In this discussion, we will go over the dopamine hypotheses of schizophrenia, the pathophysiology of schizophrenia, other hypotheses of schizophrenia, and the mechanism of action of antipsychotics
Review of Schizophrenia
The subtypes of schizophrenia are paranoid, disorganized, and catatonic. It affects roughly 1% of the population worldwide, and its onset usually begins during late adolescence.
Genetics plays an important component. A study showed that monozygotic twins and children of two patients with schizophrenia have a 40-50% chance of developing schizophrenia.
Schizophrenia presentations comprised of positive symptoms, negative symptoms, cognitive symptoms, and mood disturbances. This leads to an impact on social and occupational dysfunction. 10% of these patients will have complete suicide, which is the highest after bipolar disorder and MDD.
If you would like more review, please check out CNS 22 post.
Dopamine Hypothesis of Schizophrenia
There are multiple improvements that have been made to the original dopamine hypothesis now. But, this began back in 1963 when Carlsson and Lindqvist studied the mechanism of chlorpromazine and haloperidol mechanism of action. These are dopamine-blocking medications. They notice that these medications improve psychosis. They also noted that amphetamine induces psychosis. This leads to a hypothesis that patients with schizophrenia have too many neurons that release dopamine.
A second modification to this hypothesis came out in 1991. The modified version added region-specificity data that was derived from post-mortem data and imaging data. They noted the hypo-dopaminergic activity in the cortex dopamine pathway and hyper-dopaminergic activity in the mesolimbic dopamine pathway. The hyper-dopaminergic activity in the mesolimbic dopamine pathway induces a huge excess of dopamine (DA) into the nucleus accumbens, leading to the development of positive symptoms. The decreased dopamine activity in the cortex means less dopamine being released to innervate the prefrontal cortex, leading to more negative symptoms.
A third modification to this hypothesis came out in 2009. In this version, there are four distinctive components:
- Multiple hits interaction to result in dopamine dysregulation.
- The locus of DA dysregulation moves from the postsynaptic D2 receptor to the presynaptic DA terminal.
- DA dysregulation is linked to psychosis rather than schizophrenia.
- DA dysregulation is hypothesized to alter the appraisal stimuli through aberrant salience.
This suggested that DA dysfunction may contribute to misattribution of salience involving both rewarding and aversive signaling.
Schizophrenia Pathophysiology
MRI studies show that patients with schizophrenia have cerebral atrophy in certain parts. These are especially prominent in the basal ganglia, prefrontal cortices, and hippocampus. Patients with schizophrenia also seem to have enlarged lateral ventricles.
The DA alteration pathway starts with an increase in DA synthesis and release capacity in the striatum. This leads to higher resting levels of DA. The impact of this is seen in the increase in D2 receptors in the basal ganglia, nucleus accumbens, and substantia nigra. Due to this, the DA release capacity is compensated in the prefrontal cortex through the decrease in DA release capacity in the prefrontal cortex.
Human post-mortem brain study in schizophrenia that studied the amount of tyrosine hydroxylase and serotonin transporter in the prefrontal cortex through the use of antibodies demonstrated that there is a dramatic reduction in tyrosine hydroxylase in patients with schizophrenia, which supports the DA hypofunction hypothesis in the prefrontal region. This reduction is specific to the DA system because there is no change in the number of the serotonin transporter.
A grey matter study demonstrated that patients with schizophrenia have dramatic grey matter loss in certain regions, such as the parietal, and occipital.
Another human post-mortem brain study also demonstrated that there is a reduction in the volume of certain brain areas as a result of a diminished number of cells, smaller somas, reduced dendritic trees, and dendritic spine density in patients with schizophrenia. Cells are also more disorganized in these patients compared to healthy controls.
An MRI hippocampus study displayed a smaller volume of hippocampus in patients with schizophrenia, which suggests decreased neuronal size and cell density.
