Schizophrenia: the biological and psychological effect

The study of psychosis has been much published within the literature. Investigations into the biological, psychological and clinical aspects of the disorder have been greatly seen. An approach which views schizophrenia as a disturbance of information processing appears promising as a way of linking all of the aspects of the disorder. A review of the research in this area led to the suggestion that the basic disturbance in schizophrenia is “a weakening of the influences of stored memories of regularities of previous input on current perception”. It is argued that the link between information processing disturbances and biological abnormalities may be facilitated by the use of paradigms derived from animal learning theory (latent inhibition and Kamin’s blocking effect). In a number of animal model studies and indeed human subject studies, on an individual’s pattern of performance in acute schizophrenics, the information gained is consistent with the cognitive model. The ways in which such an information-processing disturbance may lead to schizophrenic symptomatology will thus be outlined, with particular reference to the formation and maintenance of delusional beliefs. The core cognitive abnormality may result from a disturbance in any of the brain structures involved in the prediction of subsequent sensory input. The proposed circuit implicates in particular the hippocampus and related areas and is consistent with studies of brain pathology in schizophrenia. Thus, this paper will aim to provide an insight into the biological and psychological effects of schizophrenia and will give an insight into the current treatments available and their effects on the individual and their biological status.

Introduction

Understanding the varied presentation of the many types of psychotic disorders is still a major challenge within today’s scientific capacity. The approaches utilized to clarify their complex nature of such disorders of the neurological system present an ongoing challenge, due to the complexity of the interaction between both biological entities (the brain) and the psychological effects.

Thus, the aim of this paper is to review the evolution of our understanding of schizophrenia in terms of the biological and psychological effects of the disorder, based upon a review of the literature findings. Studies, which have been conducted regarding the life-long evolution of mental illnesses, especially schizophrenia, have been publicized for decades and this has managed to initiate the early standing of schizophrenia and of the nature of its chronic states. These experiences have further contributed to the views we hold today regarding the illness, leading in a third phase to the development of a biological-psychosocial model of its evolution which has proved useful for both theoretical and practical purposes. Finally, an understanding of therapeutic experiences and theoretical explorations based on the biological and psychological has helped to minimize the effects of the disease within the patient population.

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Biological basis of schizophrenia

Across the findings within the literature, the question of whether schizophrenia is associated with structural or functional abnormalities of the nervous system, or both, appears to have become the principal focus in many of the biological studies of schizophrenia. A number of different methods of investigation of this system have been conducted including computed tomography studies, which have been able to reveal ventricular enlargement and cortical atrophy in a subgroup of schizophrenic patients. When such enlargement is found within the brain of the majority of patients in the early stages of the illness, they appear to be most severe in patients with negative symptoms and poor outcome. Quantitative neuropathological studies have tentatively demonstrated decreased volume of specific brain areas, neuronal loss, and other changes in the limbic system, basal ganglia, and frontal cortex. Dopamine (DA) remains the neurotransmitter most likely to be involved in schizophrenia, although there is also evidence for disturbances of serotonin and norepinephrine. Post-mortem and positron emission tomographic studies suggest an increased number of D2 DA receptors in some schizophrenics. Neuroendocrine studies reinforce the role of DA in schizophrenics. Viral infections and autoimmune disturbances may be responsible for some types of schizophrenia, but there is no firm experimental evidence to support either hypothesis. The possibility that mixtures of structural abnormalities and functional changes involving DA occur in the same patients rather than independently as part of two syndromes (Type I, II) seems attractive.

The symptoms of schizophrenia patients appear to be diverse, with different elements of the disease having different impacts on different individuals. Since Bleuler’s (1950) conception of the schizophrenias as a heterogenous disease composed of symptomaticlly different subgroups, attempts have been made to identify biological correlates of specific behavioral dysfunction. Diagnosis of the illness could be seen to have been fraught with difficulties. The initial lack of differentiation between the manic episodes of bipolar affective disorder and schizophrenia still presents as being greatly problematic within studies published within the literature, and subsequent attempts to differentiate between subgroups of schizophrenics have yielded no discrete classification system. The search for an etiology has also been bedeviled by this lack of distinct classification. Nevertheless, the publication of and the conduction of a number of biological theories have contributed to an understanding of schizophrenia by identifying specific dysfunctional neural areas in determining biochemical changes associated with symptomatology and in formulating new etiological hypotheses.

