Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force.

BACKGROUND: Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of established and off-label ADHD therapies in BD. METHODS: We included studies of ADHD medications in BD patients, which involved cognitive and/or safety measures. We followed the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed, Embase and PsycINFO from inception until June 2023. Two authors reviewed the studies independently using the Revised Cochrane Collaboration's Risk of Bias tool for Randomized trials. RESULTS: Seventeen studies were identified (N = 2136), investigating armodafinil (k = 4, N = 1581), methylphenidate (k = 4, N = 84), bupropion (k = 4, n = 249), clonidine (k = 1, n = 70), lisdexamphetamine (k = 1, n = 25), mixed amphetamine salts (k = 1, n = 30), or modafinil (k = 2, n = 97). Three studies investigated cognition, four ADHD symptoms, and 10 the safety. Three studies found treatment-related ADHD symptom reduction: two involved methylphenidate and one amphetamine salts. One study found a trend towards pro-cognitive effects of modafinil on some cognitive domains. No increased risk of (hypo)mania was observed. Five studies had low risk of bias, eleven a moderate risk, and one a serious risk of bias. CONCLUSIONS: Methylphenidate or mixed amphetamine salts may improve ADHD symptoms in BD. However, there is limited evidence regarding the effectiveness on cognition. The medications produced no increased mania risk when used alongside mood stabilizers. Further robust studies are needed to assess cognition in BD patients receiving psychostimulant treatment alongside mood stabilizers.

Low-dose topiramate in alcohol dependence: a single-blind, placebo-controlled study.

INTRODUCTION: Topiramate (TOP) and anticonvulsants in general are considered safe and effective drugs for the treatment of alcohol dependence, even though TOP-induced adverse events are quite common, especially for high initial doses or if titration to 300 mg/d is too rapid. The aim of the present study was to assess the efficacy and tolerability profile of low-dose TOP for relapse prevention. METHODS: After detoxification, 52 patients were randomized into 2 groups as follows: 26 patients received 100 mg of TOP (oral, twice daily), titrated over 2 weeks, and 26 patients received placebo (PLA). Both groups underwent rehabilitation twice a week. RESULTS: After 6 weeks of treatment, compared with the PLA group, patients receiving TOP showed the following: (1) fewer drinking days (P < 0.05); (2) less daily alcohol consumption (P < 0.05); (3) more days of treatment (P < 0.05); (4) reduced levels of craving (Obsessive-Compulsive Drinking Scale) and withdrawal symptoms (Clinical Institute Withdrawal Assessment for Alcohol-Revised); and (5) improvement of anxiety, depression, and obsessive-compulsive symptom severity (Symptom Check List 90 Revised). CONCLUSIONS: Despite the small sample size and the short follow-up period, the present PLA-controlled study demonstrated the potential usefulness of TOP, even when administered at a dosage of 100 mg/d, for the treatment of detoxified alcohol-dependent subjects, confirming results from previous studies testing higher doses of TOP.

Evaluating endophenotypes for bipolar disorder.

BACKGROUND: Phenotypic heterogeneity is a major impediment to the elucidation of the neurobiology and genetics of bipolar disorder. Endophenotype could help in reducing heterogeneity by defining biological traits that are more direct expressions of gene effects. The aim of this review is to examine the recent literature on clinical, epidemiological, neurobiological, and genetic findings and to select and evaluate candidate endophenotypes for bipolar disorder. Evaluating putative endophenotype could be helpful in better understanding the neurobiology of bipolar disorder by improving the definition of bipolar-related phenotypes in genetic studies. In this manner, research on endophenotypes could be useful to improve psychopathological diagnostics in the long-run by dissecting psychiatric macro phenotypes into biologically valid components. MAIN BODY: The associations among the psychopathological and biological endophenotypes are discussed with respect to specificity, temporal stability, heritability, familiarity, and clinical and biological plausibility. Numerous findings regarding brain function, brain structure, neuropsychology and altered neurochemical pathways in patients with bipolar disorder and their relatives deserve further investigation. Overall, major findings suggest a developmental origin of this disorder as all the candidate endophenotypes that we have been able to select are present both in the early stages of the disorder as well as in subjects at risk. CONCLUSIONS: Among the stronger candidate endophenotypes, we suggest circadian rhythm instability, dysmodulation of emotion and reward, altered neuroimmune state, attention and executive dysfunctions, anterior cingulate cortex thickness and early white matter abnormalities. In particular, early white matter abnormalities could be the result of a vulnerable brain on which new stressors are added in young adulthood which favours the onset of the disorder. Possible pathways that lead to a vulnerable brain are discussed starting from the data about molecular and imaging endophenotypes of bipolar disorder.

Neuropsychological Performance in Alcohol Dependent Patients: A One-Year Longitudinal Study.

OBJECTIVE: Despite several studies that have highlighted the harmful effects of alcohol consumption on cognitive functions it remains unclear whether certain brain areas are more sensitive than others are or whether alcohol causes widespread cognitive deficit. Moreover, the role of continued abstinence has yet to be clarified regarding the quality of recovery on the different cognitive domains. The aim of this 1-year longitudinal study was to evaluate the recovery of cognitive deficits in the medium (6 months) and long term (12 months) after the interruption of drinking. METHODS: Forty-one alcohol-dependent patients were recruited from two outpatient treatment facilities and cognitive functions were compared on a control group of forty healthy controls. The patients were then re-assessed at 6 and 12 months. Changes in neuropsychological measures were evaluated with repeated measures analysis of variance (ANOVA). We also compared 1-year follow-up scores with control data (unpaired t tests) to identify tests on which significant differences persisted. RESULTS: Patients performed significantly worse than controls in all cognitive domains investigated and this cognitive impairment was evident in recently abstinent patients. A year of abstinence resulted in a significant improvement in all cognitive domains assessed after detoxification from alcohol. After year 1, alcoholic subjects had returned to normal levels compared to healthy controls on all domains except for general non-verbal intelligence, verbal memory and some visuospatial skills. CONCLUSION: Our results support the hypothesis of widespread impairment resulting from alcohol consumption. The recovery of cognitive functions is not homogeneous during prolonged abstinence.

A meta-analysis of cognitive performance in melancholic versus non-melancholic unipolar depression.

BACKGROUND: Recently there is increasing recognition of cognitive dysfunction as a core feature of Major Depressive Disorder (MDD). The goal of the current meta-analysis was to review and examine in detail the specific features of cognitive dysfunction in Melancholic (MEL) versus Non-Melancholic (NMEL) MDD. METHODS: An electronic literature search was performed to find studies comparing cognitive performance in MEL versus NMEL. A meta-analysis of broad cognitive domains (processing speed, reasoning/problem solving, verbal learning, visual learning, attention/working memory) was conducted on all included studies (n=9). Sensitivity and meta-regression analyses were also conducted to detect possible effects of moderator variables (age, gender, education, symptom severity and presence of treatments). RESULTS: MEL patients were older and more severly depressed than NMEL subjects. The MEL group was characterized by a worse cognitive performance in attention/working memory (ES=-0.31), visual learning (ES=-0.35) and reasoning/problem solving (ES=-0.46). No difference was detected in drug-free patients by sensitivity analyses. No effect was found for any of our moderators on the cognitive performance in MEL vs NMEL. CONCLUSION: Our findings seem to support a moderate but specific effect of melancholic features in affecting the cognitive performance of MDD, in particular as regards visual learning and executive functions.

Cognitive markers of psychotic unipolar depression: a meta-analytic study.

BACKGROUND: The goal of the current meta-analysis was to review and examine in detail the features of cognitive performance in psychotic (MDDP) versus non-psychotic (MDD) major depressive disorder. METHODS: An electronic literature search was performed to find studies comparing cognitive performance in MDDP versus MDD. A meta-analysis of broad cognitive domains (processing speed, reasoning/problem solving, verbal learning, visual learning, attention/working memory) and individual cognitive tasks was conducted on all included studies (n=12). Demographic and clinical features were investigated via meta-regression analysis as moderators of cognitive performance. RESULTS: No difference in socio-demographic and clinical variables was detected between groups. In general, a poorer cognitive performance was detected in MDDP versus MDD subjects (ES=0.38), with a greater effect size in drug-free patients (ES=0.69). MDDP patients were more impaired in verbal learning (ES=0.67), visual learning (ES=0.62) and processing speed (ES=0.71) tasks. A significantly poorer performance was also detected in MDDP patients for individual tasks as Trail Making Test A, WAIS-R digit span backward and WAIS-R digit symbol. Age resulted to have a negative effect on tasks involved in working memory performance. CONCLUSION: In line with previous meta-analyses, our findings seem to support an association between psychosis and cognitive deficits in the context of affective disorders. Psychosis during the course of MDD is associated with poorer cognitive performance in some specific cognitive domains, such as visual and verbal learning and executive functions.

