Antipsychotics were discovered in the 1950s. This first-generation class of antipsychotics are known as classical or typical antipsychotics. Atypical antipsychotics were discovered in the 1960s. Introduction of antipsychotics into psychiatric treatment was revolutionary and largely replaced riskier, less ethical treatments used at the time for psychotic disorders such as Electroconvulsive therapy and lobotomy (Ramachandraiah et al. 2009). They have a mechanistic mode of action which strongly supports the theory of psychosis having a biological substrate rather than cognitive and work by reducing the action of specific neurotransmitters. Furthermore, the effectiveness of antipsychotics supported the case for biological underpinnings of schizophrenia and challenged popular theories of the time; helping put to rest dominant unscientific theories such as laying blame for the condition on mothers due to alleged child rearing inadequacies (Harrington, A. 2012).

It wasn’t until the late 1960s and 1970s that the underlying biological effects of these drugs were revealed. Initially with typical antipsychotics, which were found to work upon D2 dopamine receptors. Thus, psychosis became increasingly attributed to abnormal dopamine flux (Bowling, H. & Santini, E. 2016). Further discoveries included atypical antipsychotics which differ in that they not only reduce positive symptoms, but unlike typical antipsychotics, they can reduce negative symptoms too. A number of subsequent antipsychotics discovered worked on a multitude of other receptors and neurotransmitters proving that it is more than just the dopamine system that influences psychotic symptoms at a biological level.

Unlike many other breakthrough drugs which had accidental discoveries, antipsychotics for the most part were discovered through deliberation. A method generating many novel antipsychotics as well as furthering insight into the neurological nature of psychosis involved selecting drugs which predictably induced a psychosis-like experience in some individuals. Following this, a drug was developed to counteract its action. The philosophy behind this approach being that if a drug can eliminate the effects of another drug which is known to cause psychosis then it may act as a standalone antipsychotic.

Haloperidol was the first antipsychotic to be discovered in this way. It was observed by Paul Jenson that professional cyclists using amphetamines to boost performance capacity were frequently subjected to psychotic episodes. Haloperidol was discovered by him in 1958 to effectively block the action of amphetamine.

Psychedelic drugs were thought to emulate psychosis and target serotonin modulation in synapses. The same methodology for haloperidol discovery was used to find drugs to block the effects of psychedelics. LSD experimentation in this way gave rise to the discovery of risperidone.

Ketamine was another psychoactive drug believed to simulate psychosis with even greater precision than the aforementioned drugs. It works on a different neurotransmitter: Glutamate. Thus, it followed that much research effort went into finding drugs to block the action of ketamine. Unfortunately, the drugs which emerged from this route, namely Bitopertin and LY-023 did not significantly reduce psychosis symptoms in research trials thus far.

Cannabis contains two main psychoactive compounds. THC: a proven psychosis inducing molecule and CBD which to some extent counteracts the effect of THC. CBD in research experiments was proven to not only reduce a variety of psychosis indicators in volunteers that had been administered THC. It was also shown to have antipsychotic effects as a standalone drug which were shown to be comparable in efficacy to Amisulpride am effective antipsychotic already on the market for psychosis and schizophrenia treatment. THC and CBD work on the CB1 receptor, with the latter also binding to other cellular components and receptors, which has added to the complexity in understanding of the underlying biological substrate of psychosis.

The most popular model for positive symptoms of schizophrenia is biological. The two most significant being the dopamine and the glutamate theories. These are easily verified by inducing psychotic symptoms in animal test subjects, using amphetamine or cocaine to elevate dopamine levels or antagonizing NMDA glutamate receptors with phencyclidine or MK-801. The negative symptoms of psychosis are however more commonly attributed to cognitive reasons (Bowling, H. & Santini, E. 2016). Furthermore, the fact that withdrawal from antipsychotics is a primary risk factor for psychotic phenotype expression enforces the biological basis moderation by these drugs.

The evidence for correlation between the biological basis for antipsychotics and their cognitive effect is hypothesised to be attributable to reduced salience to abnormal processing of thoughts and perceptions (Kapur S. & Mamo D. 2003).

There is still considerable research required to verify the extent to which biological underpinnings precipitate psychotic symptoms. Antipsychotic drugs have clearly been pivotal in developing the neuro-biological foundation for psychosis. They have advanced our understanding significantly and will undoubtedly continue to do so with current and novel drug development.

 

References:-

Ramachandraiah, C. T., Subramaniam, N., & Tancer, M. (2009). The story of antipsychotics: Past and present. Indian journal of psychiatry, 51(4), 324–326

Anne Harrington (2012). The fall of the schizophrenogenic mother. Vol 379 April 7, 2012

Kapur S, Mamo D. (2003). Half a century of antipsychotics and still a central role for dopamine D2 receptors. Progress in Neuropsychopharmacology & Biological Psychiatry. 2003 Oct;27(7):1081-90.

Heather Bowling & Emanuela Santini (2016). Unlocking the Molecular Mechanisms of Antipsychotics – a New Frontier for Discovery. Biomedical intelligence, Published 11 July 2016, doi:10.4414/smw.2016.14314

Sneader, Walter (2005). Drug discovery : a history (Rev. and updated ed.). Chichester: Wiley. p. 124. ISBN 978-0-471-89979-2. Archived from the original on 2015-12-08