR gene in the mice striatum completely prevented the extrapyramidal motor side-effects (catalepsy) induced by the dopamine 2 receptor (D2R) antagonist haloperidol, which is the most widely used typical antipsychotic drug. Conversely, a lack of striatal mTOR in mice did not affect catalepsy triggered by the dopamine 1 receptor (D1R) antagonist SCH23390. Along with the lack of cataleptic effects, the administration of haloperidol in mTOR mutants failed to increase striatal phosphorylation levels of ribosomal protein pS6 (S235/236) as seen in control animals. To confirm the observations of the genetic approach, we used a pharmacological method and determined that the mTORC1 inhibitor rapamycin has a profound influence upon post-synaptic D2R-dependent functions. We consistently found that pretreatment with rapamycin entirely prevented (in a time-dependent manner) the haloperidol-induced catalepsy in wild-type mice. Collectively, our data indicate that striatal mTORC1 blockade may offer therapeutic benefits with regard to the prevention of D2R-dependent extrapyramidal motor side-effects of haloperidol in psychiatric illness.

Evaluation of Antipsychotic Activity of Ethanolic Extract of Dhatryadi Ghrita on Wistar Rats

Objective: Herbal formulations based on plants are effective against psychosis. The effects of Dhatryadi Ghrita on Wistar rats against psychosis were investigated. Background: An increased preference nowadays is obvious towards the use of herbal drugs in the treatment of chronic ailments. Treatment of psychiatric diseases has become easier, but the extrapyramidal motor disorders are the major adverse effect exists with most of the antipsychotic drugs. Methods: For the assessment of neuroleptic activity of the ethanolic extract of Dhatryadi Ghrita, prepared with different antipsychotic animal models, three doses of the extract (100, 200 and 300 mg/kg) were used for the study with different animal models. Result: A significant reduction of amphetamine-induced stereotype and conditioned avoidance response was observed in the extract-treated animals compared to control. Minor signs of catalepsy were visible in the extract-treated group as compared to the control group. Conclusion: The study revealed that the extract may be possessing the property to alleviate the positive symptoms of Psychosis.