Selegiline

Authors:

Alessandro Vellucci, Andrea Sobrino, Andrea de Bartolomeis, Carlo Ignazio Cattaneo, Claudio Caiazza, Felice Iasevoli, Flavia Rossano, Henricus G. Ruhé, Ken Gillman, Michele Fornaro, Niccolò Solini, Nicolas Zotti, Stephen Stahl, Tom K. Birkenhager, Vincent Van den Eynde

Findings:

Selegiline (oral and transdermal) significantly outperformed placebo in reducing depressive symptoms (SMD=-0.96) and improving depression response rates (RR=1.61), particularly for atypical depression (RR=2.23). However, it did not show significant efficacy over placebo for negative or positive symptoms of schizophrenia, ADHD symptoms reduction, or smoking abstinence rates. Selegiline showed comparable acceptability (all-cause discontinuation) to placebo but was associated with significantly higher rates of insomnia and application site reactions (transdermal) and xerostomia (oral).

Participants:

Systematic review (42 studies) and meta-analysis (23 studies) involving human participants (any age) with primary psychiatric disorders, including depression (MDD, atypical, bipolar; k=10, n=1308 for symptoms; k=9, n=1238 for response; k=3, n=136 for atypical response), schizophrenia (k=4, n=191 for negative symptoms), ADHD (children, adolescents, adults; k=2, n=68 vs methylphenidate; k=2, n=48 vs placebo), smoking addiction (k=4, n=402 for abstinence), cocaine addiction (1 study included in SR), and social phobia (1 study included in SR).

Dosage:

Systematic review covered various oral (e.g., 5mg BID/TID, 10-60mg/day) and transdermal (STS 6mg/24h, 6-12mg/24h, 10-20mg/24h) formulations and dosages. Oral doses ≥20 mg/day mentioned for non-selective MAOI activity. STS 6-12 mg/24h approved for MDD.

Study Quality Assessment:

Systematic review and meta-analysis following PRISMA guidelines (PROSPERO registered: CRD42022359815). Searched multiple databases (PubMed/MEDLINE/Cochrane-Central/WHO-ICTRP/Clarivate-WebOfScience, Chinese-Electronic-Journal Database) up to 10/26/2022. Included interventional controlled studies (randomized and non-randomized). Used random-effects meta-analyses, assessed heterogeneity (I², τ², Q-test, GOSH), publication bias (funnel plot, Egger's test), and risk of bias (RoB2 for RCTs, ROBINS-I for non-randomized studies). Conducted sensitivity, subgroup, and meta-regression analyses. Confidence assessed using GRADE. 21/23 meta-analyzed studies were RCTs (RoB: 13 low, 3 unclear, 5 high). Confidence rated low/very-low for most outcomes, moderate for transdermal selegiline in depression symptom reduction. Acknowledged limitations include high heterogeneity for specific outcomes.

All Effects:

Authors:

M Naoi

Findings:

This review indicates preclinical studies show neuroprotective functions for MAO-B inhibitors rasagiline and selegiline, including preventing mitochondrial apoptosis, inducing anti-apoptotic (Bcl-2) and pro-survival neurotrophic factors (BDNF, GDNF), and mitigating α-synuclein toxicity. MAO-A is also implicated in rasagiline's neuroprotective signaling. Despite preclinical promise, clinical trials have largely failed to demonstrate clear disease-modifying effects in synucleinopathies, highlighting the need for improved clinical trial strategies.

Participants:

Review summarizing studies involving cellular models (e.g., SH-SY5Y, U118MG, iPSCs), animal models (rats, mice, non-human primates), healthy human subjects, and patients with synucleinopathies (Parkinson's disease (PD), dementia with Lewy body (DLB), multiple system atrophy (MSA)) or mild cognitive impairment (MCI).

Dosage:

Selegiline: 10 mg/day (oral trials/pharmacokinetics), 5 mg/day (CSF study), 6 mg/24h (transdermal). Rasagiline: 1 mg/day or 2 mg/day (oral trials/pharmacokinetics), 0.1-0.25 mg/day (non-human primate study), 1 mg/day (MSA trial). In vitro concentrations mentioned (e.g., rasagiline 10⁻⁷–10⁻¹⁰ M for GDNF induction, selegiline 10⁻⁷–10⁻⁹ M for BDNF induction).

