S-Equol mitigates motivational deficits and dysregulation associated with HIV-1.

Motivational deficits (e.g., apathy) and dysregulation (e.g., addiction) in HIV-1 seropositive individuals, despite treatment with combination antiretroviral therapy, necessitates the development of innovative adjunctive therapeutics. S-Equol (SE), a selective estrogen receptor ß agonist, has been implicated as a neuroprotective and/or neurorestorative therapeutic for HIV-1 associated neurocognitive disorders (HAND); its therapeutic utility for motivational alterations, however, has yet to be systematically evaluated. Thus, HIV-1 transgenic (Tg) and control animals were treated with either a daily oral dose of SE (0.2 mg) or vehicle and assessed in a series of tasks to evaluate goal-directed and drug-seeking behavior. First, at the genotypic level, motivational deficits in HIV-1 Tg rats treated with vehicle were characterized by a diminished reinforcing efficacy of, and sensitivity to, sucrose. Motivational dysregulation was evidenced by enhanced drug-seeking for cocaine relative to control animals treated with vehicle. Second, treatment with SE ameliorated both motivational deficits and dysregulation in HIV-1 Tg rats. Following a history of cocaine self-administration, HIV-1 Tg animals treated with vehicle exhibited lower levels of dendritic branching and a shift towards longer dendritic spines with decreased head diameter. Treatment with SE, however, led to long-term enhancements in dendritic spine morphology in HIV-1 Tg animals supporting a potential underlying basis by which SE exerts its therapeutic effects. Taken together, SE restored motivated behavior in the HIV-1 Tg rat, expanding the potential clinical utility of SE to include both neurocognitive and affective alterations.

Síndrome amotivacional en consumidores crónicos de marihuana. Una revisión narrativa para la aproximación al concepto / Amotivational syndrome in chronic marijuana users. A narrative review to approach the concept

Introducción: Durante los últimos sesenta años se ha construido evidencia sobre los efectos adversos relacionados con el consumo crónico de cannabis. Los problemas de memoria y concentración, el riesgo de esquizofrenia en sujetos predispuestos y el síndrome amotivacional han sido referenciados. Con los primeros al parecer no hay muchas dudas, pero en relación con el último, existe controversia. Objetivo: revisar la evidencia científica existente sobre el síndrome amotivacional. Material y Métodos: La revisión se realizó mediante una búsqueda en bases de datos académicas, se tomaron en cuenta las publicaciones que estuvieran relacionadas con trastornos mentales relacionados con el consumo crónico de marihuana en los que se hacía referencia al síndrome amotivacional que cumplieran con criterios de calidad de los artículos apegados a estándares internacionales. Desarrollo: Se incluyó un total de 31 artículos, de los cuales 16 incluían la definición de síndrome amotivacional. Una vez integradas todas las fuentes, se determinó organizar la evidencia encontrada en 15 factores: apatía; desinterés; pasividad; indiferencia; demora en la realización de tareas; pereza; presentismo; desgano para actividades prolongadas que requieran atención o tenacidad; abandono del cuidado personal; desinterés sexual; disminución de los reflejos; autoeficacia disminuida; deterioro de las habilidades comunicativas; retraimiento social y afecto no alterado. Conclusiones: A partir de los hallazgos, se sugiere que el síndrome amotivacional es una constelación de síntomas y/o signos relacionados, lo que podría constituir una morbilidad propia del consumo crónico de cannabis, se espera que en el futuro se desarrollen investigaciones que prueben o rechacen su existencia(AU)

Introduction: Over the past sixty years, evidence for the adverse effects of chronic cannabis use has been demonstrated. Memory and concentration problems, the risk of schizophrenia in predisposed subjects, and amotivational syndrome have been referenced. There is not much doubt in relation to the first effect mentioned, but there is controversy around the last. Objective: To review the existing scientific evidence for the amotivational syndrome. Material and Methods: The review was conducted through academic database searching. The publications related to mental disorders associated with the chronic marijuana use, which referred to amotivational syndrome that fulfilled the criteria for articles attached to international standards, were taken into account. Results: A total of 31 articles were included. Of them, 16 presented the definition of amotivational syndrome. Once all the sources were integrated, the evidence found in 15 factors was organized. These factors included: apathy; disinterest; passivity; indifference; delay to perform tasks; sloth; presentism; reluctance to do prolonged activities that require attention or tenacity; abandonment of personal care; sexual disinterest; decreased reflexes; decreased self-efficacy; impairment in communication skills; social withdrawal, and unaltered affection. Conclusions: Based on these findings, we suggest that the amotivational syndrome is a constellation of symptoms and / or related signs which could constitute a typical morbidity caused by chronic cannabis use, so we expect that future research will be developed to demonstrate or discard their existence(AU)

Bupropion for the Treatment of Apathy in Alzheimer Disease: A Randomized Clinical Trial.