Neurological correlation between neurological studies and the effects of schizophrenia have been examined by research conducted through the use of magnetic resonance imaging, computed and positron emission tomography, and, also postmortem morphological changes (Koning et al, 2010). Studies of cognitive function in association with metabolic and cerebrovascular activity have contributed to the identification of discrete neural dysfunction. In addition, development of the dopamine theory and its relationship to positive symptoms has assisted in diagnostic differentiation, while recent studies on the modulatory role of neuropeptides on neurotransmitters have expanded the scope of the dopamine theory.

Several biological theories have been proposed for an etiology of schizophrenia. (Krabbendam et al, 2004) Perinatal complications and viral infection have been suggested either in isolation or in conjunction with genetic factors. Low birth weight has also been proposed as a predisposing or associated factor in the subsequent development of schizophrenia. The viral hypothesis has received impetus from recent research into retroviruses capable of genetic transmission and causing latent disease onset. It is also recognized that factors other than biological, in particular,

Psychosocial influences may play an etiological role in schizophrenia. Discussion of these factors, however, will not be discussed in great detail in this paper due to time restrictions.

The difficulty of diagnosis

As etiological studies rely to a large extent on accurate diagnosis, it is important initially to identify diagnostic problems because this aids an understanding between the interplay between biological and psychological effects, which can be noted in schizophrenics. It has long been recognized that the term “schizophrenia” incorporates a heterogeneous collection of subgroups, possibly with different etiologies, disease processes, and outcomes. The subsequent categorization of such patients into meaningful groups therefore relies upon differences in symptomatology and long term outcome, and fall broadly into three categories- paranoid versus nonparanoid, negative versus positive, and chronic versus acute (Goldstein & Tsuang, 1988)

The literature proposes that paranoid groups show a better premorbid adjustment, cognitive performance, and prognosis than the nonparanoid group (Kumra and Schulz, 2008), it has been suggested that this represents a measurement artifact and depends on whether absolute or relative measures of paranoia are used. Studies using absolute predominance measures to the exclusion of other symptoms reject many subjects displaying both sets of symptoms. Many nonpredominance studies show no differences between the groups of an increase in negative outcome as paranoid symptoms increase.

Other researchers have proposed that schizophrenics could be categorized into two types placed into their category upon the basis of positive or negative symptom preponderence. Type I, or the positive symptom group, display some of the Schneiderian first rank symptoms of hallucinations and delusions, while Type 2, or the negative symptom group, show affective loss or extinction, speech content poverty, psychomotor deficits, and a general loss of drive or will.

One of the problems with this categorization is that many schizophrenics display both sets of symptoms and that schizophrenics with primary positive symptoms often develop negative symptoms over time (Phillips and Silverstein, 2003).

This would mean that studies using young subjects showing predominantly

Positive symptoms may not be adequately differentiating between groups. Recent refinements of the positive/negative dichotomy have led to a redefinition of negative symptoms congruent with familial genetic factors, developmental dys- function, and the development of psychometric scales to measure relative symptomatology (Pickett-Schnenk et al, 2006). However, the influence of neuroleptic drugs on attentional and extrapyramidal functioning could also contribute to the development of differential symptoms. Furthermore, the effects of early environmental factors, such as perinatal trauma and familial environment, and of concurrent disorders, such as depression, are not adequately taken into account in such studies. Thus, this highlights the difficulties, which can be seen when trying to relate the biological and psychological effects of schizophrenia to a certain pathological aspect of brain development.

Within the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R; APA, 1987) chronicity is defined as persistence of disturbance for more than two years with further residual diagnosis if subsequent symptoms are primarily negative. It is assumed to be associated with negative symptoms within Crow’s typography (Crow, 1980). This classification is the most common in the literature because of its basis in psychiatric diagnosis and its relationship to poor prognosis and to biological and cognitive deficits. For the purpose of biological research, the argument appears to be somewhat circular however because, for example, research attempts to find biological correlates of subgroups that are often operationally defined by their biological correlates. Moreover, there is significant overlap between the two groups in that many initially acute schizophrenics subsequently become chronic (by definition).

While researchers across the literature publications acknowledge the heterogeneity of the disease, they continue to rely operationally on a dichotomous diagnosis. Multiple research strategies on the same subgroup would assist in isolating behavioural and biological attributions and in refining diagnostic criteria.

Biochemical research and the impact on our understanding of the effects of schizophrenia

Disruptions of neural biochemical processes have been extrapolated both from the effects of psychomimetic drugs and from the actions of symptom-reducing neuroleptic drugs. Drugs such as amphetamine and L-dopa, which cause psychotic conditions (e.g., hallucinations and paranoia), are known to involve excesses of dopamine release (Goodwin, 1972). Although different classes of neuroleptics are known to block acetylcholine, noradrenaline, or serotinin transmission, all of them block dopamine, and symptom reduction is thought to emanate from the latter (Millar et al, 2001). Within the dopamine theory two models of dysfunction have been proposed: autoreceptor excess, and postsynaptic receptor mechanism deficit. Different classes of neuroleptics vary in whether action is pre- or postsynaptic, but an inhibition of dopamine transmission is effected by all classes.

Two classes of dopamine receptors have been identified-D1 and DP as previously mentioned, and it is believed that they are related to schizophrenia and neuroleptic effects. Distinctions between the two are based upon their actions on adenylate cyclase: stimulatory for Dl and distinct or inhibitory for D2 (Murray et al, 2008). Dl

neurons, which project from the substantia nigra to the corpus striatum, are implicated in Parkinson’s disease. Inhibition of Dl receptors is believed to be the

origin of neuroleptic side effects, such as tardive dyskinesia and parkinsonianism. D2 receptors are associated with the antipsychotic effects of neuroleptic drugs and form the mesolimbic dopamine system which projects to the frontal cortex and some limbic forebrain structures (Tseng et al, 2008).

The proposition that schizophrenic symptoms are caused by an excess of D2 receptors was initially difficult to substantiate due to drug effects and disease process. In most postmortem studies showing higher densities of dopamine receptors, previous antipsychotic drug use is also implicated (Seeman, 1986). However, in several studies subjects had never been treated with neuroleptics and still evinced increased dopamine receptor density (Trower et al, 2004).

The role of dopamine receptor anomalies has also been studied using differential effects of classes of neuroleptics on dopamine receptors. In vivo Positron Emission Tomography (PET) research using the ligand [“Cl raclopride has indicated that diverse classes of neuroleptic drugs administered in clinically effective doses block D2 dopamine receptors in the putamen. suggesting increased D2 dopamine density in schizophrenic subjects (Thompson et al, 2001). Research on the role of the atypical neuroleptic, clozapine, on dopamine receptors has however yielded inconsistent results. It is thought that the relative absence of extrapyramidal side effects with clozapine administration is due to a selective effect on D2 dopamine activity in the ventral tegmental area and nucleus accumbens but not in the substantia nigra or striatum. Haloperidol, on the other hand, reduces dopamine activity in both areas. The effects of both drug classes have been observed in rats using in vivo extracellular single-unit recordings (Tseng et al, 2009).

