Current Psychopharmacology - Volume 8, Issue 1, 2019

The investigation of the efficacy and safety of drugs requires assessments of their effects on alertness/sleepiness. Unfortunately, there is confusion about the nature of ‘sleepiness’, the factors which influence it, and how it can be measured under different circumstances. This review aims to clarify these matters and to offer some suggestions about how current difficulties might be overcome. Different meanings of the word ‘sleepiness’ are examined initially. Methods that purport to measure ‘sleepiness’ are then examined, including their testretest reliability and the relationship between the results of different measurements within the same subjects. Some objective methods are found not to be as reliable as was initially reported. Information about the reliability of several other methods is either inadequate or nonexistent. One assumption which underlies two frequently used objective methods for measuring ‘sleepiness’ (the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test) is that the ‘sleepier’ a person is, the quicker they will fall asleep. While this assumption has face validity, other assumptions about these tests are re-examined and are found wanting, at least sometimes. The difficulty arises in part because it is not always clear when the sleep onset process begins and ends. ‘Sleepiness’ is found to be influenced much more by short-term factors, such as the subject’s posture at the time and during the preceding few minutes, than has been acknowledged previously. Some possible solutions to these difficulties are suggested, including a new conceptual model of sleep-wake control, with implications for the design of drug trials.

Calcium is a versatile signaling molecule; a key regulator of an array of diverse cellular processes ranging from transcription to motility to apoptosis. It plays a critical role in neuronal signal transmission and energy metabolism through specialized mechanisms. Dysregulation of the Ca2+ signaling pathways has been linked to major psychiatric diseases. Here, we focus on molecular psychiatry, exploring the role of calcium signaling in neurological disease development and aggravation, specifically in Alzheimer’s and Huntington’s diseases. Understanding the molecular underpinnings helps us first to identify common mechanistic patterns, and second to develop targeted therapeutics for symptom alleviation. Specifically, we propose potential protein-level hallmarks of dysregulation that can be targeted using calcium-based chimeras (synthetic fusions of unrelated modular proteins) for localized pharmacotherapy.

Background: Deep brain stimulation (DBS) is a modern neuromodulation method used in the treatment of advanced movement disorders such as Parkinson’s disease (PD) and dystonia. Patients with PD may have multiple psychiatric comorbidities, notably anxiety, depression, mania or hypomania, and psychosis. DBS surgery may indirectly alleviate psychiatric symptoms by allowing reduction of dopaminergic medications, or as a result of functional improvement. Patients who are considering DBS for PD often have more advanced disease and may be more vulnerable to perioperative psychiatric decline. Albeit infrequently, increased depression, apathy, irritability, hypomania or mania, and suicidal behavior have been observed after DBS surgery. Objective: This review aimed to present current evidence and empirical recommendations for the management of the psychiatric symptoms in patients with PD treated with DBS. Method: Relevant literature was reviewed and synthesized, along with recommendations informed by the authors’ clinical experience in a large, academic DBS center. Results: Careful evaluation of DBS candidacy, including assessing the risk for perioperative psychiatric decompensation is advised. Maintaining at least eight weeks of psychiatric stability prior to DBS surgery is strongly recommended. Postoperative management can be challenging due to advanced disease, concurrent psychiatric comorbidities, and possible DBS stimulation-related effects on mood and impulse control. Stimulation-induced elevated mood states (mania, hypomania) have started to be recognized as distinct clinical entities, although not included in the current psychiatric nomenclature. Conclusion: Insufficient evidence-based strategies for managing psychiatric symptoms in PD patients with DBS exist at this time. Further research is necessary to uncover best practices in this complex, expanding field.

Background: The role of dopamine receptor sub-families in the rewarding and reinforcing effects of drugs of abuse has been established in numerous studies. Objectives: In view of the extensive role of mesolimbic dopaminergic transmission in rewarding and reinforcing effect of abused drugs including ethanol, the present study evaluated three mechanistically different drugs viz a partial dopaminergic agonist (PDA, aripiprazole), preferential D3 (mixed D2/D3) receptor antagonist (nafadotride), and a preferential D2 antagonist (haloperidol), on ethanol-induced conditioned place preference (CPP) in mice. Method: The study was carried out in Swiss strain albino mice. Ethanol (20%, 2g/kg) was used to induce CPP in mice. After the acquisition of CPP, behavioral tests (elevated plus maze and locomotor activity) were conducted and effect of drugs on expression and on reinstatement (after extinction) was studied. Results: We found that aripiprazole (1 and 2 mg/kg but not 0.5mg/kg), haloperidol (0.2 mg/kg), and nafadotride (4.5 mg/kg) administered for 1 week during the conditioning phase prevented acquisition, expression and reinstatement of ethanol-induced CPP. All the three drugs reduced the ethanol-induced locomotor stimulation and produced antianxiety effects in elevated plus maze following the acquisition of ethanol CPP. Conclusion: Partial dopaminergic agonism by aripiprazole was found to be a better strategy for normalizing dopaminergic neurotransmission in alcoholics as seen in rodents.

