Schizophrenia

Question 1

Introduction

Answer 1

With a lifetime risk of 1%, schizophrenia constitutes an extremely debilitating psychiatric disorder associated with high mortality rates, alongside immense societal and economic burdens of £16.7 billion annually.
The pathophysiology of schizophrenia remains unclear, with immense debate as to whether dysfunction lies within the dopaminergic or the glutamatergic system.
Whilst the dopamine theory was first explored over 50 years ago, fixation on the dopamine system led to a stagnation in therapeutics development.
An improved knowledge of the neurobiology is paramount for developing targeted therapies alongside prophylactics to alleviate the immense cost of the condition, not only on the sufferer but society as a whole.

Question 2

Paragraph 1 - DA hypothesis

Formulation

Answer 2

The dopamine (DA) hypothesis was formulated following indirect observations that DA-increasing compounds i.e. amphetamine induced psychotic symptoms, while DA depleting compounds e.g. reserpine reduced psychosis.

Question 3

Paragraph 1 - DA hypothesis
Crystallisation
Seeman et al (1970s)

Answer 3

The DA theory was finally crystallised in the 1970s when Seeman et al illustrated a direct correlation between clinical dose of antipsychotics (APs) and the affinity for the D2 receptor. In spite of this, several limitations such as the effect of reserpine and amphetamines on additional monoamines alongside the locus of DA dysfunction needed to be addressed.

Question 4

Paragraph 1 - DA hypothesis

Kaalund et al (2014)

Answer 4

Given that all clinically available APs block D2R, research has focussed on elucidating whether D2R availability is altered or if dysfunction occurs earlier in neurotransmission.
Kaalund et al (2014) analysed post mortem samples and demonstrated that the expression of presynaptic D2 autoreceptors was increased by genotype expression studies of D2 related SNPs.

Question 5

Paragraph 1 - DA hypothesis

Schizophrenia Working Group

Answer 5

The implication of altered D2Rs is also corroborated by advances in genetic analysis; in 2014 the Schizophrenia Working Group conducted a GWAS identifying 108 schizophrenia associated loci, within which the DRD2 gene was strongly implicated.

Question 6

Paragraph 1 - DA hypothesis

Answer 6

Nonetheless evidence from living patients is critical since post-mortem studies are limited given the difficulty in controlling for the confounding effects of APs, alongside the inability to link changes in symptom expression with the development of the disorder. Advances in PET/SPECT imaging have enabled refinement of the DA theory. A meta-analysis of studies using radioligand imaging by Howes et al (2012) found no difference in D2R density in patients who had not undergone AP treatment cf. controls, suggesting that D2R changes result from APs which induce their upregulation, rather than a direct result of disease.