Importance: Apathy is a frequent neuropsychiatric symptom in dementia of Alzheimer type and negatively affects the disease course and patients' and caregivers' quality of life. Effective treatment options are needed. Objective: To examine the efficacy and safety of the dopamine and noradrenaline reuptake inhibitor bupropion in the treatment of apathy in patients with dementia of Alzheimer type. Design, Setting, and Participants: This 12-week, multicenter, double-blind, placebo-controlled, randomized clinical trial was conducted in a psychiatric and neurological outpatient setting between July 2010 and July 2014 in Germany. Patients with mild-to-moderate dementia of Alzheimer type and clinically relevant apathy were included. Patients with additional clinically relevant depressed mood were excluded. Data analyses were performed between August 2018 and August 2019. Interventions: Patients received either bupropion or placebo (150 mg for 4 weeks plus 300 mg for 8 weeks). In case of intolerability of 300 mg, patients continued to receive 150 mg throughout the study. Main Outcomes and Measures: Change on the Apathy Evaluation Scale-Clinician Version (AES-C) (score range, 18-72 points) between baseline and week 12 was the primary outcome parameter. Secondary outcome parameters included measures of neuropsychiatric symptoms, cognition, activities of daily living, and quality of life. Outcome measures were assessed at baseline and at 4, 8, and 12 weeks. Results: A total of 108 patients (mean [SD] age, 74.8 [5.9] years; 67 men [62%]) were included in the intention-to-treat analysis, with 54 randomized to receive bupropion and 54 randomized to receive placebo. The baseline AES-C score was comparable between the bupropion group and the placebo group (mean [SD], 52.2 [8.7] vs 50.4 [8.2]). After controlling for the baseline AES-C score, site, and comedication with donepezil or galantamine, the mean change in the AES-C score between the bupropion and placebo groups was not statistically significant (mean change, 2.22; 95% CI, -0.47 to 4.91; P = .11). Results on secondary outcomes showed statistically significant differences between bupropion and placebo in terms of total neuropsychiatric symptoms (mean change, 5.52; 95% CI, 2.00 to 9.04; P = .003) and health-related quality of life (uncorrected for multiple comparisons; mean change, -1.66; 95% CI, -3.01 to -0.31; P = .02) with greater improvement in the placebo group. No statistically significant changes between groups were found for activities of daily living (mean change, -2.92; 95% CI, -5.89 to 0.06; P = .05) and cognition (mean change, -0.27; 95% CI, -3.26 to 2.73; P = .86). The numbers of adverse events (bupropion group, 39 patients [72.2%]; placebo group, 33 patients [61.1%]) and serious adverse events (bupropion group, 5 patients [9.3%]; placebo group, 2 patients [3.7%]) were comparable between groups. Conclusions and Relevance: Although it is safe, bupropion was not superior to placebo for the treatment of apathy in patients with dementia of Alzheimer type in the absence of clinically relevant depressed mood. Trial Registration: EU Clinical Trials Register Identifier: 2007-005352-17.

Effect of istradefylline on mood disorders in Parkinson's disease.

Depression is the most common psychiatric complication in patients with Parkinson's disease (PD). Istradefylline, a new anti-parkinsonian agent with completely different mechanism, improves depression-like symptoms in an experimental disease model; however, there is no report of its effects in PD patients. In this study, the effectiveness of istradefylline for treatment of mood disorders in patients with PD was examined in an open-label trial. Thirty PD patients were enrolled. All patients had scores of higher than cut-off level in at least one of the following batteries: Snaith-Hamilton Pleasure Scale Japanese version (SHAPS-J), Apathy scale, or Beck Depression Inventory-2nd edition (BDI). Following study enrollment, all patients received 20 mg of istradefylline, and the dose was increased to 40 mg after 4 weeks. Results from these 3 batteries and the Unified Parkinson's Disease Rating Scale (UPDRS) score were assessed every 2-4 weeks until 12 weeks and the changes in these scores were analyzed. Following administration of istradefylline, the scores of SHAPS-J, Apathy scale, and BDI were significantly improved over time. Significant improvement was also found in the UPDRS score; however, no significant correlation was observed between the score change in these 3 batteries and UPDRS motor function. This is the first study to show the effectiveness of istradefylline for treatment of mood disorders in PD independent of improvement of parkinsonian motor symptoms. In the future, this should be confirmed in a double-blind placebo-controlled trial.