Background: Kratom is a traditional medicinal herb with mild addictive properties. Nevertheless, current available data on substance use disorder related to kratom use is scarce. This study aims to clinically evaluate and identify factors that are associated with kratom use disorder among regular kratom tea/juice users in traditional settings in Malaysia. Method: 150 regular kratom users were recruited through convenient sampling for this crosssectional study. They were interviewed with Mini International Neuropsychiatric Interview (M.I.N.I.) to diagnose substance use disorder related to kratom use, while the Ketum Dependence Scale (KDS) and Clinical Opioid Withdrawal Scale (COWS) were administered to evaluate kratom dependence and withdrawal severity. Results: All subjects were males with the majority being Malays (99%, n=148/150). More than half were single (n=84/150), had secondary education (91%, n=136/150), and were employed (93%, n=139/150). Almost all (99%) fulfilled the criteria for substance use disorder related to kratom use, 95% reported withdrawal symptoms on abstinence, 87% reported tolerance, and 93% craving for kratom. Results from Chi-square analysis indicated that higher quantity (>3 glasses) of daily kratom tea/juice consumption was significantly associated with severe kratom dependence (OR: 2.1: 1.0-4.5: p<.041) and moderate withdrawal (OR: 3.1: 1.5-6.3: p<.002). Similarly, those who consumed >3 glasses of brewed kratom tea daily had higher odds of reporting longer kratom use history (>7 years) (OR: 4.4: 2.2-8.8: p<.001) and higher frequency of daily kratom use (>5 times) (p<.001), compared to those who consumed less than three glasses of kratom daily. Conclusion: Our findings indicated that regular and chronic (>3 glasses daily) kratom tea/juice consumption was associated with kratom use disorder, severe kratom dependence and moderate withdrawal.

Background: Essential Tremor (ET) is a disease present in neurodegenerative disorders, such as Parkinson´s disease. Besides the motor dysfunction, ET also causes sleep problems, including excessive daytime sleepiness. To manage ET, several compounds are prescripted, such as primidone. However, no evidence is available regarding the effects of primidone on sleep. Objective: We analyzed the effects of systemic injections of primidone on sleep in rats. Method: Rats with sleep electrodes received different doses of primidone (0, 5, 10 or 50mg/Kg, i.p.) at the beginning of the lights-on period. Next, the effects of primidone on the states of vigilance were characterized. Results: At the highest dose of primidone (50mg/Kg), animals displayed an increase in Wakefulness (W) whereas Slow Wave Sleep (SWS) and Rapid Eye Movement Sleep (REMS) were decreased. In addition, sleep parameters such as the number of bouts, mean duration and latency were affected in primidone-treated animals. In this regard, the drug caused an enhancement in the number of bouts of W and SWS while the number of events of REMS showed a diminution. Regarding the mean duration, we found that SWS was decreased after primidone treatments whereas W and REMS remained with no statistical changes. Lastly, the latency of SWS was enhanced in primidone-treated animals while no statistical changes were found in REMS. Conclusion: Our findings demonstrate that primidone, a drug that is used to control ET, provokes wake-inducing effects in rats.

Background: Aescin or β-escin is the main and active constituent of horse chestnut seed (Aesculus hippocastanum) used for the treatment of inflammatory edema, venous insufficiency and ischemic ulcerations. Aescin has many actions due to induction of endothelial nitric oxide and prostaglandin F2-α production moreover; aescin antagonizes the effect of histamine and 5HT at receptor levels. Objective: The aim of the present study was to evaluate the neurobehavioral effects of aescin on normal healthy volunteers. Method: A total number of 65 healthy participants with mean age of 21+1.1 years were recruited to study the effects of aescin on the neurobehavioral effects of normal healthy volunteers compared to placebo. The neurobehavioral effects were assessed by psychomotor performances and sensorimotor reaction, cortical arousal and central integrity processes and assessment of memory capacity. Results: Placebo produced insignificant amelioration of TRT and RRT p>0.05, with mild significant effect on MRT p=0.03. Aescin produced a significant effect in the amelioration of psychomotor performances and sensorimotor reaction p=0.0001. Regarding the differential effect of placebo and aescin on the cortical arousal and central integrity processes, placebo illustrated insignificant effect at p>0.05 whereas; aescin showed mild significant effect on Critical Fusion Frequency (CFFA) p<0.05 and highly significant effect on the other parameters p<0.01 except for critical-fusion frequency threshold when aescin illustrated insignificant effect at p>0.05. Aescin illustrated significant acceleration of II-back WMA, III-back WMA and Second trial Short-Term Memory (STM) at p<0.01 compared to the placebo effect. Conclusion: Short-term therapy with aescin improves the neurobehavioral effects on healthy volunteers.