According Coyle etal (2015), dopamine is a vital neurotransmitter involved in various functions, including movement, emotion, reward, and cognition. In humans, there are five dopaminergic pathways namely: nigrostriatal, mesolimbic, mesocortical, tuberinfundibular, and thalamic. However, the mesolimbic and mesocortical dopaminergic pathways are the most significant to the pathophysiology of schizophrenia. Elevated dopaminergic activity in the mesolimbic pathway is responsible for the production of the positive symptoms of schizophrenia. While the reduced dopaminergic activity of the mesocortical pathway is responsible for the negative symptoms and cognitive dysfunction associated with schizophrenia.

Dopamine receptors are G-protein-coupled receptors (GPCRs) with different identified receptor subtypes and isoforms. The five commonly identified dopamine receptor subtypes include D1-D5, withD2 and D4 having the most significant role in schizophrenia. Meanwhile, the mechanism of action of most antipsychotic drugs is inhibiting the expression of the D2 receptors. Most antipsychotic drugs achieve antipsychotic effects at D2 receptor efficacy of sixty to eighty percent. While efficacy greater than eighty percent is linked to neurological adverse effects of the typical antipsychotics such as the chlorpromazine and haloperidol (Coyle etal, 2015).

The neurological adverse effects include akathisia, or extreme restlessness, extrapyramidal symptoms such as Parkinson-like symptoms and dystonias. Typical antipsychotics associated with involuntary muscular contractions or tardive dyskinesia which is seen in D2 receptor inhibition in the mesolimbic pathway elicits antipsychotic effects. While inhibition of D2 receptor in the nigrostriatal pathway results in extrapyramidal symptoms. Inhibition of the pituitary leads to hypersecretion of prolactin, potentially resulting in galactorrhea in men and menstrual dysfunctions in women. Also, there are cases of hypogonadism, erectile dysfunction in men, and gynecomastia also in men. According to Biala etal (2022), the first antipsychotic medication, chlorpromazine is discovered in 1951. It’s discovered inadvertently while treating intraoperative autoimmune stress. According to Biala etal (2022), chlorpromazine is the prototype for the first-generation antipsychotics called typical antipsychotics or neuroleptics. In 1990, the first prototype of the atypical antipsychotics, clozapine is introduced. As already mentioned, antipsychotics act by inhibiting the subtype of dopamine receptor s that include D2 and D4.

The atypical or second-generation antipsychotics are invented to address the neurological side effects associated with the typical antipsychotics. While inhibiting D2 receptor, the atypical antipsychotics also inhibit other receptors especially, serotonin-2A or 5-Hydroxytryptamine-2A(5-HT2S) receptors thereby, mitigating the neurological symptoms associated with the typical antipsychotics. Also, the inhibition at 5-HT2A receptors stimulates striatal dopamine release that elicits some antipsychotic response.

Meanwhile, atypical antipsychotics are not the magic antidote anticipated because they can also result in weight gain, increase in metabolic syndrome including hyperglycemia, increased susceptibility to diabetes mellitus type II, and dyslipidemia.

GABAERGIC AND GLUTAMAERGIC NEUROTRANSMISSION

The gamma aminobutyric acid (GABA) is the dominant inhibitory neurotransmitter. While the glutamate is the dominant excitatory or stimulatory neurotransmitter in the CNS. Available research evidence validates the link between GABA neurotransmission and the pathophysiology of schizophrenia. GABAergic changes have been detected in schizophrenia patients, post mortem, including GABAergic neurotransmission. According to Coyle etal (2015), animal models of schizophrenia show an impaired GABAergic neurotransmission primary to cognitive impairment. While cognitive impairment is secondary to the inhibitory effects of the antagonists of glutamate receptors that exacerbate psychotic symptoms in humans such as phencyclidine and ketamine. Hence, research study has indicated the potential pathophysiological link between the pathology of schizophrenia and decreased neurotransmission at glutamate receptor (Coyle etal, 2015).

