The Role of Peroxisome Proliferator-Activated Receptor in Addiction: A Novel Drug Target.

The peroxisome proliferator activated receptors (PPARs) are a superfamily of well-recognized ligand-binding nuclear receptors comprising three isoforms: PPARα, PPARγ, and PPARß/δ. In response to endogenous lipid messengers, PPARs trigger the transcription of genes related to a wider spectrum of physiological phenomena, including fatty acid oxidation, inflammation, adipogenesis, among many others. Thus, the importance of PPARs as putative protective therapy in health issues has increased the interest of studying these nuclear receptors, including the management of neurodegenerative disorders, multiple sclerosis, and likely addiction. In recent years, several pieces of evidence from animal models have demonstrated the promising role of PPARs as a critical element for interventions in addictive behaviors by reducing the reinforcing properties of addictive substances such as alcohol. However, there is a lack of data in the scope and has so far been unexplored the function of PPARs in additional drugs such as cannabis, opioids, methamphetamine, or cocaine. A similar scenario has been found for the management of binge-type eating disorders. Thus, here we review recent advances in understanding the relevance of the PPAR controlling addiction.

The retinoid X receptor: a nuclear receptor that modulates the sleep-wake cycle in rats.

RATIONALE: The nuclear receptor retinoid X receptor (RXR) belongs to a nuclear receptor superfamily that modulates diverse functions via homodimerization with itself or several other nuclear receptors, including PPARα. While the activation of PPARα by natural or synthetic agonists regulates the sleep-wake cycle, the role of RXR in the sleep modulation is unknown. OBJECTIVES: We investigated the effects of bexarotene (Bexa, a RXR agonist) or UVI 3003 (UVI, a RXR antagonist) on sleep, sleep homeostasis, levels of neurochemical related to sleep modulation, and c-Fos and NeuN expression. METHODS: The sleep-wake cycle and sleep homeostasis were analyzed after application of Bexa or UVI. Moreover, we also evaluated whether Bexa or UVI could induce effects on dopamine, serotonin, norepinephrine epinephrine, adenosine, and acetylcholine contents, collected from either the nucleus accumbens or basal forebrain. In addition, c-Fos and NeuN expression in the hypothalamus was determined after Bexa or UVI treatments. RESULTS: Systemic application of Bexa (1 mM, i.p.) attenuated slow-wave sleep and rapid eye movement sleep. In addition, Bexa increased the levels of dopamine, serotonin, norepinephrine epinephrine, adenosine, and acetylcholine sampled from either the nucleus accumbens or basal forebrain. Moreover, Bexa blocked the sleep rebound period after total sleep deprivation, increased in the hypothalamus the expression of c-Fos, and decreased NeuN activity. Remarkably, UVI 3003 (1 mM, i.p.) induced opposite effects in sleep, sleep homeostasis, neurochemicals levels, and c-Fos and NeuN activity. CONCLUSIONS: The administration of RXR agonist or antagonist significantly impaired the sleep-wake cycle and exerted effects on the levels of neurochemicals related to sleep modulation. Moreover, Bexa or UVI administration significantly affected c-Fos and NeuN expression in the hypothalamus. Our findings highlight the neurobiological role of RXR on sleep modulation.

Sleep and Neurochemical Modulation by DZNep and GSK-J1: Potential Link With Histone Methylation Status.

Histone methylation/demethylation plays an important modulatory role in chromatin restructuring, RNA transcription and is essential for controlling a plethora of biological processes. Due to many human diseases have been related to histone methylation/demethylation, several compounds such as 3-deazaneplanocin A (DZNep) or 3-((6-(4,5-Dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid; N-[2-(2-pyridinyl)-6-(1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-4-pyrimidinyl]-ß-Alanine (GSK-J1), have been designed to inhibit histone methylase or suppress histone demethylase, respectively. In the present study, we investigated the effects on the sleep-wake cycle and sleep-related neurochemical levels after systemic injections of DZNep or GSK-J1 given during the light or dark phase in rats. DZNep dose-dependently (0.1, 1.0, or 10 mg/kg, i.p.) prolonged wakefulness (W) duration while decreased slow wave sleep (SWS) and rapid eye movement sleep (REMS) time spent during the lights-on period with no changes observed in dark phase. In opposite direction, GSK-J1 (0.1, 1.0, or 10 mg/kg, i.p.) injected at the beginning of the lights-on period induced no statistical changes in W, SWS, or REMS whereas if administered at darkness, we found a diminution in W and an enhancement in SWS and REMS. Finally, brain microdialysis experiments in freely moving animals were used to evaluate the effects of DZNep or GSK-J1 treatments on contents of sleep-related neurochemicals. The results showed that DZNep boosted extracellular levels of dopamine, norepinephrine, epinephrine, serotonin, adenosine, and acetylcholine if injected at the beginning of the lights-on period whereas GSK-J1 exerted similar outcomes but when administered at darkness. In summary, DZNep and GSK-J1 may control the sleep-wake cycle and sleep-related neurochemicals through histone methylation/demethylation activity.