Topiramate in Alcohol Use Disorders: Review and Update.

To date, a limited number of pharmacological agents exist to treat alcohol use disorders (AUDs), and there is growing interest in new therapeutic tools. In this framework, topiramate may represent a useful treatment option, although its use is not yet approved for AUDs. The main focus of this review is to discuss all the existing data supporting the use of topiramate in AUDs, with an emphasis on the most recent and relevant clinical implications. In addition, the profile of the alcoholic patient who may benefit more from the use of topiramate is outlined. In this regard, the authors conducted a PubMed search of clinical human studies published in English using the following key words: topiramate alcohol dependence, topiramate alcohol withdrawal and topiramate alcoholism. The evidence suggests that topiramate could be an effective treatment option for the management of AUDs, while there are limited results for its use to treat alcohol withdrawal syndrome. In particular, topiramate shows a greater beneficial effect in subjects with a typology of craving characterised by drinking obsessions and automaticity of drinking. Topiramate, within the dosage range of 75-300 mg/day, could be considered as a first-line treatment option for the management of AUDs. Its use appears to be safe and well-tolerated, especially in light of very recent findings.

Clinical insights by the presence of bipolar disorder in pseudohypoparathyroidism type 1A.

Pseudohypoparathyroidism type 1A and its association with bipolar disorder (BD) have never been reported so far. We report a new case with both clinical entities and discuss the potential pathophysiological mechanisms of this association (protein kinase A hypoactivation, parathyroid hormone, hypocalcemia, protein kinase C activation, vitamin D deficiency). In this patient, the correction of the underlying calcium and vitamin D deficiencies leads to a better BD outcome and lower dosage of psychopharmacological agents. The conclusions might be generalized for a better understanding and management of these conditions.

Co-occurrence of alcohol use disorder and behavioral addictions: relevance of impulsivity and craving.

PURPOSE: The aims of the study were to evaluate the occurrence of behavioral addictions (BAs) in alcohol use disorder (AUD) subjects and to investigate the role of impulsivity, personality dimensions and craving. METHODS: 95 AUD outpatients (DSM-5) and 140 homogeneous controls were assessed with diagnostic criteria and specific tests for gambling disorder, compulsive buying, sexual, internet and physical exercise addictions, as well as with the Barratt Impulsiveness Scale (BIS-11) and Temperamental and Character Inventory-Revised (TCI-R). The Obsessive Compulsive Drinking Scale (OCDS) and Visual Analogue Scale for craving (VASc) were also administered to the AUD sample. RESULTS: 28.4% (n=27) of AUD subjects had at least one BA, as compared to 15% (n=21) of controls (χ(2)=6.27; p=.014). In AUD subjects, direct correlations between BIS-11 and Compulsive Buying Scale (CBS), Internet Addiction Disorder test (IAD), Exercise Addiction Inventory-Short Form (EAI-SF) scores (p<.01), between OCDS obsessive and CBS and VASc and CBS, IAD scores (p<.003), were found. BIS-11 (t=-2.36; p=.020), OCDS obsessive (Z=-4.13; p<.001), OCDS compulsive (Z=-2.12; p=.034) and VASc (Z=-4.94; p<.001) scores were higher in AUD subjects with co-occurring BAs. The occurrence of BAs was associated with higher impulsivity traits (BIS-11 scores; OR=1.08; p=.012) and higher craving levels (VASc scores; OR=2.48; p<.001). CONCLUSIONS: Our findings emphasize a significant rate of co-occurrence of BAs in AUD. High levels of impulsivity and craving for alcohol seem to be associated with other addictive behaviors.

A possible new option for migraine management: agomelatine.

BACKGROUND: Migraine is a primary headache disorder characterized by recurrent episodes of headache associated with gastrointestinal, neurologic, and autonomic symptoms. Some evidence in literature suggests that the melatonergic system possibly plays an important role in the pathogenesis of migraine. Few studies have been performed on the use of melatonin as an antimigraine agent. Other than amitriptyline, few antidepressants have been found to be efficacious for migraine prophylaxis. Among antidepressants, agomelatine has a novel neurochemical mechanism. It is an melatonin receptor 1 and melatonin receptor 2 melatonergic receptor agonist and a selective antagonist of the 5-hydroxytryptamine (serotonin) receptor 2C receptors. CASES: We report two cases of patients with migraine successfully treated with agomelatine; one patient presented with comorbid depression, whereas the other had no comorbidities. DISCUSSION: Given its specific mechanism of action and similarity with melatonin, agomelatine may be a promising new treatment option for migraine prophylaxis. The potential therapeutic action of agomelatine could be due to its synergistic action on both melatonergic and 5-HT2C receptors.

