Neurological mechanisms
By Saerom Youn (997569983)

There are many neurological changes that are known to occur in schizophrenic patients, with novel advances in research adding onto the complexity of existing pathways. Neurologic mechanisms behind schizophrenic symptoms can be divided into two large groups: biochemical and structural changes of the brain. The principle model garnering most support from experts of the field explaining the biochemical alterations observed is the dopamine hypothesis. For a more comprehensive understanding of current findings however, roles of other proteins working alongside dopamine in disease mechanism must be discussed. fMRI and other imaging studies elucidated specific areas of the cortex that has shown significant changes in schizophrenic patients, which may be related the cognitive deficits associated with the disease. In addition, possibility in classifying schizophrenia as either neurodegenerative or neurodevelopmental diseases will be discussed.

1.1 Dopamine hypothesis

Dopamine hypothesis is the prevailing model in scientific literature to explain the psychotic symptoms observed in schizophrenic patients. The model states that abnormal hyperactivity in dopaminergic pathways and subsequent signal transduction are responsible for the condition[1]. Dopamine (figure 1) receptor antagonists constituted a large portion of antipsychotics, giving initial support to the theory, and subsequently, many studies using different pharmacologic agents were performed[1] . Although the theory has been postulated for over 20 years, solid support was established only recently using novel neuroimaging tools such as PET and SPECT[2,3]. Note that the hypothesis does not conclude that excessive activation of dopamine is the sole cause of schizophrenia, rather seeing it as one of many synaptic dysfunction resulting in disorder[1]. Other molecules, such as glutamate and serotonin, as well as NMDA receptors, seem to also play a role in psychosis of schizophrenic patients, idea supported by the effectiveness of atypical antipsychotics as treatment[4].
Figure 1. Dopamine chemical structure

The dopamine hypothesis postulates that positive symptoms of schizophrenia are mainly due to excessive activation of D2 receptors, and numerous studies performed gave support[1]. Prolonged usages (in large amounts) of dopamine releasing drugs such as amphetamine and cocaine led to psychotic symptoms indistinguishable from the positive symptoms of schizophrenia[5]. Even Parkinson’s patients, who usually suffer from lack of dopamine in the brain, can be induced such symptoms upon overdose of levodopa, drug enhancing dopamine action[6]. In addition, when schizophrenic patients were challenged with dopamine-like molecule, such as methylphenidate, at a moderate level (not enough to induce to psychotic symptoms in control population), 75% of them experienced increased level of symptoms similar to psychosis[5]. Hence, induction any dopamine-like compounds or ones that enhance dopamine action within the brain in schizophrenic patients can lead to worsened psychosis, illustrating the critical role that dopamine plays in the disease mechanism.
In addition to studies increasing dopamine action, ones testing its decrease were also performed, giving further support to the dopamine hypothesis. Reduction of positive symptoms were observed when dopamine binding onto its receptors (D2 dopamine receptors, particularly) were antagonized using phenothiazines (a group of pharmacologics including variety of antipsychotic drugs)[1]. Furthermore, binding affinity of antipsychotic drugs onto D2 dopamine receptor was inversely proportional to therapeutic dosage[7]. This suggests that dopamine receptor activation is causally related to therapeutic effectiveness[8].
However, evidences opposing this hypothesis have also been shown in a number of studies. Technological advancements made in the field of neuroimaging allowed live visualization of drug action within the brain, showing results which contradicted the proposed therapeutic role of dopamine blocking in schizophrenic patients[2]. For example, patients who have been suffering from psychosis for 10 to 30 years experienced lack of reduction in psychotic symptoms, even with over 90% blockage of D2 receptors using antipsychotic drugs[9]. Although 60-70% blockage of D2 receptors using caripiprazole (antipsychotic drug) on first-episode patients was effective (even at low doses), lack of response in chronic patients still raised concerns for validity of the dopamine hypothesis[9].
Figure 2. D2 receptor antagonist action
Figure 2. D2 receptor antagonist action

Moreover, while modification of dopamine levels using dopamine inhibiting medications occur within minutes, actual improvements in psychotic symptoms does not occur until a few days later6. This time lag between induction of the drug and functional effect may be indicative of the existence of an alternate, indirect mechanism by which dopamine acts through. Discovery of a novel type of antipsychotic drugs, called atypical antipsychotics, supported this idea. These new drugs were determined to be as effective in treating psychotic symptoms as the classic typical antipsychotics, and even more effective in treating the negative symptoms[4]. Strangely, these atypical antipsychotics had weaker binding affinity to dopamine receptors than to receptors of other neurotransmitters, rapidly binding and unbinding the D2 receptors repeatedly[4]. These drugs demonstrated inverse antagonistic binding to serotonin receptors, indicating the possible involvement of serotonergic pathways in schizophrenic psychological deficits, especially in language-related tasks[4]. Similarly, possible role that variety of other neurotransmitters may play have been proposed and studied. Discoveries of various other pathological changes of the brain in schizophrenic patients (ex. density of grey vs. white matter, etc.) have all indicated different pathologies in which schizophrenia can manifest in, other than dopamine[1].
Overall, current literature demands modifications to be made to dopamine hypothesis to reflect the complex neurological pathologies involved, as well as addressing the inconclusive results many studies have illustrated[6]. Although the results of studies using dopamine blocking neuroleptic drugs supported dopamine hypothesis, its effect may be observed from decreasing its symptoms through overall neurological suppression rather than reversing the actual disease mechanism[6]. Mechanisms behind induction of psychosis using stimulants have not yet been elucidated. Since stimulants cause alteration in other neurotransmitter levels aside from dopamine, to attribute development of psychosis solely on changing dopamine level is illogical. While some studies have demonstrated increase in L-dopa intake into striatum in schizophrenic patients, some have not, and presence of increased concentration of dopamine or its receptor in post mortem brain tissues have been inconclusive or negative[10]. Furthermore, dopamine induced behavioural changes in patients (i.e., arousal, stress, attention and movement) have been rarely observed[1]. Comparison between other psychiatrical conditions causing symptoms similar to ones caused by increased dopamine (ex. increased arousal) have not been made[6]. Hence, attributing psychotic symptoms or schizophrenia solely to hyperactivation of dopamine is no longer supported by current data.

1.2 Serotonin

Traditional antipsychotic drug chosen to treat schizophrenic patients were mainly dopamine receptor antagonists except for one—an atypical neuroleptic called clozapine[11]. This new class of medication is involved antagonization of not only the dopamine receptors (especially D4), but serotonin receptors as well, leading to antipsychotic outcome[4]. Furthermore, both typical and atypical antipsychotics had high affinity to serotonin receptor[4]. As a result, possible involvement of neurotransmitter serotonin (5-HT) in producing the negative symptoms of schizophrenia was derived. In addition, many hallucinogenic agents such as indolamine and phenethylamine act on serotonin receptors, indicated that hallucinations caused by schizophrenia may also work through related mechanism[11]. Further research went onto study the role of serotonin in development of schizophrenia.
Studies showed that changes in sensitivity of serotonin receptors were consistent in response to neuroendocrine challenges[12]. Specific symptoms shown in schizophrenic patients were associated with certain changes in the serotonergic system, indicating the existence of a correlation[12]. Moreover, neuroleptics used to treat the negative symptoms of schizophrenia, or resistant schizophrenia, were inferior in efficacy to serotonin receptor antagonists in new antipsychotics[4]. The critical role of serotonin regulating the dopaminergic system in vivo was supported through in vivo human and animal studies using various pharmacologics, including atypical antipsychotics[12].

1.3 Glutamate and NMDA receptor

Link between symptoms of schizophrenia and reduced number of NMDA receptors in specific glutamate pathways have recently been extensively studied to elucidate the role of glutamate in production of schizophrenic symptoms[1]. Low number of NMDA receptors found in post mortem brains of schizophrenic patients and effectiveness of glutamate antagonists in mimicking schizophrenic symptoms (ex. cognitive deficits) indicate that low activation of NMDA receptors lead to pathologies shown in schizophrenic patients[13]. Current literature states that role of glutamate may be responsible for negative, affective and cognitive symptoms of schizophrenia due to hypoactivation of mesocortical dopaminergic pathway[13]. This can result from elimination of tonic excitation by decreasing action of NMDA receptor in cortex-brainstem projections[14]. Positive symptoms can be attributed to the increase in activity of mesolimbic dopaminergic pathway resulting from hypoactivated NMDA receptor, which is in accordance with the dopamine hypothesis, resulting in lack of regulation of dopamine levels[14].

2.1 Structural changes in the brain

Technological advancements in the field of neuroimaging led to development of variety of imaging tools such as fMRI, DT-MRI, CT, PET, and many more, allowing high resolution images of brain activity to be constructed[9]. Many studies have compared average volumes of various cortical structures between schizophrenic and non schizophrenic patients to try to create a single neuroanatomical profile representative of the condition[15]. However, due to heterogeneity of the disorder, no single model schizophrenic cortical structure could be derived[15]. Neurobiological alterations in brain structures are extremely unique to the individual, and not one structural defect can be found consistently in all patients classified under schizophrenia[15]. Nonetheless, common features seen in majority of patients can be analyzed for possible functional deficits, leading to schizophrenic symptoms[9].

