Amir I.A. Ahmed

Efficacy and safety of medical cannabinoids in older subjects: a systematic review.

This systematic review aims to integrate the evidence on indications, efficacy, safety and pharmacokinetics of medical cannabinoids in older subjects. The literature search was conducted using PubMed, EMBASE, CINAHL and Cochrane Library. We selected controlled trials including solely older subjects (≥65 years) or reporting data on older subgroups. 105 (74%) papers, on controlled intervention trials, reported the inclusion of older subjects. Five studies reported data on older persons separately. These were randomized controlled trials, including in total 267 participants (mean age 47-78 years). Interventions were oral tetrahydrocannabinol (THC) (n=3) and oral THC combined with cannabidiol (n=2). The studies showed no efficacy on dyskinesia, breathlessness and chemotherapy induced nausea and vomiting. Two studies showed that THC might be useful in treatment of anorexia and behavioral symptoms in dementia. Adverse events were more common during cannabinoid treatment compared to the control treatment, and were most frequently sedation like symptoms. Although trials studying medical cannabinoids included older subjects, there is a lack of evidence of its use specifically in older patients. Adequately powered trials are needed to assess the efficacy and safety of cannabinoids in older subjects, as the potential symptomatic benefit is especially attractive in this age group.

Neuropsychiatric adverse events of varenicline: a systematic review of published reports

Introduction Over the past years, the impact of varenicline in patients with mental illness has been debated as serious neuropsychiatric adverse events (AEs) have been reported with varenicline use. Aim To identify and summarize published case reports of neuropsychiatric AEs ascribed to varenicline and to determine potential risk factors for these AEs. Methods A literature search of MEDLINE, the Cochrane Library, EMBASE, and PsychInfo database was conducted for case reports concerning the neuropsychiatric AEs of varenicline published in English from 2006 (approval year by the US Food and Drug Administration and the Dutch Medicines Evaluation Board) to January 1, 2012. Results We identified 25 published cases. In most reports, patients had been admitted to psychiatric hospitals with serious neuropsychiatric AEs due to varenicline. The average patient age was 46.4 years, and 56% were men; 68% of patients had a psychiatric history. The onset of symptoms started 2 days to 3 months after the initiation of varenicline. One report described completed suicide in a man with no psychiatric history. In most cases (84%), the neuropsychiatric symptoms resolved after the discontinuation of varenicline. Analysis of all reports using the Naranjo causality scale, a method for estimating the probability of adverse drug reactions, indicated probable causality in 76% of the cases and definite causality in 12% of cases. Conclusion Varenicline is associated with an increased risk of serious neuropsychiatric AEs, especially in patients with a psychiatric illness. It is strongly recommended that varenicline be administered only to mentally stable patients and under close monitoring.

Tetrahydrocannabinol for neuropsychiatric symptoms in dementia: A randomized controlled trial

Objective: To study the efficacy and safety of low-dose oral tetrahydrocannabinol (THC) in the treatment of dementia-related neuropsychiatric symptoms (NPS). Methods: This is a randomized, double-blind, placebo-controlled study. Patients with dementia and clinically relevant NPS were randomly assigned to receive THC 1.5 mg or matched placebo (1:1) 3 times daily for 3 weeks. Primary outcome was change in Neuropsychiatric Inventory (NPI), assessed at baseline and after 14 and 21 days. Analyses were based on intention-to-treat. Results: Twenty-four patients received THC and 26 received placebo. NPS were reduced during both treatment conditions. The difference in reduction from baseline between THC and placebo was not significant (mean difference NPItotal: 3.2, 95% confidence interval [CI] −3.6 to 10.0), nor were changes in scores for agitation (Cohen-Mansfield Agitation Inventory 4.6, 95% CI −3.0 to 12.2), quality of life (Quality of Life–Alzheimers Disease −0.5, 95% CI −2.6 to 1.6), or activities of daily living (Barthel Index 0.6, 95% CI −0.8 to 1.9). The number of patients experiencing mild or moderate adverse events was similar (THC, n = 16; placebo, n = 14, p = 0.36). No effects on vital signs, weight, or episodic memory were observed. Conclusions: Oral THC of 4.5 mg daily showed no benefit in NPS, but was well-tolerated, which adds valuable knowledge to the scarce evidence on THC in dementia. The benign adverse event profile of this dosage allows study of whether higher doses are efficacious and equally well-tolerated. Classification of evidence: This study provides Class I evidence that for patients with dementia-related NPS, low-dose THC does not significantly reduce NPS at 21 days, though it is well-tolerated.

