Dopamine hypothesis of schizophrenia

Question 1

Write an introduction to antipsychotics

Answer 1

• The emergence of antipsychotic drugs has transformed the lives of many people afflicted with schizophrenia and related conditions.
• Once a condition contained within asylums, the discovery of treatment options for psychosis now allows patients to be discharged to their homes (Garrett, 2015).
• Pharmacotherapy is the current primary treatment, having well-established evidence for use in acute psychosis and relapse prevention (NICE, 2014).
• Medication is beneficial to positive symptoms, however only 14-20% fully recover as negative symptoms typically remain problematic (NICE, 2014).
• This essay will discuss the biological basis of schizophrenia, mechanisms of antipsychotics, and newer research, in the hopes of providing direction for development of improved antipsychotics.

Question 2

Outline schizophrenia, its treatment, and the dopamine hypothesis

Answer 2

• Schizophrenia is a severe psychosis-related mental illness characterised by positive symptoms of hallucinations, delusions, and thought disorder; plus negative/cognitive symptoms including apathy, psychomotor retardation, poverty of speech, and social withdrawal (NICE, 2014)
• Early first-generation antipsychotics (FGAs) such as Chlorpromazine and Haloperidol were greatly successful at the time, however their mechanisms of actions were unknown (Garrett, 2015).
• Drug-induced psychosis provided insight into a biological basis with amphetamines, cocaine, and methylphenidate mirroring the positive symptoms of schizophrenia (Young, 2019).
• Researchers discovered these drugs increased dopaminergic activity, which led to the dopamine hypothesis (Laruelle et al., 1996).
• This stated that schizophrenia involves excessive dopaminergic activity in the brain (Garrett, 2015).

Question 3

Briefly outline evidence supporting the dopamine hypothesis of schizophrenia

Answer 3

• It is now known that Chlorpromazine and Haloperidol are pure D2 receptor antagonists (Young, 2019), further supporting the dopamine hypothesis.
• Furthermore, some evidence exists that schizophrenics possess more D2 receptors.
• However, later reviews deem this unlikely to be the primary cause of schizophrenia (Stone et al., 2007).

Question 4

Discuss FGAs, SGAs, and Clozapine

Answer 4

• Drug development has since produced second-generation antipsychotics (SGAs) that avoid the pitfall of extrapyramidal symptoms in FGAs.
• Their mechanisms largely involve D2 blockade, with additional interactions with serotonin (5HT), histamine, and/or noradrenaline (NA) receptors (Young, 2019).
• Yet, evidence suggsts their antipsychotic efficacies are remarkably similar to FGAs to the point both are equally considered as first-line treatment (NICE, 2014).
• D2 blockade provides significant improvment to positive symptoms (NICE 2014), with some SGAs having additional effects on negative/cognitive symptoms.
• Clozapine is the only drug licenced for treatment-resistant schizophrenia, a SGA also affecting negative/cognitive symptoms (NICE, 2014).
• Contrary to the simple mechanism of Chlorpromazine and Haloperidol, Clozapine has a relatively low affinity for D2 receptors, and a stronger affinity for D4 and 5HT receptors, also targeting a variety of different receptors (NICE, 2014).
• Currently, it is unknown which of these is responsible for the superior antidepressant effects of clozapine (NICE, 2014).
• It also introduces questions into the dopamine hypothesis, and whether the pursuit of D2 antagonism should be continued for newer drug development.

Question 5

How do the drugs phencycladine, ketamine, and LSD relate to schizophrenia?

Answer 5

• Other drugs such as Phencyclidine, Ketamine, and LSD produce effects similar to schizophrenia.
• Phencyclidine and Ketamine are NMDA glutamate receptor antagonists that mimic positive, negative, and cognitive symptoms (psychotomimetic).
• LSD is a 5HT receptor agonist known for hallucinogenic properties (Young, 2019)

Question 6

Is there a serotonin hypothesis of schizophrenia?

Answer 6

• A serotonin hypothesis of schizophrenia is difficult to assess.
• The neurotransmitter has widespread interactions with all other neurotransmitter systems in the brain.
• Its biochemical changed in schizophrenia remain unknown (Young, 2019).

Question 7

Discuss the evidence for a glutamate hypothesis of schizophrenia

Answer 7

• Fortunately, a glutamate hypothesis has substantially more evidence and may be a bette target due to its blockade completely mimicking schizophrenic symptomology.
• Neuroanatomical studies have implicated two separate pathways for explaining positive and negative/cognitive symptoms as distinct entities (Carlson, 2010).
• Findings implicate mesocortical hypoactivity causes negative/cognitive symptoms.
• NMDA antagonism induces prefrontal hypoactivity and has been associated with mesolimbic hyperactivity (Carlson, 2010).

Question 8

Outline a unified glutamate hypothesis for schizophrenia

Answer 8

• A unified biochemical hypothesis for schizophrenia is as follows:
• Prefrontal hypoactivity creates a core deficit in cortical glutamate systems projecting to the ventral tegmental area (VTA).
• This reduces dopaminergic neurone activity within the mesocortical pathway,
• Also reduces GABAergic neurone activity within the VTA leading to disinhibition of the mesolimbic dopaminergic neurones (Carr & Sesack, 2002).
• Therefore, producing a model underlying both positive and negative/cognitive symptoms of schizophrenia.

Question 9

Discuss the problems of implementing glutamate-based treatments

Answer 9

• However, developing treatment based on this revolutionary glutamate research is still in its preliminary stages.
• Further research is required to fully develop our understanding of the role of glutamate in schizophrenia (Moghaddam & Javitt, 2012).
• This is complicated by the fact glutamate cannot be directly administered due to its key role in initiating and propagating seizures, and epileptogenesis (Meldrum, 1994).

Question 10

Write a conclusion

Answer 10

• In conclusion, current antipsychotics have greatly changed the management of schizophrenia since their discovery.
• The primary mechanism of action is D2 antagonism to prevent excess mesolimbic dopamine thought to underlie the disorder.
• Despite these drugs, only 14-20% of service users fully recovery due to lasting negative/cognitive symptoms.
• Newer research provides strong evidence for a glutamate hypothesis originating from research into ketamine-induced psychosis mirroring the complete symptomology.
• NMDA receptor antagonism provides direction for schizophrenia research that could revolutionise its management once again.
• Yet, this is still in its early stages as knowledge gaps exist and glutamate itself is known to induce seizures, meaning indirect glutamate agonism may be the future of treatment.