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Causes of schizophrenia
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Causes of schizophrenia
The causes of schizophrenia that underlie the development of schizophrenia, a psychiatric disorder, are complex and not clearly understood. A number of hypotheses including the dopamine hypothesis, and the glutamate hypothesis have been put forward in an attempt to explain the link between altered brain function and the symptoms and development of schizophrenia.
The exact pathophysiology of schizophrenia remains poorly understood. The most commonly supported theories are the dopamine hypothesis and the glutamate hypothesis. Other theories include the specific dysfunction of interneurons, abnormalities in the immune system, abnormalities in myelination, and oxidative stress.
The first formulations of the dopamine hypothesis of schizophrenia came from post-mortem studies finding increased numbers of D2/D3 receptors in the striatum, and elevated cerebrospinal fluid levels of dopamine metabolites. Subsequently, most antipsychotics were found to have affinity for D2 receptors. Later investigations have suggested a link between striatal dopamine synthesis and positive symptoms, as well as increased dopamine transmission in subcortical regions, and decreased transmission in cortical regions.
A meta-analysis of molecular imaging studies observed increased presynaptic indicators of dopamine function, but no difference in the availability of dopamine transporters or dopamine D2/D3 receptors. Both studies using radio labeled L-DOPA, an indicator of dopamine synthesis, and studies using amphetamine release challenges observed significant differences between those with schizophrenia and control. These findings were interpreted as increased synthesis of dopamine, and increased release of dopamine respectively. These findings were localized to the striatum, and were noted to be limited by the quality of studies used. A large degree of inconsistency has been observed in D2/D3 receptor binding, although a small but nonsignificant reduction in thalamic availability has been found. The inconsistent findings with respect to receptor expression has been emphasized as not precluding dysfunction in dopamine receptors, as many factors such as regional heterogeneity and medication status may lead to variable findings. When combined with findings in presynaptic dopamine function, most evidence suggests dysregulation of dopamine in schizophrenia.
Exactly how dopamine dysregulation can contribute to schizophrenia symptoms remains unclear. Some studies have suggested that disruption of the auditory thalamocortical projections give rise to hallucinations, while dysregulated corticostriatal circuitry and reward circuitry in the form of aberrant salience can give rise to delusions. Decreased inhibitory dopamine signals in the thalamus have been hypothesized to result in reduced sensory gating, and excessive activity in excitatory inputs into the cortex.
One hypothesis linking delusions in schizophrenia to dopamine suggests that unstable representation of expectations in prefrontal neurons occurs in psychotic states due to insufficient D1 and NMDA receptor stimulation. This, when combined with hyperactivity of expectations to modification by salient stimuli is thought to lead to improper formation of beliefs.
Beside the dopamine hypothesis, interest has also focused on the neurotransmitter glutamate and the reduced function of the NMDA glutamate receptor in the pathophysiology of schizophrenia. This has largely been suggested by lower levels of glutamate receptors found in postmortem brains of people previously diagnosed with schizophrenia and the discovery that glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with the condition.
The fact that reduced glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function and that glutamate can affect dopamine function, all of which have been implicated in schizophrenia, have suggested an important mediating (and possibly causal) role of glutamate pathways in schizophrenia. Positive symptoms fail however to respond to glutamatergic medication.
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Causes of schizophrenia
The causes of schizophrenia that underlie the development of schizophrenia, a psychiatric disorder, are complex and not clearly understood. A number of hypotheses including the dopamine hypothesis, and the glutamate hypothesis have been put forward in an attempt to explain the link between altered brain function and the symptoms and development of schizophrenia.
The exact pathophysiology of schizophrenia remains poorly understood. The most commonly supported theories are the dopamine hypothesis and the glutamate hypothesis. Other theories include the specific dysfunction of interneurons, abnormalities in the immune system, abnormalities in myelination, and oxidative stress.
The first formulations of the dopamine hypothesis of schizophrenia came from post-mortem studies finding increased numbers of D2/D3 receptors in the striatum, and elevated cerebrospinal fluid levels of dopamine metabolites. Subsequently, most antipsychotics were found to have affinity for D2 receptors. Later investigations have suggested a link between striatal dopamine synthesis and positive symptoms, as well as increased dopamine transmission in subcortical regions, and decreased transmission in cortical regions.
A meta-analysis of molecular imaging studies observed increased presynaptic indicators of dopamine function, but no difference in the availability of dopamine transporters or dopamine D2/D3 receptors. Both studies using radio labeled L-DOPA, an indicator of dopamine synthesis, and studies using amphetamine release challenges observed significant differences between those with schizophrenia and control. These findings were interpreted as increased synthesis of dopamine, and increased release of dopamine respectively. These findings were localized to the striatum, and were noted to be limited by the quality of studies used. A large degree of inconsistency has been observed in D2/D3 receptor binding, although a small but nonsignificant reduction in thalamic availability has been found. The inconsistent findings with respect to receptor expression has been emphasized as not precluding dysfunction in dopamine receptors, as many factors such as regional heterogeneity and medication status may lead to variable findings. When combined with findings in presynaptic dopamine function, most evidence suggests dysregulation of dopamine in schizophrenia.
Exactly how dopamine dysregulation can contribute to schizophrenia symptoms remains unclear. Some studies have suggested that disruption of the auditory thalamocortical projections give rise to hallucinations, while dysregulated corticostriatal circuitry and reward circuitry in the form of aberrant salience can give rise to delusions. Decreased inhibitory dopamine signals in the thalamus have been hypothesized to result in reduced sensory gating, and excessive activity in excitatory inputs into the cortex.
One hypothesis linking delusions in schizophrenia to dopamine suggests that unstable representation of expectations in prefrontal neurons occurs in psychotic states due to insufficient D1 and NMDA receptor stimulation. This, when combined with hyperactivity of expectations to modification by salient stimuli is thought to lead to improper formation of beliefs.
Beside the dopamine hypothesis, interest has also focused on the neurotransmitter glutamate and the reduced function of the NMDA glutamate receptor in the pathophysiology of schizophrenia. This has largely been suggested by lower levels of glutamate receptors found in postmortem brains of people previously diagnosed with schizophrenia and the discovery that glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with the condition.
The fact that reduced glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function and that glutamate can affect dopamine function, all of which have been implicated in schizophrenia, have suggested an important mediating (and possibly causal) role of glutamate pathways in schizophrenia. Positive symptoms fail however to respond to glutamatergic medication.