Peptide YY Causes Apathy-Like Behavior via the Dopamine D2 Receptor in Repeated Water-Immersed Mice.

Apathy is observed across several neurological and psychiatric conditions; however, its pathogenesis remains unclear. We clarified the involvement of brain-gut signaling in the disruption of goal-directed behavior. Male C57BL/6J mice were exposed to water immersion (WI) stress for 3 days. Food intake and nesting behavior were measured as indexes of motivation. Repeated WI caused decrease in food intake and nesting behavior. Plasma levels of peptide YY (PYY), IL-6, and ratio of dopamine metabolites in the striatum were significantly elevated after WI. PYY and IL-6 administration significantly decreased nesting behavior. The reductions in feeding and nesting behavior were blocked by PYY receptor (Y2R) antagonist or dopamine agonist. The ameliorative effect of the Y2R antagonist was diminished by the dopamine D2 receptor (D2R) antagonist. The reduction in goal-directed behavior is associated with dysfunction of D2R signaling via increased peripheral PYY, suggesting that PYY antagonism is a novel candidate for decline of motivation in several depressive diseases.

Is bupropion useful in the treatment of post-stroke thalamic apathy? A case report and considerations.

Post-stroke apathy is considered to be one of the clinical consequences of lesions affecting the structures of the prefrontal cortex, basal ganglia, thalamus and limbic system. However, there is no current consensus on the treatment of post-stroke apathy, which mainly depends on the underlying etiology and comorbidities. A 62-year-old man, affected by hemorrhagic stroke in the left thalamus, presented with mood depression, anhedonia, hyporexia and marked apathy. The patient underwent clinical evaluation before and after receiving two different pharmacological therapies: escitalopram and bupropion. Only after treatment with the latter drug did the patient show changes: high motivation and willingness to pursue activities, greater interest in the external environment and social life activities, and an overall reduction of apathy. On the basis of our observations in this case, we hypothesize that the thalamic lesion resulted in disconnection of the fronto-striatal-thalamic circuits, and that loss of the dopaminergic striatal innervation caused the patient's apathetic state. The resolution of the apathetic disorder may be attributable to the action of the dopaminergic drug bupropion on the mesocortical pathway.

Testing the Amotivational Syndrome: Marijuana Use Longitudinally Predicts Lower Self-Efficacy Even After Controlling for Demographics, Personality, and Alcohol and Cigarette Use.

The marijuana amotivational syndrome posits that cannabis use fosters apathy through the depletion of motivation-based constructs such as self-efficacy. The current study pursued a two-round design to rule out concomitant risk factors responsible for the connection from marijuana intake to lower general self-efficacy. College students (N = 505) completed measures of marijuana use, demographics (age, gender, and race), personality (extraversion, agreeableness, conscientiousness, openness, and neuroticism), other substance use (alcohol and tobacco), and general self-efficacy (initiative, effort, and persistence) in two assessments separated by a month. Hierarchical regression models found that marijuana use forecasted lower initiative and persistence, even after statistically ruling out 13 pertinent baseline covariates including demographics, personality traits, alcohol use, tobacco use, and self-efficacy subscales. A cross-lagged panel model involving initiative, effort, persistence, alcohol use, cigarette use, and marijuana use sought to unravel the temporal precedence of processes. Results showed that only marijuana (but not alcohol or tobacco) intake significantly and longitudinally prompted lower initiative and persistence. Furthermore, in the same model, the opposite temporal direction of events from lower general self-efficacy subscales to marijuana use was untenable. Findings provide partial support for the marijuana amotivational syndrome, underscore marijuana as a risk factor for decreased general self-efficacy, and offer implications and insights for marijuana prevention and future research.

Bupropion for the treatment of apathy in Huntington's disease: A multicenter, randomised, double-blind, placebo-controlled, prospective crossover trial.