Safety and pharmacokinetics of oral delta-9-tetrahydrocannabinol in healthy older subjects: A randomized controlled trial

There is a great concern about the safety of THC-based drugs in older people (≥65 years), as most of THC-trials did not include such group. In this phase 1, randomized, double-blind, double-dummy, placebo-controlled, cross-over trial, we evaluated the safety and pharmacokinetics of three oral doses of Namisol(®), a novel THC in tablet form, in older subjects. Twelve healthy older subjects (6 male; mean age 72±5 years) randomly received a single oral dose of 3mg, 5mg, or 6.5mg of THC or matching placebo, in a crossover manner, on each intervention day. The data for 11 subjects were included in the analysis. The data of 1 subject were excluded due to non-compliance to study medication. THC was safe and well tolerated. The most frequently reported adverse events (AEs) were drowsiness (27%) and dry mouth (11%). Subjects reported more AEs with THC 6.5mg than with 3mg (p=0.048), 5mg (p=0.034) and placebo (p=0.013). There was a wide inter-individual variability in plasma concentrations of THC. Subjects for whom the Cmax fell within the sampling period (over 2h), Cmax was 1.42-4.57ng/mL and Tmax was 67-92min. The AUC0-2h (n=11) was 1.67-3.51ng/mL. Overall, the pharmacodynamic effects of THC were smaller than effects previously reported in young adults. In conclusion, THC appeared to be safe and well tolerated by healthy older individuals. Data on safety and effectiveness of THC in frail older persons are urgently required, as this population could benefit from the therapeutic applications of THC.

Tetrahydrocannabinol in Behavioral Disturbances in Dementia: A Crossover Randomized Controlled Trial.

OBJECTIVES Neuropsychiatric symptoms (NPS) are highly prevalent in dementia, but effective pharmacotherapy without important side effects is lacking. This study aims to assess the efficacy and safety of oral tetrahydrocannabinol (THC) in the treatment of NPS in dementia. DESIGN Randomized, double-blind, placebo-controlled, repeated crossover trial, consisting of six treatment blocks of 2 weeks each. SETTING Two hospital sites in The Netherlands, September 2011 to December 2013. PARTICIPANTS Patients with dementia and clinically relevant NPS. INTERVENTION Within each block THC (0.75 mg twice daily in blocks 1-3 and 1.5 mg twice daily in blocks 4-6) and placebo were administered in random order for 3 consecutive days, followed by a 4-day washout. MEASUREMENTS Primary outcome was change in Neuropsychiatric Inventory (NPI) score. Analyses were performed intention-to-treat. Data from all subjects were used without imputation. Sample size required for a power of 80% was 20 patients, because of repeated crossover. RESULTS 22 patients (15 men, mean age 76.4 [5.3] years) were included, of whom 20 (91%) completed the trial. THC did not reduce NPI compared to placebo (blocks 1-3: 1.8, 97.5% CI: -2.1 to 5.8; blocks 4-6: -2.8, 97.5% CI: -7.4 to 1.8). THC was well tolerated, as assessed by adverse event monitoring, vital signs, and mobility. The incidence of adverse events was similar between treatment groups. Four non-related serious adverse events occurred. CONCLUSIONS This is the largest randomized controlled trial studying the efficacy of THC for NPS, to date. Oral THC did not reduce NPS in dementia, but was well tolerated by these vulnerable patients, supporting future higher dosing studies.

