The Neurotransmitter Theory and Effect of Drugs
Schizophrenia is a severe psychiatric condition with a chronic course that manifests with a range of cognitive deficits and impaired memory. Neurochemical aberrations during inhibitory neurotransmission in the mesolimbic and mesocortical pathways are etiologic for this disorder.
Among the candidate neurotransmitter systems implicated in its pathology are dopamine and GABA. The dopamine theory hypothesizes that the activation of post-synaptic dopamine receptors in the mesolimbic pathway of the brain increases dopaminergic activity, resulting in positive symptoms – delusions and hallucinations (Yang & Tsai, 2017, p. 2). However, administration of dopaminergic stabilizers or antagonists does not treat cognitive deficits linked to mesocortical dysfunction in schizophrenia patients.
The mesocortical pathway is also relevant to the neurobiology of cognitive/functional loss. The inhibition of N-methyl-D-aspartate receptors (NMDARs) linking cortical and thalamic regions to the limbic system is believed to cause cognitive impairments associated with schizophrenia (Yang & Tsai, 2017). Further, GABA neurons, through interactions with dopamine neurotransmitters, play a role in generating neural networks and synchrony that are important in memory.
Therefore, GABA receptor dysfunctions are linked to working memory impairment and perceptive deficits (Yang & Tsai, 2017). The psychotic effects of serotonin-dopamine antagonists have also led to the hypothesis that serotonergic dysfunction plays a role in schizophrenia pathophysiology.
The mechanism of action of the drugs used to treat schizophrenia involves transmitter receptors. Antipsychotics act as D2 partial agonists or antagonists; they inhibit the dopamine transmission pathway and block receptor response (Yang & Tsai, 2017). In contrast, atypical stabilizers (serotonin-dopamine antagonists) such as clozapine act through 5-HT2A receptor antagonism. They enhance dopaminergic release in the nigrostriatal pathway to treat cognitive deficits that result from mesocortical dysfunction.
Evaluation of Risks and Benefits
Clozapine is an atypical antipsychotic indicated as first-line therapy for treatment-resistant schizophrenia. Unlike other available drugs, this serotonin-dopamine antagonist is associated with minimal extrapyramidal side effects and a high success rate, especially in patients not responding to haloperidol. In a clinical trial, 30% of clozapine-treated subjects showed improvement in schizophrenic symptoms after six weeks, compared to 4% of chlorpromazine-treated individuals (Taylor, 2017). Another benefit of clozapine is that it has a low agranulocytosis risk.
Potential side effects of second-generation antipsychotic drugs are weight gain and myocardial infarction (Taylor, 2017). These medications are also associated with a high incidence of cardiovascular disease (CVD) – overweight and T2DM. According to Taylor (2017), CVD accounts for over 60% of premature mortality in schizophrenic patients. The one-year mortality ratio is estimated to be 0.6 per 100 patients for clozapine-treatment individuals, compared to 1.1 for those under non-clozapine antipsychotics (Wimberley et al., 2017). Therefore, clozapine has a lower mortality rate than other available medications.
Untreated schizophrenia could cause neurological degeneration and psychosis. Neurotoxicity is linked to brain damage, reduced response to therapy, severe cognitive deficits (Taylor, 2017). The natural course of schizophrenia is characterized by psychosis that affects the cortical and temporal regions of the brain, resulting in irreversible disability (Yang & Tsai, 2017). Positive symptoms such as illusions and reduced cognitive function exacerbate as the duration of untreated schizophrenia increases. Therefore, spontaneous recovery may not be possible due to neurotoxicity. The mortality rate (ratio) when untreated with any antipsychotics is 0.95 (Wimberley et al., 2017).
The modes of treatment available are the slow and rapid titration of antipsychotics. A 14-day gradual administration of clozapine (25mg daily dose) is recommended to minimize side effects such as hypotension and agranulocytosis (Yang & Tsai, 2017). However, rapid titration can eliminate the need for combination antipsychotic therapy to control aggression associated with slow clozapine administration.
References
Aronson, J. K. (Ed.). (2016). Meyler’s side effects of drugs: The international encyclopedia of adverse drug reactions and interactions (16th ed.). London, UK: Elsevier Science.
Nielsen, S. (2015). Benzodiazepines. Current Topics in Behavioral Neurosciences, 34, 141-159.
PubChem. (2018). Flunitrazepam. Web.
Taylor, D. M. (2017). Clozapine for treatment-resistant schizophrenia: Still the gold standard? CNS Drugs, 31(3), 177-180. Web.
Wimberley, T., MacCabe, J. H., Laursen, T. M., Sørensen, H. J., Astrup, A., Horsdal, H. T., … Støvring, H. (2017). Mortality and self-harm in association with clozapine in treatment-resistant schizophrenia. American Journal of Psychiatry, 174(10), 990-998. Web.
Yang, A. C., & Tsai, S. (2017). New targets for schizophrenia treatment beyond the dopamine hypothesis. International Journal of Molecular Science, 18, 1-14. Web.