OBJECTIVE: To evaluate the efficacy and safety of bupropion in the treatment of apathy in Huntington's disease (HD). METHODS: In this phase 2b multicentre, double-blind, placebo-controlled crossover trial, individuals with HD and clinical signs of apathy according to the Structured Clinical Interview for Apathy-Dementia (SCIA-D), but not depression (n = 40) were randomized to receive either bupropion 150/300mg or placebo daily for 10 weeks. The primary outcome parameter was a significant change of the Apathy Evaluation Scale (AES) score after ten weeks of treatment as judged by an informant (AES-I) living in close proximity with the study participant. The secondary outcome parameters included changes of 1. AES scores determined by the patient (AES-S) or the clinical investigator (AES-C), 2. psychiatric symptoms (NPI, HADS-SIS, UHDRS-Behavior), 3. cognitive performance (SDMT, Stroop, VFT, MMSE), 4. motor symptoms (UHDRS-Motor), 5. activities of daily function (TFC, UHDRS-Function), and 6. caregiver distress (NPI-D). In addition, we investigated the effect of bupropion on brain structure as well as brain responses and functional connectivity during reward processing in a gambling task using magnetic resonance imaging (MRI). RESULTS: At baseline, there were no significant treatment group differences in the clinical primary and secondary outcome parameters. At endpoint, there was no statistically significant difference between treatment groups for all clinical primary and secondary outcome variables. Study participation, irrespective of the intervention, lessened symptoms of apathy according to the informant and the clinical investigator. CONCLUSION: Bupropion does not alleviate apathy in HD. However, study participation/placebo effects were observed, which document the need for carefully controlled trials when investigating therapeutic interventions for the neuropsychiatric symptoms of HD. TRIAL REGISTRATION: ClinicalTrials.gov 01914965.

Bupropion improved apathy in behavioral variant frontotemporal dementia: a case report.

Apathy is a common neurobehavioral sign in cases of behavioral variant frontotemporal dementia. However, there is still no established sustained effective treatment. We present the case of a 65-year-old man with behavioral variant frontotemporal dementia who suffered from severe apathy, but his apathy improved after a 10-month period of bupropion treatment. His single photon emission computed tomography report also showed slight improvement. To the best of our knowledge, such a case with imaging evidence has never been reported. Further studies to correlate the effects of bupropion on apathy in behavioral variant frontotemporal dementia patients are clearly needed.

Considerations in psychotropic treatments in dementia--can polypharmacy be avoided?

Physicians treating demented individuals are confronted with complex clinical presentations. This complexity results from the multi-factorial nature of clinical phenomena, the aetiologies of these phenomena, which differ from similar symptoms in younger populations, limited physiological reserves and the multiple co-morbidities and medications. This intricacy is well exemplified within the clinical presentation and management of psychological and behavioural symptoms of dementia. The latter are associated with a poor quality of life, increased burden for both patient and caregivers. A further challenge and source for frustration is the fact that many of the medications used to treat cognitive and behavioural symptoms of dementia are only marginally effective or not effective at all, on the one hand, and associated with increased risk for morbidity and mortality on the other hand. In the present review, we discuss these factors in the context of polypharmacy and suggest further clinical and research strategies that may enable more accurate and less harmful therapeutic strategies.

Thyrotoxic psychosis in an elderly woman and haloperidol use: a case report.

Thyrotoxic patients may occasionally present with affective disorders. Here, we discuss a case of a 61-year-old woman with misidentification and persecutory delusions, olfactory hallucinations, and apathy associated with thyrotoxicosis. After definitive antithyroid and antipsychotic agent haloperidol treatments, the patient was released within 4 weeks. Thyrotoxic psychosis with apathy is a rare entity that can be misdiagnosed as affective psychosis. Haloperidol may be an alternative treatment in resolving psychotic features beside the treatment of hyperthyroid state.

Role of apathy in the effectiveness of weight management programmes.

AIMS: Obesity, which is at epidemic proportions in the USA, is associated with a higher risk of several co-morbid diseases including, cardiovascular disease, cancer and sleep apnea. Weight loss and weight maintenance programmmes are difficult to sustain for long term. Mental health problems such as apathy may be a major factor in patients unsuccessful in adhering to weight loss programmes. We propose that treating apathy will result in better weight loss in obese patients. METHODS: This was a randomized prospective pilot study. Obese patients (n = 101) were randomized in a 1:2:2 ratio to either (i) standard nutrition counselling; or (ii) the Department of Veterans Affairs weight loss programme called 'motivate obese veterans everywhere ' (MOVE); or (iii) methylphenidate treatment plus the MOVE programme together. The intervention was for 6 months (26 weeks). RESULTS: For the within groups analysis, the absolute changes in weight (kg) are as follows, for MOVE (mean: -1.84; 95% confidence interval (CI): -4.56 to 0.87; p = 0.25), Methylphenidate (mean: -4.61; 95% CI: -7.90 to -1.33; p = 0.04), standard nutrition counselling (mean: -0.60; 95% CI: -2.59 to 1.39; p = 0.21), which indicates that although all three groups lost weight, only the methylphenidate group achieved statistical significance. The between group differences of the relative change in weight were not statistically different. The apathy evaluation score and the patient activation measure improved in all groups. CONCLUSION: Together these data suggest that treating apathy might be an important factor in the success of weight management programmes.