ACETYLCHOLINE NEUROTRANSMISSION AND PARKINSON’S-LIKE SYMPTOMS

According to Meyer & Quenzer (2019), the most debilitating side effects of classic antipsychotics are dyskinesias that resemble Parkinson’s disease. The manifestations include extrapyramidal symptoms such as tremors, akinesia, muscle rigidity, akathisia, and loss of facial expression.

The cholinergic drugs, such as the benztropines are used to counter the involuntary muscular contractions or dyskinesias associated with antipsychotics. Correll etal (2022) describes schizophrenia as an often-debilitating chronic behavioral illness with high risk of relapse. According to Chen etal (2003), some second generation or atypical antipsychotics (SGAs) are considered more efficacious than the first-generation antipsychotics thus, they are mostly recommended.

Meanwhile, Coyle etal (2015) emphasizes the following points in describing schizophrenia:

Ø  Schizophrenia is a chronic psychosis occurring in 1% to 1.5% of the population world-wide during late adolescence or early adulthood

Ø  Men have an earlier onset and poorer outcome than women

Ø  Schizophrenia is a thought-processing disorder marked by grandiosity and delusion

Ø  The positive symptoms are episodic, often leading to diagnosis. The positive symptoms include: hallucinations, delusion, disorganized speech, and grandiosity

Ø  The negative symptoms include absence of normal functioning, amotivation, social isolation, apathy, anhedonia, and catatonia etc.

Comer (2016) highlights the positive and negative symptoms of schizophrenia as follow:

The positive symptoms include the pathological excess or bizarre additions to a person’s behavior such as delusional thinking, disorganized speech, irritability, hypersensitivity, hallucinations, inappropriate emotional expression. Hallucinations can manifest in different dimensions such as visual, auditory, olfactory, gustatory, and psychosomatic. The negative symptoms are the pathological deficits such as restricted speech, anhedonia, indecision or ambivalence, social isolation, catatonia etc.

According to Meyer & Quenzer (2019), drugs used to treat schizophrenia are called antipsychotics or neuroleptics. While adjuvant therapies include anxiolytics such as the benzodiazepines, and antidepressants. Natural alternatives include supplementation with niacin, multivitamin, garlic etc. (Salaman, 1998). Over the counter drugs include melatonin, 5-HT, SAM-e, St. John’s worth etc.,

References

American Psychiatric Association (2022). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Sheridan Books, Inc. www.psychiatry.org

Comer, R.J. (2016). Fundamentals of Abnormal Psychology (8th ed.). Worth Publishers. http://www.macmillanhighered.com

Correll, C.U., Martin, A., Patel, C. et al. Systematic literature review of schizophrenia clinical practice guidelines on acute and maintenance management with antipsychotics. Schizophr 8, 5 (2022). https://doi.org/10.1038/s41537-021-00192-x

Coyle, J.T., Rowland, L.P., & Zigmond, M.J. (2015). Neurobiology of Brain Disorders: Biological Basis of Neurological and Psychiatric Disorders. Academic Press. www.elsevier.com

Davis JM, Chen N, Glick ID. A Meta-analysis of the Efficacy of Second-Generation Antipsychotics. Arch Gen Psychiatry. 2003;60(6):553–564. doi:10.1001/archpsyc.60.6.553

Meyer, J.S. & Quenzer, L.F. (2019). Psychopharmacology: Drugs, the Brain, and Behavior (3RD ed.). Oxford University Press. www.oup.com/us/he

Orzelska-Górka, J., Mikulska, J., Wiszniewska, A., & Biała, G. (2022). New Atypical Antipsychotics in the Treatment of Schizophrenia and Depression. International Journal of Molecular Sciences, 23(18), 10624. https://doi.org/10.3390/ijms231810624

Salaman, M.K. (1998). All Your Health Questions Answered Naturally. MKS Inc. Mountain View, CA 94043.