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CHAPTER 15 ■ Schizophrenia Spectrum and Other Psychotic Disorders
a large focus of research, at least in part because of their relevance in drug pharmacological treatment, there are several other neurotransmitter dysregu- lations apparent in individuals with schizophrenia. These are discussed below. Other Biochemical Hypotheses Abnormalities in the neurotransmitters norepi- nephrine, serotonin, acetylcholine, and gamma-am- inobutyric acid and in the neuroregulators, such as prostaglandins and endorphins, have all been impli- cated in the predisposition to schizophrenia. Excess of serotonin has been hypothesized to be responsible for both positive and negative symptoms of schizo- phrenia, and the effectiveness of medications such as clozapine (a strong serotonin antagonist) lends support to this hypothesis. Recent research has implicated the neurotrans- mitter glutamate in the etiology of schizophrenia. The N -methyl-d-aspartate (NMDA) receptor is acti- vated by the neurotransmitters glutamate and gly- cine. Psychopharmacological studies have shown that the drug class of glutamate antagonists (e.g., phencyclidine [PCP]; ketamine) can produce schizophrenia-like symptoms in individuals without the disorder (Hashimoto, 2006; Stahl, 2013). In one study, participants experiencing ketamine-induced schizophrenia-like psychotic symptoms were treated with a drug trial of a glycine transporter-1 inhibitor (D’Souza et al., 2012). This medication was shown to reduce the psychotic symptoms induced by the NMDA receptor antagonism of ketamine, so it is hoped it may also have benefits in schizophrenia treatment. Despite evidence of a glutamate link in schizophrenia (Hu et al., 2014), more research is needed on the implications for treatment. Previous studies have focused on reducing glutamate levels in patients who have advanced illness, but current research has identified that glutamate levels may be more important in the transition to psychosis, which is supported by the fact that first episodes of psycho- sis are often precipitated by stress, and glutamate increases under stress (Nauert, 2015). When gluta- mate levels are very high, the hippocampus becomes hypermetabolic and then begins to atrophy. Hippo- campal atrophy has been identified as a significant finding in many individuals with schizophrenia. Future research may find that interventions target- ing glutamate are beneficial in high-risk individuals or those in early stages of illness to prevent onset or slow the progression of the disease (Nauert, 2015).
Biochemical Factors The oldest and most thoroughly explored biological theory in the explanation of schizophrenia attributes a pathogenic role to abnormal brain biochemistry. Notions of a “chemical disturbance” as an explana- tion for insanity were suggested by some theorists as
early as the mid-19th century. The Dopamine Hypothesis
This theory suggests that schizophrenia (or schizo- phrenia-like symptoms) may be caused by an excess of dopamine-dependent neuronal activity in the brain (Fig. 15–1). This excess activity may be related to increased production or release of the substance at nerve terminals, increased receptor sensitivity, too many dopamine receptors, or a combination of these mechanisms. Pharmacological support for this hypothesis came from the observation that amphetamines, which increase levels of dopamine, induced symptoms that mimic those of psychosis. First generation antipsy- chotics (e.g., chlorpromazine or haloperidol) lower brain levels of dopamine by blocking dopamine receptors (particularly at D 2 receptors), thus reduc- ing psychotic symptoms, including those induced by amphetamines. Postmortem brain studies of individuals with schizophrenia reveal alterations in the presynap- tic and postsynaptic dopaminergic system, and more recent in vivo studies using positron emission tomography (PET) and single photon emission com- puted tomography (SPECT) imaging have revealed increased dopamine synthesis capacity in patients with schizophrenia (Howes et al., 2015). Clients with positive symptoms such as delusions and hallucina- tions (referred to as positive symptoms because they are “added” to the clinical picture) respond with greater efficacy to dopamine-reducing drugs than do clients with negative symptoms (deficits such as apa- thy, poverty of ideas, and loss of drive). Positive and negative symptoms are listed in Box 15–2. Over time we have learned that there are several different types of dopamine receptors (D 1 , D 2 , D 3 , D 4 , and D 5 ), and research continues to identify the specific role of each in the course of schizophrenia as well the implications for treatment. Clozapine, for example, an atypical antipsychotic with a unique clinical profile, has more affinity for D 4 receptors. D 3 receptors, found in several areas of the brain, have been identified as relevant in the expression of nega- tive symptoms. While dopamine receptors have been
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