Selective serotonin reuptake inhibitors in the context of Sigma-1 receptor

Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, insomnia, and seizures. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955, and was made available in 1960 by Hoffmann–La Roche, which followed with the development of diazepam (Valium) three years later, in 1963. By 1977, benzodiazepines were the most prescribed medications globally; the introduction of selective serotonin reuptake inhibitors (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide.

Benzodiazepines are depressants that enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABA_A receptor, resulting in sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties. High doses of many shorter-acting benzodiazepines may also cause anterograde amnesia and dissociation. These properties make benzodiazepines useful in treating anxiety, panic disorder, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal and as a premedication for medical or dental procedures. Benzodiazepines are categorized as short-, intermediate-, and long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia; longer-acting benzodiazepines are recommended for the treatment of anxiety.

Akathisia (/æ.kə.ˈθɪ.si.ə/ a-kə-THI-see-ə) is a movement disorder characterized by a subjective feeling of inner restlessness accompanied by mental distress and/or an inability to sit still. Usually, the legs are most prominently affected. Those affected may fidget, rock back and forth, or pace, while some may just have an uneasy feeling in their bodies. The most severe cases may result in poor adherence to medications, exacerbation of psychiatric symptoms, and, because of this, aggression, violence, and/or suicidal thoughts. Akathisia is also associated with threatening behaviour and physical aggression in mentally disordered patients. However, the attempts to find potential links between akathisia and emerging suicidal or homicidal behaviour were not systematic and were mostly based on a limited number of case reports and small case series. Apart from these few low-quality studies, there is another more recent and better quality study (a systematic review from 2021) that concludes akathisia cannot be reliably linked to the presence of suicidal behavior in patients treated with antipsychotic medication.

Antipsychotic medication, particularly the first generation antipsychotics, are a leading cause. Other agents commonly responsible for this side-effect may also include selective serotonin reuptake inhibitors, metoclopramide, and reserpine, though any medication listing agitation as a side effect may trigger it. It may also occur upon stopping antipsychotics. The underlying mechanism is believed to involve dopamine. When antidepressants are the cause, there is no agreement on the distinction between activation syndrome and akathisia. Akathisia is often included as a component of activation syndrome. However, the two phenomena are not the same since the former, namely antipsychotic-induced akathisia, suggests a known neuroreceptor mechanism (e.g., dopamine-receptor blockade). Diagnosis is based on the symptoms. It differs from restless leg syndrome in that akathisia is not associated with sleeping. However, despite a lack of historical association between restless leg syndrome and akathisia, this does not guarantee that the two conditions do not share symptoms in individual cases.