Pathophysiology and management of Akathisia 70 years after the introduction of the chlorpromazine, the first antipsychotic.

OBJECTIVE: Akathisia is among the most troubling effects of psychiatric drugs as it is associated with significant distress on behalf of the patients, and it limits treatment adherence. Though it most commonly presents during treatment with antipsychotic drugs which block dopamine D2 receptors, Akathisia has also been reported during treatment with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), stimulants, mirtazapine, tetrabenazine and other drugs. MATERIALS AND METHODS: This article was designed as a narrative review on akathisia with a focus on its clinical presentation, pathophysiology and management. A PubMed search for akathisia was conducted which returned 8481 articles. RESULTS: Akathisia is experienced as severe restlessness commonly accompanied by dysphoria and purposeless movement which relieves subjective tension. It has been attributed to an imbalance between dopaminergic and noradrenergic neurotransmission in the basal ganglia. Acute akathisia commonly resolves upon treatment discontinuation but tardive and chronic akathisia may persist after the causative agent is withdrawn and prove resistant to pharmacological treatment. Even drugs which induce no other extrapyramidal side effects (such as clozapine, quetiapine, aripiprazole and cariprazine) may induce akathisia. A high index of suspicion should be maintained in patients with motor disabilities, drug-induced parkinsonism and those under mechanical restraint. Propranolol and low-dose mirtazapine are the most thoroughly studied pharmacological interventions for akathisia, though benzodiazepines, voltage-gated calcium channel blockers (gabapentin, pregabalin) and opioids may be effective. CONCLUSIONS: Pharmacological management may pose a challenge in chronic akathisia. Rotation between different pharmacological management strategies may be optimal in resistant cases. Discontinuation of the causative drug and use of b-blockers, mirtazapine, benzodiazepines or gabapentinoids for symptomatic relief is the basis of management.

Converging dopaminergic neurotoxicity mechanisms of antipsychotics, methamphetamine and levodopa.

OBJECTIVE: Drugs affecting dopaminergic neurotransmission may exert toxic and beneficial effects that persist after discontinuation by modulating gene expression in key brain regions. Drug addiction, cravings and the tardive symptoms associated with chronic exposure to antipsychotics are among the most common processes attributed to long-term dopaminergic neurotoxicity. The purpose of this review was to investigate the mechanisms of dopaminergic neurotoxicity induced by neuroleptic drugs, dopamine agonists, levodopa, stimulants and known dopaminergic neurotoxins MATERIALS AND METHODS: A PubMed search for each of the dopaminergic compounds in question was carried out. The heterogenous nature of the relevant preclinical studies precluded a systematic review, so a narrative review was carried out. RESULTS: The dopaminergic neurotoxins 6-oxidopamine and 1-methyl-4-phenyl-tetrahydropyridine (MPTP) promote oxidative stress and inhibit mitochondrial function, while their affinity for the dopamine transporter ensures they are attain toxic intracellular concentrations exclusively in dopaminergic neurons. Stimulants which inhibit the vesicular monoamine transporter such as amphetamine and its derivatives promote oxidative stress by greatly increasing intracellular dopamine concentrations and enabling dopamine autooxidation. Antipsychotics increase dopamine release and turnover by blocking autoinhibitory D2 receptors and lead to upregulation of post-synaptic D2 receptors. Dopamine agonists may slow the progression of Parkinson's disease by reducing dopamine turnover, but downregulation of D2 receptors may underlie their behavioural toxicity. CONCLUSIONS: Though the mechanisms have not been completely elucidated yet, it seems drugs which affect dopaminergic neurotransmission may exert long-term effects which reverse slowly upon discontinuation, if at all. Until the nature of these changes is clear it would be best to utilize drugs which affect dopaminergic neurotransmission cautiously especially if prolonged treatment is required.