However, clozapine also acts antagonistically on cholinergic, a-adrenergic, his-

tamine, and serotonin receptors and, in addition, the combination of haloperidol with the a-noradrenergic antagonist, prazosin, produces similar effects to clozapine administration, namely, reduced basal dopamine release in the striatum but not in the nucleus accumbens (Thimm et al, 2010). Studies on cerebrospinal fluid (CSF) levels of prolactin following clozapine administration have also yielded inconsistent reslults. Prolactin release is inhibited by dopamine and increased by conventional neuroleptics. However, in at least one study it has been found that administration of clozapine to human schizophrenic subjects produced no significant increase in prolactin levels 11 hours after administration, despite moderate to marked therapeutic effects (Meltzer, Goode, Schyve, Young, & Fang, 1979).

Several recent studies have also implicated Dl receptor blocks in the therapeutic effects of clozapine.

A further obstacle to the initial acceptance of the dopamine theory has been

the time discrepancy between drug administration and antipsychotic symptomatic effects. PET studies have shown immediate binding to dopamine receptor sites, yet their clinical effect is often delayed for several weeks (Tarrier et al, 1999).

There have been suggestions that receptors blocks produce an initial overactivity of dopamine release to compensate for inhibition. Further evidence for the dopamine theory has come from measurements of CSF, and plasma levels of the dopamine metabolite, homovanillic acid (HVA).

Although findings in unmedicated patients have not yielded consistent differences in HVA levels between schizophrenics and controls, neuroleptic treatment increases HVA levels (Abubaker et al, 2008). In unmedicated patients, a correlation between low HVA levels and cortical atrophy and ventricular enlargement has been found in at least one study.

This has led to the suggestion that dopamine excess is related to Type 1

schizophrenia, an interpretation which is supported by a good response to neuroleptic drugs in this group (Crow, 1985). In addition, Allen et al (2008) has suggested a possible deficiency of dopamine in Type 2 schizophrenics. However, the Type l-Type 2 typography has not been fully supported, and there is evidence that neuroleptic drugs elicit response in negative symptom sufferers (Allen et al, 2008). From the evidence there is little doubt of the biological role of dopamine within some forms of schizophrenia.

The influence of serotonin in schizophrenia was suggested by the antagonistic activity of the psychomimetic drug, D-lysergic acid diethylamide (LSD), on serotonin transmission (Addinton and Addington, 1993). This has been studied in CSF by measuring levels of the serotonin precuresor, tryptophan, and the metabolite 5- hydroxyindole acetic acid (5-HIAA). At least one study has found reduced levels of 5-HIAA in schizophrenics and no difference between those on and off neuroleptics, but the latter group had only been drug free for a short time (three weeks). Therefore residual effects cannot be discounted. It was not stated whether subjects were also suffering from depression, which is known to decrease serotonin levels (Akbarian and Huang, 2009). Neither increasing nor decreasing serotonin levels have had a beneficial effect on schizophrenic symptoms (Akbarian and Huang, 2009).

Monoamine oxidase (MAO) metabolizes dopamine, serotonin, and noradrenaline, as well as endogenous stimulants or hallucinogens such as phenylethylamine and diethltryptamine. It has therefore been hypothesized that decreased

MAO activity could be contributory to schizophrenia. Studies have been conducted into platelet MAO activity in schizophrenics with varying results. Meltzer and Arora (1980) found that decreased MAO platelet activity was positively correlated with paraniod and positive symptoms. Other studies have found no un- usual MAO platelet activity in paranoid or hallucinating schizophrenics (Arts et al, 2008)

Recent research has also considered the role of neuro-peptides in modulating

CNS functions and the possible implications for schizophrenic symptomatology.

Endorphins have been the subject of the most intensive study because of their

association to proposed neural deficit areas both in biochemical and neuropathlogical research. The B, y, and (Y endorphins originate in the basal hypothalamus

and modulate neurotransmitter activity in several structures of the limbic system

and brain stem.