Sleep disorders, nightmares, depression and anxiety in an elderly patient treated with low-dose metoprolol

In the Netherlands, the prescription of beta-blockers to patients older than 70 years has increased sharply in recent years. The neuropsychiatric adverse reactions associated with the use of beta-blockers are relatively uncommon and they are mostly seen with poisoning or overdose. We describe an 81-year-old man who developed sleep disorders, nightmares, depression and anxiety as probable adverse effect of low-dose metoprolol (25 mg/day). This case illustrates not only the neuropsychiatric adverse reactions of beta-blockers, but also that diagnosis of these reactions can be easily missed in elderly patients.

A man who wanted to commit suicide by hanging himself: an adverse effect of ciprofloxacin.

In this case report, we describe a man who developed recurrent depression and suicidal ideation with a serious plan to commit suicide as definite adverse effect of ciprofloxacin, which had been prescribed for recurrent prostatitis.

Potentially inappropriate prescribing in older patients admitted to psychiatric hospital

The objectives of this study are to determine the prevalence of potentially inappropriate prescribing including potentially inappropriate medications (PIMs) and potential prescription omissions (PPOs) and to assess related risk factors in older people with major psychiatric illness.

Medicinal Use of Cannabis and Cannabinoids in Older Adults: Where Is the Evidence?

required biphasic positive airway pressure support. She denied all retrosternal or pleuritic chest pain, palpitations, or calf pain. Her physical examination revealed rales and decreased breath sounds on the right and bilateral expiratory wheezes. Her laboratory test results were remarkable for a creatinine of 7.2 mg/dL (her baseline), blood glucose of 95 mg/dL, and white blood cell count of 12,300 cells/ mL. Her electrocardiogram was unchanged, troponin I was 0.02 mg/dL, and chest X-ray demonstrated a 50%, right pleural effusion (Figure 1). She was admitted to the medical intensive care unit for respiratory support and started on moxifloxacin for a presumed infectious process. The diagnostic and therapeutic thoracentesis produced 1.6 L of clear fluid, white blood cells of 35/mL, red blood cells 45/mL, total protein of 0.3 g/dL, lactate dehydrogenase of 20 U/L, and glucose of 302 mg/dL, consistent with a transudate. Pleural fluid glucose was significantly greater than blood glucose, which is consistent with dialysate fluid. Her respiratory status improved after the thoracentesis, and she was discharged on hospital day 3. Her CAPD was discontinued, and she was started on hemodialysis. As an outpatient, she will remain on hemodialysis until imaging and treatment of a possible pleuroperitoneal communication is complete. A “sweet” hydrothorax is the result of pleuroperitoneal communications in an individual undergoing CAPD. This is a rare cause of a pleural effusion, and it is has been infrequently reported. The dialysate migrates into the pleural space and can cause life-threatening respiratory distress from the resulting effusion. A review of one case series found the incidence of “sweet” hydrothoraxes to be 1.9% of individuals undergoing CAPD. The diagnosis is confirmed through analysis of the pleural fluid, which will have a glucose measurement significantly greater than the blood glucose. A difference of more than 50 mg/dL was found to be 100% specific and sensitive for identifying a “sweet” hydrothorax. Acute treatment is thoracentesis and conversion to hemodialysis. For individuals who wish to return to CAPD, pleuroperitoneal communication can sometimes be visualized using technetium-99 m peritoneal scintigraphy or video-assisted thoracic surgery, and the opening can be closed using pleurodesis. In one series, talc pleurodesis was successful in six of seven individuals. Some older adults with ESRD choose CAPD for longterm management because it allows greater personal autonomy. Acute presentation with respiratory symptoms in these individuals should prompt clinicians to consider sweet syndrome (effusion due to pleuroperitoneal communications) as a possible etiology.

A manic episode in a 64-year-old man: an adverse effect of varenicline.

Varenicline is a novel treatment for smoking cessation. However, it has not been well studied in patients with medical and psychiatric comorbidity. We report a case of an acute manic episode in a 64-year-old man with a history of bipolar disorder post stroke, who was started on varenicline. This case demonstrates the importance of monitoring neuropsychiatric adverse drug reactions after the start of varenicline therapy in patients with a current or past history of mental illness.