Association of Isotretinoin With Depression and Suicide: A Review of Current Literature.

Acne vulgaris, a condition that can affect people at any age, is the most common cause of referral to a dermatologist. Isotretinoin (ITT) is the most effective treatment available, but serious adverse effects, including a possible association with depression and suicide, limit its use. We review the current literature regarding the association of ITT with depression and suicide. Case reports and database studies show a clear association, and this association is biologically plausible. Although prospective studies have opposite results, limitations make them unsuitable to identify a subgroup of patients who may be at risk of developing depression or suicidal ideation with ITT. Overall, it seems some people might be at risk, particularly those with a personal or family history of mental disorder, but further studies are needed to identify those patients who would benefit from an early referral to a mental health professional when ITT is initiated. Currently, no conclusions can be drawn, and it seems appropriate to regularly screen all patients on ITT for depressive symptoms and suicidal ideation and promptly refer them to a mental health professional if any are found.

Onset of psychosis at age 81? With regard to frontal lobe syndromes / Psicose inaugural aos 81 anos? A propósito das síndromes do lobo frontal

When the frontal lobe of the brain is affected important behavioral changes may occur mainly at the level of executive functioning, i.e., planning, decision-making, judgment and self-perception. However, the behavioral changes may be of different nature with marked indifference and apathy. We report a clinical case of an 81-year-old patient with sudden onset of behavioral changes that were initially interpreted as an acute confusional episode of infectious etiology, but actually they were due to an ischemic lesion in the frontal lobe.

O lobo frontal, quando afetado, pode provocar alterações importantes do comportamento, principalmente na função executiva: planejamento, tomada de decisões, juízo e autopercepção. Contudo, as alterações podem ser de outra natureza, caracterizando-se por marcada indiferença e apatia. É relatado aqui o caso de uma paciente de 81 anos, com alterações súbitas do comportamento, que foram interpretadas inicialmente como um quadro confusional agudo de natureza infecciosa, mas que se mostraram provocadas por uma lesão isquêmica na região frontal.

A psychosomatic approach to severe nausea and vomiting in liver transplant recipients with familial amyloid polyneuropathy: clinical outcome in 10 cases.

After transplant, patients with familial amyloid polyneuropathy may manifest several medical and psychiatric symptoms that can be difficult to diagnose and treat. We describe 10 liver transplant candidates with familial amyloid polyneuropathy who had severe somatic signs and symptoms (nausea and vomiting) after transplant. Their physical examinations were performed by physicians from different specialties. Before transplant, the patients' evaluations did not reveal relevant medical or psychiatric symptoms. After transplant, they had severe nausea and vomiting and high scores on the Hospital Anxiety and Depression Scale. A psychopharmacological trial with a selective serotonin reuptake inhibitor plus an antiemetic drug was unsuccessful. Remission was obtained with tricyclic antidepressants and low-dose atypical antipsychotic agents. Previous researchers had concluded that the mental quality of life in patients with familial amyloid polyneuropathy was worse after receiving a liver transplant, unlike other transplant recipients. The 10 cases described in this study are a good example of comorbid physical and mental symptoms occurring after transplant in patients with familial amyloid polyneuropathy. The conclusions of this study have implications for clinical practice, showing how a careful holistic approach in the posttransplant period is relevant in these cases.

[Effectivity of screening, concepts and attitudes towards metabolic síndrome: a study in bipolar patients followed in Hospital Santa Maria psychiatric consultation]. / Efectividade do rastreio, análise de conceitos e atitudes perante o síndrome metabólico: um estudo em doentes bipolares da consulta de psiquiatria do Hospital Santa Maria.