Of all the biochemical theories of schizophrenia, the dopamine hypothesis has been the most consistently substantiated in research. The implication of other neurotransmitters, however, suggests a possible diffuse dysfunction with dopamine eliciting the most severe disruption. Efforts have been made to control for medication, but residual drug effects cannot be discounted. Many studies now use chlorpromazine equivalents to control for the effects of varying medication levels. The problem with this method is that, although different classes of neuroleptics all reduce dopamine levels either pre- or postsynaptically, they do not have equivalent effects on serotonin, MAO, or noradrenalin. Further problems are encountered when attempts are made to ascribe an etiological function to neurotransmitter activity. It is equally probable that any such changes are caused by the disease process rather than their being causal.

Structual brain abnormalities

The neuropathology of schizophrenia has received considerable recent interest

in the light of positron emmission tomography (PET), postmortem, cognitive function and cerebral blood flow (CBF) research. While PET scans and postmortem investigation have concentrated on structural measurements, cognitive studies have provided tacit support for such structural changes. It has been

hypothosized that neuropathological abnormalities identified in subgroups of

schizophrenics could be in vitro developmental disorders either genetically transmitted or resulting from prenatal trauma (Ashburner et al, 2008).

The most consistent findings across the publications within the literature have been differences in ventricular size, in some sections of the temporal limbic and nigrostriatal systems and basal ganglia, and in the prefrontal cortex.

Measurements of ventricular size have however, shown considerable inconsistency, with some studies finding no significant difference between subjects and non-schizophrenic controls (Bles et al, 2010), and some reporting significant differences between chronic paranoid and hebephrenic subjects and normal controls (Bales et al, 2010).

Evidence to date suggests that ventricular enlargement is only salient for a small subgroup of schizophrenics subject to chronicity or other, as yet unidentified, factors. Inconsistency in the results could be due to deviations in subject samples. It has been proposed that atrophy of specific neural areas could account for some schizophrenic symptoms. While some evidence has come directly from postmortem studies. Abnormalities have also been inferred from the results of PET and CAT scans and CBF measurements performed in conjunction with cognitive tasks designed to activate specific neural areas.

Postmortem studies have identified significant cortical atrophy in the lateral

nigro-striatal area (Birchwood et al, 2004) and in the limbic portions of the temporal lobe, specifically the amygdala, hippocampus, and parahippocampal gyrus

(Birchwood et al, 2004).

Psychotherapies and social treatments

The psychological effects and impacts of schizophrenia must be emphasized. Due to the impact of the different, aforementioned parts of the brain and the CNS in schizophrenia, the psychological impact of the disease is obviously one, which takes great effect as previously mentioned. Psychotherapies are thought to be important within the current treatment lines in schizophrenia and although antipsychotic medications are the mainstay of treatment for schizophrenia, pharmacotherapy alone produces only limited improvement in negative symptoms, cognitive function, social functioning and quality of life. Additionally, it has been found that a great number of patients continue to suffer from persistent positive symptoms and relapses particularly when they fail to adhere to prescribed medications. This underlines the need for multi-modal care including psychosocial therapies as adjuncts to antipsychotic medications to help alleviate symptoms and to improve adherence, social functioning and quality of life (Patterson and Leeuwenkamp, 20008). A short review of the evidence that has accumulated on the efficacy of the major modalities of psychosocial treatment highlights that treatments involving social skills training, psychoeducation and cognitive behavioural therapies (CBTs) can all have a role in the treatment of individuals with schizophrenia. The reasoning behind the success of each treatment can give guidance into the psychological effects of the disease. For example, Psychoeducational interventions provide information about the disorder and its treatment to patients and their family members, and additionally inform the patients and family members about strategies to cope with schizophrenic illness. From the literature findings, it is evident that an extensive body of literature has accumulated regarding the efficacy of these interventions. Meta-analyses suggest that these interventions reduce high expressed emotion among relatives, and decrease relapse and rehospitalization rates (Pitschel et al, 2002; Giron et al, 2010).

In general, interventions that include family members are found to have a much greater level of success (Pharaoh et al, 2006). Multi-family psychoeducation group approaches, which provide family psychoeducation and additionally offer an expanded social network, are found to reduce rates of relapse as are peer-to-peer education programs for families and patients (Chien et al, 2006).