The dorsal-lateral prefrontal cortex also experiences alteration as well. It has been shown that a damage or loss of neurons can cause a lack of initiation, cognitive, flexibility, inability to shift attention, and poor self-care. These deficits are consistent with the negative symptoms of schizophrenia.
The inability to shift attention and hypoactivity of the frontal lobes can be tested with the Wisconsin Card Sorting Test. Patients with schizophrenia cannot shift their strategy and will continue to sort cards according to the original strategy.
A glucose uptake study demonstrates that the brains of patients with schizophrenia are a lot less active during the card sorting test when compared with a healthy individual.
A gene expression profiling study using DNA microarray looked at a number of genes. In patients with schizophrenia, there is a decrease in the expression of genes that are responsible for the presynaptic secretory machinery, synaptic vesicles, glutamate, and GABA.
Another human post-mortem brain study using in-situ hybridization noticed a reduction in GABA uptake in the prefrontal cortex of patients with schizophrenia. This contributes to prefrontal cortical dysfunction.
Another in-situ hybridization study looked at the level of cholecystokinin and somatostatin. Patients with schizophrenia have a decrease in both.
Stages of Schizophrenia
- Early stage: this is when the first hits happen where genetic predisposition causes an alteration of gene expression. When this happens in conjunction with environmental insults, such as virus, toxin, birth complications, or activated immune system, it leads to an abnormality in neuro-development that can occur from conception to early adulthood. This results in neuronal disorganization and synaptic pruning and cell death.
- Latent stage: this is where symptoms are starting to occur, but are not that noticeable. These are motor abnormalities, social withdrawal, and deficits in attentional processing tasks.
- Late stage: This is where the positive, negative, and cognitive problems manifest themselves.
Neurodevelopmental Hypothesis
This hypothesis involves certain pathology. It relies on the fact that there is an increase in neuronal density in certain brain regions, smaller cell sizes, and decreased synaptic spine density of certain neurons.
There was a study done on pyramidal dendrites. Patients with schizophrenia have a dramatic loss and reduction in the number of dendritic spines on the prefrontal cortical pyramidal neurons.
Neurodevelopmental Hypothesis Explanation
Prenatal insult and environmental insult affect brain development in the early stages. Combined with genetic or epigenetic impairment, this leads to a malformation of the neuro-pathway.
During early adolescence, there is a reorganization of the cortical network that induces certain vulnerabilities by increasing high-frequency oscillation. This leads to a transient de-stability of the neuronal network. Synaptic pruning and problem with GABA and dopamine are the results.
In late adolescence and early adulthood, there is a large-scale disintegration and the saturation process where the network fails to work causing psychotic symptoms.
This hypothesis relied on the fact that synaptic contact is less active. Since pruning depends on the synaptic activity, less active synaptic are more susceptible to pruning. Since patients with schizophrenia have less active synaptic, there are more pruning in these patients. This results in the loss of essential synaptic.
This theory doesn’t have a lot of support yet.
Glutamate Theory
This theory revolves around psychosis induction. We know that PCP induces psychosis, and that PCP blocks the NMDA receptors (glutamate.) Schizophrenia may be a disorder of NMDA hypo-functioning or inhibition.
NMDA receptors are located on the GABA neuron in the cortex. If the NMDA receptors of the Chandelier cell are hypo-active as stated in this theory, GABA neurons cannot be stimulated properly. This results in a reduction in GABA released onto glutamate neurons the in the prefrontal cortex This disinhibition of GABA neurons leads to an increase in glutamate release.
A study has shown that EEAT1 and EAAT2, which are excitatory amino acid transporters decreased in mediodorsal and ventral thalamus in patients with schizophrenia.
Serotonin in Schizophrenia
This is not a hypothesis or theory.
Serotonin plays a role in schizophrenia. Psychosis can be a result of the hyper-activation of serotonin 5-HT2A. Due to the excess serotonin and up-regulation of the receptor, it leads to the downstream release of glutamate into the ventral tegmental. THis activates the mesolimbic pathway, which is responsible for the excess DA in the ventral striatum.