Study Quality Assessment:

Review mentions preclinical studies and clinical trials. Specific trials cited include: DATATOP (double-blind placebo-controlled), ADAGIO (controlled, randomized, delayed-start), TEMPO (controlled trial), PRESTO, LARGO, PROUD (delayed-start), LEAP (delayed-start), a phase III selegiline trial (randomized double-blind placebo-controlled), a phase 2 ladostigil trial (randomized, double-blind, placebo-controlled), an MSA trial (randomized, placebo-controlled), depression trials (double-blind, placebo-controlled). Assessment methods mentioned: Unified Parkinson’s Disease Rating Scale (UPDRS), PET imaging (β-CIT SPECT, [18F]fluorodopa PET, [11C]clorgyline PET). Acknowledges limitations of clinical trials (difficulty differentiating disease-modifying vs symptomatic effects, need for better trial design/markers).

All Effects:

Authors:

Annarita Capone, Chiara Zucchella, Francesco Pierelli, Giorgio Sandrini, Michelangelo Bartolo

Findings:

Selegiline (10 mg/day for 6 weeks) significantly improved performance on most neuropsychological tests after 2 and 6 weeks compared to placebo in stroke patients. Attention and executive functions benefited most. Both groups showed significant functional status improvement, but there was no significant difference between the selegiline and placebo groups regarding functional status.

Participants:

N=47 patients enrolled within two weeks of first-ever ischaemic or haemorrhagic stroke, with MMSE score 10-23 and FIM score ≤ 60. Randomly assigned to Study Group (n=23) or Control Group (n=24).

Dosage:

Selegiline 10 mg/day once a day for six weeks.

Study Quality Assessment:

Randomized controlled study; placebo-controlled (matched placebo); N=47 (23 treatment, 24 control); specific inclusion/exclusion criteria detailed; statistical methods mentioned (Student's t-test, Mann–Whitney U-test, chi-square test, Friedman test); conflict of interest declared none; funding source mentioned (donation from CHIESI Farmaceutici S.p.a.); study design suggestions acknowledged.

All Effects:

Authors:

Hart

Participants:

Studies involving Parkinson's Disease (PD)

Study Quality Assessment:

Study type: Synthesis of studies (likely systematic review or meta-analysis)

Findings:

Selegiline (oral and transdermal) significantly outperformed placebo in reducing depressive symptoms (SMD = -0.96) and improving depression response rates (RR = 1.61), particularly for atypical depression (RR = 2.23). However, selegiline failed to show significant superiority over placebo for negative or positive symptoms of schizophrenia, ADHD symptom reduction, or smoking abstinence rates. Selegiline acceptability (all-cause discontinuation) did not significantly differ from placebo, but it was associated with higher rates of xerostomia (RR = 1.58), insomnia (RR = 1.61), and application-site reactions for the transdermal formulation (RR = 1.81).

Participants:

Systematic review included studies on humans (any age) with primary psychiatric disorders (depression, schizophrenia, ADHD, smoking addiction, cocaine addiction, social phobia). Meta-analysis included N=23 studies involving patients with depression (N=1308 for symptoms, N=1238 for response), schizophrenia (N=191), ADHD (N=68 vs methylphenidate, N=48 vs placebo), and smoking addiction (N=402 endpoint, N=572 follow-up). Specific studies included adults, adolescents (12-17y), and children (4-16y).

Dosage:

Oral formulations studied ranged from 5mg BID (twice daily) or TID (thrice daily) up to 60mg/day (with doses ≥20mg/day noted for non-selective MAOI activity). Transdermal Selegiline System (STS) doses studied included 6mg/24h, 6-12mg/24h, and up to 20mg/24h patches.

Study Quality Assessment:

Systematic review and meta-analysis following PRISMA guidelines (PROSPERO registered: CRD42022359815). Searched multiple databases (PubMed, MEDLINE, Cochrane Central, ClinicalTrials.gov, WHO-ICTRP, Chinese Electronic Journal Database, Clarivate WebOfScience) until October 26th, 2022. Included 42 studies (SR), 23 (MA) - randomized (parallel, crossover) and non-randomized controlled trials (placebo-controlled, active comparator). Used random-effects meta-analysis models, assessed heterogeneity (I², τ², GOSH plots), publication bias (funnel plots, Egger's test), and risk of bias (RoB2, ROBINS-I tools). Conducted sensitivity, subgroup, and meta-regression analyses. GRADE framework used for evidence confidence (rated low/very-low for most outcomes, moderate for transdermal depression symptom reduction). High heterogeneity noted for some outcomes (e.g., depressive symptoms I²=97.9%). Significant publication bias detected for depression outcomes via Egger's test.

All Effects: