SCHIZOPHRENIA AND THE THREE MAJOR THEORIES OF ETIOLOGY

Schizophrenia and the Three Major Theories of Etiology Rhea Byrd George Mason University Abnormal Psychology 15 June 2012

Abstract

SCHIZOPHRENIA: THREE MAJOR THEORIES OF ETIOLOGY

This paper will begin by introducing schizophrenia, it positive and negative symptomatology and common characteristics. The first hypothesis of etiology will be the traditional dopamine hypothesis, which points out the effects of mesolimbic dopamine overabundance and mesocortical dopamine deficiency and their parallel to some of the psychotic symptoms of schizophrenia. The next hypothesis discussed with be the glutamate hypothesis, which suggests that many of the symptoms of psychosis and inadequate regulation of dopamine levels in the brain may be attributed to NMDA receptor hypofunction. The last hypothesis discussed will be the adenosine hypothesis, which suggest that purinergic dysfunction causes a deficiency in the neuromodulator adenosine, which may be responsible for the abnormal levels of dopamine and glutamate in the brain. Current treatments and research implications of possible future treatment research are discussed.

Schizophrenia And The Three Major Theories of Etiology

SCHIZOPHRENIA: THREE MAJOR THEORIES OF ETIOLOGY

Schizophrenia is a severe psychological disorder characterized by disorganization in thought, perception, and behavior. The name Schizophrenia means split-mind, but not in the sense of personality. A split in cognition and affect is apparent in patients with schizophrenia; these individuals do not think in a logical sense, have a distorted perception of the world, and do not behave in a way that permits normal every day life of work. Schizophrenia is a debilitating life long sentence, manifested by an array of negative and positive symptoms, which usually include the common symptoms of psychosis in addition to a disorganization of thought and speech. Positive symptoms are a group of symptoms that are experienced by schizophrenic individuals, but not by the general population. Some examples include disorganized thought and speech, delusions, auditory hallucinations, visual hallucinations, tactile hallucinations, gustatory hallucinations, or olfactory hallucinations. A hallucination is defined by the DSM IV as, A sensory perception that has the compelling sense of reality of a true perception but that occurs without external stimulation of the relevant sensory organ. The most common type of hallucinations are the auditory hallucinations, which usually command the patient to engage in some type of activity. These command hallucinations may be ego-syntonic or ego-dystonic. Ego-syntonic command hallucinations instruct the individual to engage in behaviors of acts that parallel needs and goals, and are consistent with ones self-image. Ego-syntonic command hallucinations are not recorded to be as common as the ego-dystonic hallucinations, which conflict values and a persons ideal self-image. Another commonly experienced positive psychotic symptom of schizophrenia are delusions, which the DSM IV defines as, False beliefs based on incorrect inference about external reality that persist despite evidence to the contrary and these beliefs are not ordinarily accepted by other members of the persons culture or subculture. These delusions may be very bizarre,

SCHIZOPHRENIA: THREE MAJOR THEORIES OF ETIOLOGY

non-bizarre, mood congruent, or mood neutral. In addition, these delusions can manifest themselves into certain themes. Some common delusions includes persecutory delusions, in which an individual believes that someone is persecuting them, or that they are a special agent or individual. An individual with this type of delusion may believe that they are an foreign spy, and that the government is attempting to track or locate them for purposes of interrogation, arrest, or execution. Another common delusion experience by schizophrenic individuals is the delusion of control or influence, in which the person believes that other people are controlling ones thoughts or behaviors. The individual may believe that their thoughts are being methodically withdrawn, being broadcast, or that thoughts and ideas are being inserted without the individuals knowledge or consent. There are many different delusional themes, including delusions of reference, delusion of grandeur, erotomanic delusions, and so forth. When engaging in conversation with an untreated schizophrenic, an individual may also note some abnormalities of speech and though production. A schizophrenic may engage in loose associations, in which there is no logical connection between thoughts. Thought blocking may also occur, resulting in long pauses in the speech of the schizophrenic. In an instance of thought blocking, it may seem almost as if the schizophrenic individual is in the process or a cognitive reboot. Another common speech abnormality present in the schizophrenic individual may be clang associations, in which speech appears to be more governed by word that sound alike, rather than theme, narrative, or events. Another, rather interesting characteristic of schizophrenia is catatonia. Catatonia is not present in all cases of schizophrenia, but rather a sub-type of the disorder in addition to the paranoid type, disorganized type, and undifferentiated type. The interesting thing about catatonia is that the individual may be completely non-responsive to external stimuli, despite displaying the

SCHIZOPHRENIA: THREE MAJOR THEORIES OF ETIOLOGY

characteristic of consciousness. This is known as a state of catatonic stupor. In addition, the catatonic individual may exhibit symptoms of wavy flexibility, in which parts of the body will remain frozen in the position that they are placed in by another individual, sometimes for hours on end. Another type of catatonia is a state of catatonic excitement, characterized by a state of purposeless activity due to agitation of excitement. Negative symptoms are characteristics present in people without the disorder, but deficient in schizophrenic individuals. Negative symptoms include blunted affect, anhedonia, avolition, alogia, and asociality. Blunted affect is a lack of emotional reactivity. Individuals with blunted or flattened affect may not reciprocate emotionality to emotion evoking events or news, such as the birth of a baby, a major accomplishment, or the death of a loved one. Anhedonia is the inability to experience pleasure from activities that one would usually find enjoyable. Anhedonia is hypothesized to be caused by a breakdown of the brains dopamine reward system. Ironically, this symptom of schizophrenia may also be caused as a side effect of antipsychotic drugs. Other negative symptom include avolition, a lack of drive or motivation to carry through on meaningful tasks or plans, and alogia, which is the decreased quality and quantity of speech. An individual suffering from alogia may not make any logic or sense when they speak, which can result from frontostriatal dysfunction. Alogia responds better than most other negative symptoms to current medication treatments. Individuals with schizophrenia may also suffer from attention deficits due to cognitive impairment, psychomotor retardation, and refrain from normal social interaction and contact. Unfortunately, negative symptoms do not respond as well as positive symptoms to current medications. Research is ongoing to unravel the bundle of cognitive abnormality that cause these eclectic array of symptoms.

SCHIZOPHRENIA: THREE MAJOR THEORIES OF ETIOLOGY

In addition to these characteristic symptoms, to be diagnosed with schizophrenia, an individual must also experience social or occupational dysfunction and continuous signs of of the disturbance for six months of more. If a person meets the criteria for schizophrenic disorder with the exception of the duration, they may be diagnosed with schizophreniform disorder. The traditional hypothesis of the physiological attributes of schizophrenia is an overabundance of the neurotransmitter dopamine in the cell synapses of the mesolimbic pathways, which include the Ventral Tegmental Area (VTA), the nucleus accumbens, amygdala, bed nucleus, and the hippocampus. The overabundance of these neurotransmitters are hypothesized to be responsible for many of the positive symptoms of the disorder. Additionally, dopamine overabundance in the mesolimbic system is paralleled by a dopamine deficiency in the mesocortical pathway, which connects the VTA to the cerebral cortex (namely the frontal cortex). This deficiency is attributed to the negative symptoms such as avolition and alogia. The dopamine hypothesis has been supported by studies that induce an increase of dopamine levels in the brain. Commonly known as cocaine or stimulant psychosis, this increase in dopamine has been observed to trigger schizophrenic-like positive symptoms such as delusions and hallucinations. This phenomena is the basis for the effectiveness of antipsychotics in the treatment of schizophrenia: Antipsychotics block dopamine receptors in an effort to reduce the symptoms of psychosis. A 2004 meta-analysis published in the British Journal of Psychiatry confirmed the brief onset of psychotic symptoms when treated stimulant drugs, which included cocaine, amphetamine, or methylphenidate). The temporary psychosis could be brought on by enough stimulant drug, regardless of mental state. The meta-analysis also found that individuals who are experiencing the positive symptoms associated with schizophrenia are more likely to experience the stimulant-induced psychosis in response to only one does of the drug.

SCHIZOPHRENIA: THREE MAJOR THEORIES OF ETIOLOGY

While the focus has been to block receptors sites to reduce the effects of dopaminergic excess, a recent study has produced findings that question the traditional mode of treatment. It is suggested that the focus on the dopamine system may be inappropriate if the true pathology lies in the modulatory processes of the dopamine system. A hyperactive ventral hippocampus is hypothesized to be the root cause of the over-responsive dopamine receptor sites (Grace, 2011). If treatments were aimed to correct a malfunction of ventral hippocampal activity, it could be expected that patients would experience a more consistent alleviation of many of the positive psychotic symptoms associated with dopamine overabundance. The glutamate hypothesis of schizophrenia basically states that a deficit in the neurotransmitter glutamate underlies much of the dysfunction observed in schizophrenia. Glutamate is an excitatory neurotransmitter, and is involved in cognitive functions such as learning and memory. Early indicators of the role played by glutamate and its corresponding MNDA receptors were initially raised when it was observed that NMDA receptor antagonist drugs produced a number of the positive and negative symptoms associated with schizophrenia, including psychosis, memory deficits, and social withdrawal. The hypothesis was tested by Olney and Farber in a 1995 study. Several decades ago, an anesthetic agent called phencyclidine was introduced to clinical medicine, but quickly withdrawn due to a high incidence of psychotic reactions. Phencyclidine is also commonly known as PCP or angel dust, and is presently used as recreational drug by substance-abusing individuals. This drug is a NMDA antagonist, and induces an effective state of NMDA receptor hypofunction (NRH). NRH might be induced in early human ontogenesis- perhaps by an excitotoxic event; once induced, it becomes a permanent condition in the brain that can serve as a latent

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mechanism that can become active and spontaneously trigger psychotic symptoms and neurodegenerative changes (Olney & Farber, 1995). Phencyclidine, when administered to rodents, causes the brain damage now termed Olneys lesion. Humans are not susceptible to this lesion because of a metabolite that breaks down NMDA antagonist. However, the pattern of damage of Olneys lesion caused by the persistent suppression of NMDA receptor function is similar to the structural characteristics observed in schizophrenia. Additionally, it was observed that in rodents with the lesion, the symptoms of psychosis did not present until the organism passed puberty. This type of NRH damage could explain why many schizophrenic individuals do not experience their first psychotic symptoms until their late teens, or early twenties. The next part of the NMDA hypofunction hypothesis is the interaction of the NMDA receptors and the D2 dopamine receptors. Stahl (2007) points out, This descending cortico-brainstem glutamate pathway normally acts as a brake on the mesolimbic dopamine pathway. It does this by communicating with dopamine neurons via an inhibitory -aminobutyric acid (GABA) interneuron in the ventral tegmental area (VTA). If the NMDA receptors in the VTA are hypoactive, they cannot regulate the mesolimbic dopamine, resulting in dopamine hyperactivity and the positive psychotic symptoms. Abnormal regulation by NMDA receptors of the mesocortical dopamine neurons could explain the negative, affective, and cognitive symptoms of schizophrenia. This particular aspect of the glutamate hypothesis may parallel the traditional hypothesis, in a way being the fire that causes the smoke. Another proposed cause of NMDA receptor hypofunction is the degeneration of the synaptic spines on the NMDA receptors. The loss of synaptic spines in attributed to abnormal phosphorylation of the ErbB4 receptor (Bennett, 2009). In this sense, regulation of NMDA hypo-

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function should be aimed at prevent abnormal phosphorylation of ErbB4 receptors. In addition, there should be focus on re-establishing the neural circuitry lost through NMDA hypofunction and spine degeneration. Direct NMDA receptor agonists cannot be used because of the risk of excitotoxicity associated with allowing too much Ca2+ ions into the neuron. An alternative to the risky business of using NMDA agonists is to disrupt the re-uptake of the NMDA co-agonist glycine (GlyT1) in the forebrain synapses. In mice, not only did glycine re-uptake disruption enhance NMDA receptor function, but there was a reduced sensitivity to the motor stimulant effect of psychomimetic drugs, and an increase in a form of associative learning known as latent inhibition (Yee et al., 2006). This deficiency in latent inhibition has been attributed to the attention deficit symptoms of schizophrenia, which is alleviated with treatment by antipsychotics. A relatively recent development in schizophrenia research is the adenosine hypothesis of schizophrenia. It does show potential for alleviating psychotic symptoms by reversing the functional imbalanced observed in the brains dopamine and glutamate activities. Adenosine is not a neurotransmitter, but a neuromodulator. Adenosine can modulate post-synaptically by de-polarizing or hyper-polarizing the neuron, and can modulate pre-synaptically by controlling the release of neurotransmitters. The adenosine hypothesis of schizophrenia suggests that reduced adenosinergic activity (to modulate) is the result of purinergic dysfunction, and a possible cause for the imbalance of dopaminergic and glutamanergic transmission (Boison et al., 2012). An increasing number of studies have shown evidence for an antagonist interaction between adenosine and dopamine receptors in the basal ganglia. (Fuxe et al., 2007) Because of adenosines inhibitory role in glutamate release and transmission adenosine receptor (A1) antagonists can be expected to increase glutamanergic activity, including the NMDA receptor. activa-

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tion through its inhibition of glutamate release in the hippocampus. This is expected to improve cognition. (Boison et al., 2012) Adenosine is unique because of its bi-directional and region specific control over neuronal excitation. Adenosine deaminase (ADA) is expressed at high levels in the placenta to protect an embryo from the mothers fluctuating adenosine levels. If the role of ADA is disrupted by pharmaceutical means, the fetus is negatively affected, indicating that increased adenosine levels corrupt development. Research suggests that if normal adenosine levels are disrupted during critical stages in-vitro, it could set off a chain of events that could cause the neuro-developmental events implicated in schizophrenia. In addition to schizophrenia, failure to adequately regulate adenosine levels in the developing fetus could result in other disorders with a neurodevelopmental etiology, such as disorders on the autism spectrum. (Boison et al., 2012) In psycho-stimulant induced hyper-locomotion studies, adenosine agonists effectively reduced the motor-stimulant effects of both dopamine receptor agonists and NMDA receptor antagonists. Adenosine antagonists exacerbated the effects of the motor-stimulant drugs. (Boison et al., 2012) Another area studied when testing the adenosine hypothesis is pre-pulse inhibition (PPI). PPI is the phenomenon in which the startling effect of a sound can be reduced if it is shortly preceded by a weak, pre-pulse stimulus that is non-startling. A deficit in this area may be suspected responsible for the schizophrenics sensation of a sensory flood. In day-to-day life, normal functioning individuals can discriminate between important and unimportant stimuli. In addition, most individuals will not be startled by a taxi cab honking their horn in New York City as they would by a taxi cab honking their horn during a 5 am jog through quiet neighborhood streets. The bombardment of unimportant city noises, smells, and visual stimuli are inhibited by our brains, loud noises and weird smells expected given the environment. To the schizophrenic,

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deficient in pre-pulse inhibition, may be just as startled by the 9th taxi cab horn as he was with the first. The loud rev of an engine, drivers shouting, and the weird smells that waft up from the storm drains will be just as important as the man giving him directions to SOHO or Times Square. Data suggests that the antagonistic interactions between adenosine signaling and dopamine signaling is implicated in the regulation of pre-pulse inhibition. In a survey of experiments observing the effects of adenosine antagonists on learning and memory, researcher consistently found that adenosine antagonism correlated with memory loss (Boison et al., 2012) The influence of adenosine receptors on schizophrenia related symptoms can greatly depend on the brain region and receptor sub-type. Although adenosine is implicated in cognitive deficits and memory impairment, it also has valuable antipsychotic potential. According to Boison et al. (2012), It is conceivable to predict that any pathological disturbance in adenosine signaling will affect bioenergetic network homeostasis, which could at least partially explain the broad symptomatology seen in schizophrenia. It is possible that focal adenosine augmentation may provide for future development of antipsychotic therapy, similar to the way it has been used in the context of epilepsy. Currently, schizophrenia is largely treated with antipsychotics, or dopamine blocking neuroplectics. Currently, there are two types of antipsychotic medication. First generation antipsychotics, also known as typical antipsychotics, were first developed in the 1950s to treat psychosis. They may still be used present day to treat agitation and acute mania. A major drawback of typical antipsychotics is the occurrence of tardive dyskinesia, which is hypothesized to be caused by dopamine hypersensitivity. In tardive dyskinesia, an individual may engage in odd, repetitive, involuntary facial movements, such as lip smacking and grimacing. This condition is not always alleviated by a discontinuation of medication.

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Second generation antipsychotics, also known as atypical antipsychotics, and more commonly used because of the lowered risk of tardive dyskinesia. Also used in the treatment of bipolar depression, atypical antipsychotics have been associated with greater efficiency, decreased risk of suicide of self destructive behaviors, better functional capacity and a greater rate of response. (Horacek et al., 2006). If the root cause of dopamine dysregulation really lies in a malfunction of ventral hippocampal activity, future treatment could aim to focus on correcting the dysfunction, and solving the issue of dopamine overabundance at the source, rather than simply blocking the dopamine receptors later on. In regards to the hypothesis of NMDA receptor hypo-function, it is possible that, rather than risking excitotoxicity with excessive glutamate, treatment could aim instead to disrupt the re-uptake of the glutamate co-agonist glycine. It may also be useful to look into treatment options for re-establishing neural circuitry lost over the course of NMDA receptor spine degeneration. Lastly, focal adenosine augmentation may be promising in alleviating the dysfunctional relation between glutamate and dopamine levels in the brain. There may not be any one simple explanation for the causes of the broad range of symptomatology experienced by people with schizophrenia. It may be systematic variance in the interaction of multiple different systems in the brain, with treatment only being truly affective when we can attend to the root causes of the malfunction of these different systems, and alleviate the dysfunction that persists between them.

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Horacek, J., Bubenikova-Valeova, V., Kopecek, M., Palenicek, T., Dockery, C., Mohr, P., & Hschl, C. (2006). Mechanism of Action of Atypical Antipsychotic Drugs and the Neurobiology of Schizophrenia. CNS Drugs, 20(5), 389405. Olney, J. & Farber, N. (1995). Glutamate receptor dysfunction and schizophrenia. Archives of General Psychiatry, 52(12), 998-1007. Stahl, S. (2007). Beyond the dopamine hypothesis to the NMDA glutamate receptor hypofunction hypothesis of schizophrenia. CNS Spectrums,12(4), 265-268.

Yee, B., Balic, E., Singer, P., Schwerdel, C., Grampp, T., Gabernet, L., Knuesel, I., Benke, D., Feldon, J., Mohler, H., Boison, D. (2006). Disruption of glycine transporter 1 restricted to forebrain neurons is associated with a procognitive and antipsychotic phenotypic profile. The Journal of Neuroscience, 26(12), 3169-3181.