INTRODUCTION: The Metabolic Syndrome (MS) is constituted by a set of specific metabolic alterations being postulated that the main dysfunction is insulin resistance, associated with abdominal type obesity, hypertension, hyperglycemia and dyslipidemia. Epidemiological data indicates prevalence of MS of about 25%. Estimates point to higher prevalence of MS in bipolar (BP) patients, between 30 to 35%. Cost-effective screening methods, not recurring to blood test, have been researched. OBJECTIVES: Test the viability of MS screening without using blood tests. Analyse knowledge and importance given to the issue of MS in Bipolar patients. METHODOLOGY: Observational, cross-sectional, exploratory study. Random sample of 15 BP patients, in euthymic phase, between 18 and 65 years. Semi-structured interview, YMRS, HAMD were applied. MS diagnosis was investigated according to the International Diabetes Federation (IDF), including blood tests. Screening of MS was defined positive if blood pressure > or = to 130/85 or on anti-hypertensive medication and Abdominal Perimeter > 90 cm in males or > 80 cm in females. Afterwards a questionnaire about knowledge, attitudes and concerns on MS was applied. MAIN RESULTS: 14 patients completed the investigation protocol, 1 patient didn't do blood testing for unknown reasons. Five patients (36%) met IDF criteria for MS. Screening sensitivity was 80% and specificity 78% on our sample (1 false positive and 2 false negative). Twelve patients (80%) were overweight or obese. Mean IMC in patients that met IDF criteria for MS was 30 while in the other group mean IMC was 26, showing statistical significance. Only 3 (20%) have ever heard about MS, but the majority of the patients were concerned, in decreasing order, about weight gain, blood pressure cholesterol and hyperglycemia control. CONCLUSIONS: Although limited by small sample size, this study strengthens the idea that MS screening can be effective in clinical practice, it also indicates the need to educate BP patients about MS and to prevent overweight.

Quality of life following liver transplantation: a comparative study between Familial Amyloid Neuropathy and liver disease patients.

BACKGROUND: It has been demonstrated in many studies that quality of life can be improved after liver transplantation in patients with liver disease. Nevertheless, quality of life improvement in specific groups of transplanted patients such as those with Familial Amyloid Polyneuropathy has not yet been explored. The present study aimed to compare the change in quality of life following liver transplantation between patients with Familial Amyloid Polyneuropathy (FAP) and patients with liver disease. RESULTS: Patient's mental quality of life showed an improvement in all liver disease patients, and a worsening in FAP patients, resulting in a significant difference between the two groups. Regarding physical quality of life, although a similar improvement was seen in both groups, FAP patients had significantly less improvement than the sub-group of decompensated liver disease (Child-Pugh B and C). CONCLUSION: It is concluded that liver transplantation has a less beneficial impact in FAP patient's physical quality of life, probably because they are not so much disabled by their disease at the moment of liver transplantation. The lesser improvement in mental quality of life of FAP patients may be due to their particular psychological profile and greater expectations towards transplantation.

Psychiatric differences between liver transplant candidates with familial amyloid polyneuropathy and those with alcoholic liver disease.

BACKGROUND: Psychiatric diagnoses are very common in liver transplant candidates, and such diagnoses are predictive of a poor clinical evolution and quality of life after transplantation. Also, nonadherence before the transplant is predictive of nonadherence after the transplant. METHODS: We studied the psychiatric and psychosocial profiles of 85 liver transplant candidates, comprising consecutive patients attending outpatient clinics of a liver transplantation unit at a public hospital. Interviews and questionnaires were used to measure personality traits, symptoms of anxiety and depression, social support, and adherence. These patients were broken into 3 groups: patients with familial amyloid polyneuropathy (n = 20), patients with alcoholic liver disease (n = 33), and patients with other liver diseases (n = 32). RESULTS: About 58% of patients had a current psychiatric diagnosis (24.8%, major depressive disorder, 22.3% generalized anxiety disorder, 8.3% adaptive disorder, 2.3% abuse of or dependence on substances other than alcohol). Current psychiatric diagnosis did not differ between patients with familial amyloid polyneuropathy and patients with alcoholic liver disease. Patients with alcoholic liver disease showed lower scores for 2 protective personality traits, social support and adherence to medication, than other patients. Patients with familial amyloid polyneuropathy showed higher scores for those traits. CONCLUSIONS: All patients waiting for a liver transplant should undergo psychiatric and psychological assessment. Some psychological characteristics such as personality traits and social support differ between clinical groups, so it may be useful to design different approaches for each group. Patients with alcoholic liver disease may require a special approach to improve adherence to medication.