Cognitive Behavior Therapy (CBT)

About a third of patients with schizophrenia continue to suffer from persistent psychotic symptoms despite adequate pharmacotherapy. Cognitive Behavior Therapy (CBT) has therefore been presented as a system of treatment which has emerged to address this need, and is based on the hypothesis that psychotic symptoms such as delusions and hallucinations stem from misinterpretations and irrational attributions caused by self-monitoring deficits. CBT seeks to help patients rationally appraise their experience of disease symptoms and how they respond to them, thereby reducing symptoms and preventing relapse (Turkington et al, 2008). Meta-analytic evaluations of this data have found CBT to be effective in ameliorating positive symptoms (Rector and Beck, 2001) although effect sizes of CBT have been noted to be inconsistent across studies and a recent meta-analysis of six blinded studies (Lynch et al, 2010) found CBT to be ineffective in reducing any symptoms of schizophrenia or in preventing relapse; the ‘fairness’ of this analysis has been questioned (Kingdon et al, 2010). CBT is reported to be ineffective in targeting negative symptoms and its effects on other treatment domains are not well studied. Although CBT is recommended as a standard of care for persons with schizophrenia (NICE, 2009) the results are thought to give the best outcomes in patients who are willing to comply with treatment.

Cognitive remediation

A substantive proportion of schizophrenia patients have impaired cognition, particularly in the domains of psychomotor speed, attention, working memory and executive function, verbal learning and social cognition. These deficits are robust and persist during the illness, and serve as rate limiting factors for functional recovery (Tandon et al, 2009). Several cognitive remediation approaches have been developed over the past two decades which involve compensation strategies to organize information, use of environmental aids such as reminders and prompts, and a range of techniques designed to enhance executive function and social cognition (Eack et al, 2010). Earlier reviews and meta-analyses which have been presented and published within the literature findings have suggested that cognitive remediation leads to modest improvements in performance on neuropsychological tests but has limited generalization to functional outcomes (Pilling et al, 2002)

One large meta-analysis published by McGurk et al, (2007), however, found that cognitive remediation was associated with significant improvements in cognitive performance and symptoms, as well as psychosocial functioning in schizophrenia. Cognitive remediation has been found to be more effective in studies that provided adjunctive psychiatric rehabilitation in addition to cognitive remediation. Thus, it appears to be the case that the durability of benefits of cognitive remediation are not yet set in stone.

Social skills training (SST)

Schizophrenia patients manifest deficits in social competence and these contribute to poor outcome. The goal of SST is to improve day-to-day living skills by focusing on components of social competence such as self-care, basic conversation, vocational skills, and recreation. These skills are practiced mostly in group settings using techniques based on operant and social learning theory. Historically, token economy was the first such intervention that sought to improve the social behavior of patients with psychiatric illness. While effective, the results did not generalize beyond the therapeutic setting. A recent meta-analysis of randomized controlled trials of social skills training in schizophrenia showed a large effect size for improvement in skills, a moderate effect size for performance-based social and community skills and for community functioning, and a small effect size for symptoms and relapse (Kurts and Mueser, 2008)

Conclusions

Thus, in conclusion, and in review of the findings published within the literature, it si clear that the impact of both biological aspects of the disease and psychological impacts are prevalent within the schizophrenic population. In summary, research on psychosocial approaches to treatment of schizophrenia has yielded incremental evidence of efficacy of CBT, SST, family psychoeducation, ACT and supported employment. Relatively few rigorously conducted trials of psychosocial interventions have been reported in the early course of schizophrenia, a phase of the illness when effective interventions may yield long-term outcome benefits . More hypothesis-driven research is needed to examine active ingredients of the therapeutic modalities that work, to identify the synergistic effects of combinations of interventions, and to use the knowledge which we have gained from the biological impact of the disease and the understandings of the neurological circuitry and its implications in schizophrenia to aid the development of new methods of reducing the effects of schizophrenia on the patient population.