Neurochemical Theories of Schizophrenia and the Mechanism of Action of Haloperidol and Clozapine

PSYCHOPHARMACOLOGY
Name:
Institution:
Date:

Introduction
Schizophrenia is classified as a mental illness and distinguished by incomprehensible or
unreasonable thoughts, peculiar behaviour and articulation, and mistaken impression or
hallucinations, which can be visual or auditory. Schizophrenia is thought to be a
neurodevelopmental disorder meaning that functional and structural changes can be seen before
birth, develop during childhood or adolescent, or both. Schizophrenia patients experience
symptoms that are classified into four groups: positive symptoms (psychotic symptoms),
negative symptoms, cognitive symptoms, and emotional symptoms. Neurochemical theories that
will be discussed in this essay explain how different neurotransmitters relate to the symptoms
experienced by schizophrenia. The three neurochemical proposed that explain the genesis of
schizophrenia are dopamine theory, glutamate theory, and serotonin theory. The mechanism of
action of two drugs that are used to treat schizophrenia is linked to the neurotransmitters by
increasing or decreasing their levels in the brain is discussed in this essay.
Dopamine theory
The dopamine theory of schizophrenia proposed is fundamental and vital towards the
understanding of the major proportions of schizophrenia such as positive and negative symptoms
(social withdraw, emotional blunting) and cognitive impairment (Katzung, Masters & Trevor,
2012). The original theory stated that there was increased activity in dopamine transmission
resulting into symptoms of schizophrenia and that drugs blocking dopamine reduced psychotic
symptoms. Dopamine is synthesised from tyrosine an amino acid through the action of two
enzymes. First tyrosine is converted into DOPA by the enzyme tyrosine hydroxylase, and then
DOPA is converted by the enzyme DOPA decarboxylase into dopamine (Alexander et al. 2013).
Dopamine is packed and stored into the vesicular monoamine transporter and stored until when it

is released into the synapse. The step requiring tyrosine hydroxylase is the rate rate-limiting step
in the production of dopamine, and it is found to be increased significantly in patients with
schizophrenia compared to normal individuals. Dopamine plays several pivotal roles in emotion,
movement, and cognition as a chemical in the brain (Schneider et al. 2017).
Evidence suggests increased dopamine activity in the brain results in aggravated
psychosis of schizophrenia or produces in some patient’s psychosis through the de novo process..
The observations that form the cornerstone of this theory is that drugs which block the D2
receptors lower the symptoms of psychosis and agonists of dopamine worsen the symptoms
(Gross, Wicke & Drescher, 2013). The density of dopamine receptors has been found to be
elevated in the brain of schizophrenic patients who were not using drugs recommended for
schizophrenia. Drugs that mediate blockage of neural storage of dopamine and dopamine
antagonists are useful in the management of the positive symptoms seen in patients with
schizophrenia. The theory further suggests that negative and cognitive symptoms present in
schizophrenic patients can be linked to lower functioning of the dopamine receptor (D1)
prefrontal cortex neurotransmission. In recent studies that have been done, there is reported
increased presynaptic synthesis capacity in patients with schizophrenia. Evidence also shows that
if synthesis of dopamine is elevated and in the face of challenges it is more sensitive to release, it
is expected that dopamine levels would be increased when the patients are psychotic (Howes et
al. 2017).
Glutamate theory
There are several excitatory neurotransmitters of the glutamate is the major one and acts
on ionotropic N-methyl-D-aspartate (NMDA) receptors in the brain of normal human beings.
The glutamate theory is based on the fact that by administering non-competitive antagonists to

NMDA receptors can induce neuropsychological and a behavioral effects in healthy people
which is similar to schizophrenia and can significantly elevate symptoms of psychosis in patients
who are schizophrenic (Yizhar et al. 2011). Due to the widespread of NMDA receptors in the
whole of the brain, the models of glutamate predict an extensive dysfunction of the cortex. The
theory suggests that one of the main repercussion of NMDA receptor lowered function is
elevated downstream release of glutamate in target areas through the blockage of GABAergic
interneurons, which are specifically sensitive to the interference effects of NMDA antagonism
(Price et al. 2014). Brain circuits regulating release of dopamine also have NMDA receptors an
indication that inadequacy of dopamine in schizophrenia may be as a result of underlying
glutamatergic dysfunction. There is a strong indication that NMDA receptors play key roles in
schizophrenia and psychosis by the evident changes in the glutamatergic metabolism and
transmission affecting regional neuronal integrity meaning it could be related to morphological
changes in brain and symptoms in schizophrenia patients (Matthysse & Kety, 2015).
Glutamate has contributory effects to development of the brain during the prenatal and
childhood period and glutamates major significance during the maturation of individuals is in
learning and memory. It is primarily important in long term potentiation that is required for
retention of new information or skills for later use, and glutamate is responsible for eighty per
cent of the energy consumed by the brain and participates in behaviour and emotion processes.
The schizophrenia disorder involves several areas of the brain that are joined by a circuit of brain
cells that depend on glutamate for communication. Evidence implies that insufficient or excess
activity of glutamate may partially cause symptoms by interacting with other neurotransmitters
such as gamma-aminobutyric acid (GABA) and dopamine. Through new research, the theory