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Effects of Antipsychotics


Antipsychotics are a group of medications that are used to relieve symptoms of psychosis such as hallucinations, delusions, paranoia, distorted thought (Finkel, Clark & Cubeddu, 2009). This essay aims at understanding the effects of these antipsychotics on dopaminergic pathways, to can gain a better knowledge of the side-effects and explain the causality in an improved fashion.


Antipsychotic drugs can be divided into two generations. First-generation antipsychotics (typical antipsychotics) were discovered in the 1950s, and second-generation antipsychotics (atypical antipsychotics) have been found in recent times (Hippius, 1989). Typical antipsychotics such as butyrophenones (haloperidol) and dihydroindoles (molindone) are dopamine receptor antagonists, i.e. they inhibit dopaminergic neurotransmission. Atypical antipsychotics such as risperidone, olanzapine and clozapine are serotonin-dopamine antagonists, i.e. they inhibit dopamine as well as serotonin neurotransmission (Chokalwala & Stevens, 2019).


Dopaminergic neurotransmission is known to have four pathways- mesolimbic, mesocortical, nigrostriatal and tuberoinfundibular (Speed, 2010). Dysfunction of dopamine in these pathways is one of the reasons for several neuropsychiatric diseases such as schizophrenia, attention-deficit hyperactivity disorder (ADHD), Parkinson's disease, obsessive-compulsive disorder (OCD) (Ayano, 2016). Antipsychotics affect the distribution of dopamine through each of these pathways that result in the experience of certain side-effects.

The mesolimbic pathway controls emotions and sensations and is responsible for the ‘reward-salience’ understanding. Hyperactivity leads to psychosis. Dopamine antagonists work towards the reduction of positive symptoms (Reddy, 2012). The mesolimbic and mesocortical pathways are known to be affected in schizophrenia (Perez & Lodge, 2014.; Marsden, 2006). Typical antipsychotics reduce the positive symptoms in schizophrenia, such as delusions and hallucinations and decrease the risk of episode repetition (Chokalwala & Stevens, 2019). The mesocortical pathway controls cognition and attention. Due to hypoactivity, it results in negative and cognitive symptoms of schizophrenia. The levels of dopamine need to be elevated to reduce the negative symptoms such as withdrawal and incongruity (Reddy, 2012, Chokalwala & Stevens, 2019). Unfortunately, typical antipsychotics block dopamine diffusion in the mesocortical pathway as well, which leads to the worsening of these symptoms, which could eventually lead to withdrawal or dysphoria. Atypical antipsychotics are better to some extent at treating this as they treat both positive and negative symptoms while reducing the risk of recurrence (Chokalwala & Stevens, 2019). Thus, if a patient of schizophrenia is acting withdrawn or ambivalent, it could be the insufficient supply of dopamine to the mesocortical pathway as a result of the action of antipsychotics.


The nigrostriatal pathway is responsible for the control of motor movements, and the tuberoinfundibular pathway controls the release of prolactin (Reddy, 2012). Dopamine in the tuberoinfundibular region is in charge of the inhibition of prolactin release (Ayano, 2016). These two pathways remain unaffected due to schizophrenia and other psychosis, but due to the antipsychotic drugs, their functioning is hampered (Ayano, 2016.; Marsden, 2006). The extrapyramidal side effects of first-generation antipsychotics can be attributed to the blockage of striatal receptors (Ayano, 2016.; Chokalwala & Stevens, 2019). This blockage leads to tremors, stiffness and impairment in motor activities (Ayano, 2016.; Perez & Lodge, 2014). The pituitary gland is responsible for the secretion of prolactin. Dopamine released by the hypothalamus inhibits this secretion. Antipsychotics affect this mechanism by blocking dopamine receptors in the pituitary, which doesn't let the inhibition of prolactin to happen. This results in the condition known as galactorrhea, i.e. inappropriate breast milk production (Ayano, 2016). Second-generation antipsychotics are better at managing these symptoms, but they still cause other side effects such as weight gain, dizziness, migraine and development of metabolic syndromes (Perez & Lodge, 2014).


Antipsychotics have been used as an effective treatment for several psychotic illnesses for a long time (Reddy, 2012). They work effectively in providing some relief to the patients, but they aren't without flaws and have some slight to severe side effects. Understanding the cause behind these side effects could facilitate better insight into the patient’s condition. The patients could be made aware of the impending difficulties in a nobler way. At the same time, knowing the root cause of the problem and the action area can instigate further pharmacological research. The research can be more goal-directed and work towards the betterment of these antipsychotics by reducing the side-effects and improving their effectiveness.



References:

Finkel, R., Clark, M. A., & Cubeddu, L. X. (Eds.). (2009). Pharmacology: Lippincott's Illustrated Reviews. Lippincott Williams & Wilkins.

Hippius, H. (1989). The history of clozapine. Psychopharmacology.

Chokhawala, K., & Stevens, L. (2019). Antipsychotic Medications. In StatPearls [Internet]. StatPearls Publishing.

Speed, N. K. (2010). The role of insulin signaling on dopamine transporter trafficking (Doctoral dissertation, Vanderbilt University).

Ayano, G. (2016). Dopamine: receptors, functions, synthesis, pathways, locations and mental disorders: review of literatures. J Ment Disord Treat2(120), 2.

Reddy, V. P. (2012). Translational PKPD Modelling in Schizophrenia: Linking Receptor Occupancy of Antipsychotics to Efficacy and Safety. University Library Groningen][Host].

Perez, S. M., & Lodge, D. J. (2014). New approaches to the management of schizophrenia: focus on aberrant hippocampal drive of dopamine pathways. Drug design, development and therapy8, 887.

Marsden, C. A. (2006). Dopamine: the rewarding years. British journal of pharmacology147(S1), S136-S144.



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