Gabapentin as add-on treatment for somatoform disorder: a case report.

Somatoform disorder is a relatively common and severe disorder for which pharmacotherapy has been minimally studied. We report a case of 30-year-old woman with treatment-resistant somatoform disorder that was successfully treated with add-on treatment of gabapentin. Our result showed that gabapentin 1800 mg/day could be tried in case of treatment-resistant somatoform disorder as an add-on strategy. However, controlled trials are needed to investigate the effectiveness of gabapentin in the management of this condition.

Pregabalin for alcohol dependence: a critical review of the literature.

INTRODUCTION: Alcohol dependence represents a severe pathological disorder associated with a significant rate of morbidity and mortality. To date, limited pharmacological agents exist to treat this disorder, and there is a growing interest for new therapies. In this context, pregabalin represents a promising strategy. Pregabalin, like gabapentin, selectively binds to the α(2)δsubunit of voltage-gated calcium channels, inhibiting release of excessive levels of excitatory neurotransmitters. The main focus of this review is the clinical use of pregabalin in alcoholic patients, but the authors also reported some data about chemistry, pharmacology, and pharmacokinetics of this drug. METHODS: The authors conducted a PubMed search of clinical human studies published in English from January 2000 to August 2012 using the following search terms: pregabalin alcohol dependence, pregabalin alcohol withdrawal, pregabalin alcoholism. RESULTS: The search revealed a total of five studies: two trials for the treatment of alcohol relapse and three articles for the management of alcohol withdrawal syndrome with pregabalin. The critical review of the literature suggests that pregabalin could be a novel and effective treatment option for the management of alcohol relapse in detoxified patients, whereas until now there have been mixed results for the treatment of alcohol withdrawal syndrome. In particular, pregabalin showed a greater beneficial effect on patients with comorbid conditions such as alcoholism and generalized anxiety disorders. The exact mechanism of action of pregabalin in the management of alcoholism is not well understood but it is thought to be due mainly to the modulation of neurotransmitters such as glutamate and norepinephrine by inhibiting activity-dependent calcium influx in nerve terminals. CONCLUSION: Pregabalin, within a dosage of 150-450 mg/day, showed beneficial effects for alcohol relapse prevention and contrasting results for the treatment of the withdrawal syndrome. Its use appears to be safe and well tolerated.

Pregabalin, tiapride and lorazepam in alcohol withdrawal syndrome: a multi-centre, randomized, single-blind comparison trial.

INTRODUCTION: The aim of this trial was to compare lorazepam with non-benzodiazepine medications such as pregabalin and tiapride in the treatment of alcohol withdrawal syndrome (AWS). These drugs were chosen for their inhibitorial effects on the hypersecretion of neurotransmitters usually observed in AWS. Craving reduction and improvement of psychiatric symptoms were the secondary end-points. METHODS: One hundred and ninety subjects affected by current alcohol dependence were considered consecutively: 111 were enrolled and divided into three groups of 37 subjects each. Within a treatment duration of 14 days, medication was given up to the following maximum doses (pregabalin 450 mg/day; tiapride 800 mg/day; lorazepam 10 mg/day). Withdrawal (CIWA-Ar), craving [visual analogue scale (VAS); Obsessive and Compulsive Drinking Scale (OCDS)], psychiatric symptoms [Symptom Check List 90 Revised (SCL-90-R)] and quality of life (QL-index) rating scales were applied. RESULTS: On the CIWA-Ar score, all the groups showed a significant reduction between times (P < 0.001) with a higher reduction for the pregabalin group (P < 0.01) on items regarding headache and orientation. Retention in treatment was lower in the tiapride group (P < 0.05), while the number of subjects remaining alcohol free was higher in the pregabalin group (P < 0.05). Significant reduction between baseline and the end of the treatment was found in all the groups at the OCDS and the VAS for craving, at the SCL-90-R and QL-index (P < 0.001). DISCUSSION: All the medications in the trial showed evidence of safety and efficacy in the treatment of uncomplicated forms of AWS, with some particular differences. The efficacy of pregabalin was superior to that of tiapride, used largely in research trials and, for some measures, to that of the 'gold standard', lorazepam. Accordingly, pregabalin may be considered as a potentially useful new drug for treatment of AWS, deserving further investigation.