Figure 3. Enlarged ventricles associated with schizophrenia
Figure 3. Enlarged ventricles associated with schizophrenia

In children with the rare child-onset schizophrenia (onset before 13 years of age), volume of grey matter loss which occurs in normal individuals from back to front of the head over several years, are exaggerated[16]. However, majority of neuronal mass lost is being attributed to loss of glial cells, vasculature, or neuropils rather than actual neurons[16]. Differences in volumes of frontal lobe and ventricles were noted in some, but not all, studies[9]. Comparison between control and first onset patients gave consistent results (less grey matter; bigger ventricular volume in patients)[16]. However, since grey matter volume is impacted by environmental factors (ex. drugs, nutrition, etc.), and since the two volumes (grey matter and ventricular volume) are correlated, exact role of the disorder remains uncertain[16]. Furthermore, ventricular volume is naturally extremely variable and is influenced heavily by external factors, making the differences in volume between control and experimental group insignificant in light of normal variation[9].

Figure 4. Loss of grey matter in schizophrenia patients
Figure 4. Loss of grey matter in schizophrenia patients

In first onset schizophrenic patients, brain regions which show structural abnormalities are the anterior cingulate cortex (ACC), prefrontal cortex (PFC), and the temporal cortex[17]. Hippocampus, medial prefrontal cortex (MPFC) and the amygdale were found to be associated with positive symptoms, while negative symptoms were related to ventral striatum and ventrolateral prefrontal cortex[17]. In addition, reduction of left superior temporal gyrus and left medial temporal lobe volume was observed in most schizophrenic studies, while half of them reported deficits in frontal gyrus, temporal gyrus and parahippocampal gyrus[16]. Deficits in PFC and DLPFC is related to cognitive dysfunction, leading to deficits in working memory and attention[18]. Disruptions in medial cortical structures such as the MPFC and ACC can lead to deficits in social cognition, as well sense of self[18].
These losses in grey matter are usually due to excessive activation of dopamine which can lead to neuronal cell death[19]. Reduction in mitochondrial cytochrome-C oxidase activity shown in schizophrenic patients can be related to inhibition of mitochondrial respiration caused by dopamine[19,20]. Depleting sources of energy can lead to decreased action of dopamine transporter, allowing dopamine to linger in the synapse longer[20]. Moreover, catabolism of dopamine by monoamine oxidase (MAO) leads to generation of hydrogen peroxide, which links to non bound iron molecules, worsening the cellular oxidative stress[20]. Fortunately, atrophy of grey matter can be lessened upon treatments using neuroleptics or antipsychotics[21].

3.1 Neurodevelopmental hypothesis

Schizophrenia is sometimes referred to as a collection of neurodevelopmental disorders due to changes in neural circuits observed over the lifetime of an individual[22]. Damages as early as late first trimester in utero can set up triggering of pathological neuronal networks during young adulthood[22]. Shifting volumes of grey matter and ventricles in accordance to progression of the disease lends support to this idea[10].
Neurodevelopmental aspect also comes into play when discussing the characteristic facial morphology of schizophrenic patients. Early brain dysmorphogenesis are often reflected onto facial dysmorphogenesis[23]. Recent development of 3D MRI morphometric techniques allowed study of facial deviations in schizophrenic patients compared to control. Lips, mouth and chin were pushed back, appearing much narrower[23]. Wider mandible, upper portion of face, and basis of skull were observed with shortened, wider palate[23]. The patients also showed low forehead with elongated middle and lower portion of face, fuller lips, smaller nose, with more laterally placed eyes and cheeks[23]. Cerebral changes occurring during fetal development of schizophrenic patients are expressed externally, shaping into this particular facial morphology[24].
Skull shape was described by various authors as brachichephalic (flat headed)[23]. Prominent abnormalities of the brain (temporal and frontal cortices), decreased grey matter volume, increase in volume of brain chambers with increased CSF were all reflected as morphometric changes of the cranium[24].

3.2 Neurodegenerative hypothesis

Schizophrenia is often regarded as a neurodegenerative disease due to neuroimaging studies indicating progressive atrophy of select cortical regions, and subsequent loss of neuronal function[20,23]. Neurodegenerative theory of schizophrenia proposes that progression of symptoms is from continued loss of neuronal function in specific regions of the brain due to death of neurons, loss of dendrites or destruction of synapses[23]. Causes of this progressive loss can be due to variety of factors: genetically programmed, in utero exposure to infections, anoxia, malnutrition or toxins, dopamine-mediated or even excytotoxicity mediated through glutamate, initially resulting in positive symptoms then developing into negative symptoms upon death of neurons[23]. Excytotoxic hypothesis postulates that neurodegeneration is caused by excessive transmission of excitatory transmitter glutamate[25]. Excytotoxicity is observed not only in schizophrenia, but various other neurological conditions such as Parkinson’s, Alzheimer’s, ALS (amyotrophic lateral sclerosis), and even stroke[25].

Schizophrenia focused research program in Canada:
Schizophrenia Society of Canada:


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