Electronic Reviews

This writing is intended to serve solely as a facilitatory synthesis of the current literature. This work is copyright, but is intended as a rapid reference for readers from divergent but related fields to gain access to current thinking in the literature. Complete references have been omitted for brevity and space as over a thousand sources were either scanned or read. However major influences and key papers are referred to wherever possible to aid computer driven database searches. Happy hunting.
 
 

A First Century of Schizophrenia

Schizophrenia remains an enigma that has fascinated the foremost minds of psychiatry and neuroscience for more than a hundred years. At stake is more than just the crucial welfare of the millions afflicted, for schizophrenia research may represent the key to an understanding of the mechanisms by which the brain filters, prioritizes and processes the relentless current of information available from the richness of its internal, social and natural environments.

In 1851 Falvet first described a 'Folie Circulaire' or cyclical madness, and some twenty years later Hecker referred to a 'Hebephrenia', or a silly, undisciplined mind after Hebe, goddess of youth and frivolity (1871). Soon after, in 1874, Kahlbaum referred to both catatonic and paranoid disorders of the mind, the term catatonia describing a movement disorder characterized by a mannequin-like muscle stiffness associated with unusual postures and a pervading fear. Then in 1878 Emil Kraepelin, perhaps auspiciously, combined these various ‘disorders’ into a single disease entity which he termed dementia praecox, or ‘dementia of early onset’ reflecting a decline of cognitive processes which he divided into four subtypes - simple, marked by slow social decline concomitant with apathy and social withdrawal; paranoid, with its attendant fear and ‘persecutory’ delusions; hebephrenic and catatonic, characterized by a poverty of movement and expression.

The inevitable inexactitudes of this emerging science continued with the dawn of the 20th Century when in 1908 Eugen Bleuler criticized the use of the term dementia praecox, arguing for an absence of evidence supporting a global dementing process. It was Bleuler who first coined the divisive term 'schizophrenia' in 1911.  Bleuler defined schizophrenia with his four "A's", referring to the blunted Affect (diminished emotional response to stimuli); loosening of Associations (by which he meant a disordered pattern of thought, inferring a cognitive deficit), Ambivalence (an apparent inability to make decisions, again suggesting a deficit of the integration and processing of incident and retrieved information) and Autism (a loss of awareness of external events, and a preoccupation with the self and one's own thoughts).

Freud’s Paradox

Sigmund Freud, after many years of formative research on the anatomy of the vertebrate nervous system, which culminated posthumously in the publication of a "Project for a Scientific Psychology" (written in 1895), he began:

"The intention is to furnish a psychology that shall be a natural science: that is, to represent psychical processes as quantitatively determinate states of specifiable material particles (which he termed neurons), thus making those processes perspicuous and free from contradiction."

However, later that same year Freud wrote in "Studies on hysteria", published in 1895, elegantly summarizing his apparent conflict of ideologies;

"...it still strikes myself as strange that the case histories that I write should read like short stories and that....they lack the serious stamp of science....The fact is that local diagnosis and electrical reactions lead nowhere in the study of hysteria....whereas a detailed description of mental processes....enables me...to obtain at least some insight into the course of that affection".  This philosophical dilemma may have been the inspiration for his development of his theory of psychoanalysis.  Freud within the same year echoes our dilemma of dreaming for a undisputed biological basis for the operations of mind, cognitive processes and behavior, contrasted against the realities of dissecting the "human condition".

The operational definition of schizophrenia

Kurt Schneider listed his ‘first rank’ features of schizophrenia in 1959 which served as the inspiration for the two guides used in the operational diagnosis of schizophrenia, the ICD-10 and the Diagnostic and Statistical Manual of mental disorders (DSM). The DSM (IV) states that two or more of the following (symptoms), each present for a significant portion of time during a one month period (only one symptom being required if delusions are bizarre or ‘auditory’ hallucinations are present). A diagnosis of schizophrenia may be made if continuing signs of a disturbance have been present for at least six months, concordant with a social and occupational dysfunction for a significant period of the time since onset, provided other medical conditions and the actions of substance abuse have first been ruled out.  This assumption is however challenged below. The classification is summarized below;
 

POSITIVE SYMPTOMS	NEGATIVE SYMPTOMS
Psychotic episode (displacement from 'reality', inability to separate real from unreal experiences) including; delusions (false beliefs/judgment); hallucinations (strong subjective perceptions of an object or event which is non-existent that may affect any or all sensory perceptions); disorganized speech or behavior; thought disorder (cognitive dysfunction)	Social and occupational dysfunction Lack of motivation, withdrawal, loss of concentration  Blunted or flat affect (loss of emotional tone or reaction) Inability to articulate

Table 1: Major features of schizophrenic phases
 
 

Subtype	Characteristics
Paranoid	A preoccupation with one or more delusions or frequent auditory hallucinations
Disorganized	Disorganized speech and behavior and a flat or inappropriate affect are all prominent
Catatonic	Two of the following must be present: A lack of a motor response to a stimulus, excessive motor activity, an absence of speech, peculiar movements and repetitions of words and phrases (echolalia) or another's movements (echopraxia)
Undifferentiated	Symptoms of schizophrenia are present but conditions for other three types are not met
Residual	Absence of prominent delusions, hallucinations, disorganized speech, and grossly disorganized and catatonic behavior despite continuing evidence of a disturbance

Table 2: The five principle subtypes in the spectrum of schizophrenic disorders

It may be instructive to derive the core features inferred from this operational definition of schizophrenia. Extreme distortions of sensory processing are apparent, with attendant difficulties in screening out various unwanted sensory stimuli or ideations (leading to delusions or hallucinations) which is suggestive of a decreased capacity to filter and process information. The resulting disorganized thought and display of behaviors that do not meet with social expectation are often associated with the development of poor memory and a shortened attention span. The apparent decline in cognitive processing is often reflected in disorganized speech, further suggestive of a deficit in information processing. A decrease in emotional tone and of reaction to social and other external stimuli may parallel a decline in social functioning, emphasizing the importance of the integrity of higher cortical circuits in mediating receptive, productive and appropriate social interaction, or 'successful' human social ‘behavior’. This reductionism and generalization leading to the definition of 'schizophrenia' as one or more related disorders resulting in a disruption of cortical processing and filtering, permits us to correlate these human behaviors with those of animal models from which the putative existence of a biochemical basis for schizophrenia might be tested.

The much maligned and misunderstood schizophrenic

Schizophrenia does not infer, from the literal translation ‘split mind’, to a dissociation of personality (Jekyll & Hyde) or multiple personality disorder. Rather Bleuler intended it to refer to a split between subjective feeling, or affect, and the thought being experienced. Most schizophrenics have not, contrary to widespread belief, been shown to be unusually prone to violence either normally or following substance abuse. Diagnosed schizophrenics receive discrimination in seeking employment, housing, health care and insurance.  Thus schizophrenia is a dysfunction with often severe social consequence.

Are there other conditions that resemble features of schizophrenia?
 

Psychoactive drugs	Disease
Crack (purified cocaine) and ice or crystal (pure methamphetamine) cause the positive symptoms of schizophrenia, and dysphoria upon withdrawal	Schizophrenia-like psychosis of epilepsy (SLPE), resulting from temporal lobe epilepsy of the left (dominant) superior temporal gyrus, have similar symptoms to schizophrenics but the predominant cause is temporal rather than in the anterior cingulate or frontal lobes, as in schizophrenia
Anti-depressants and serotonin reuptake blockers, such as ecstacy, prozac & LSD create hallucinations and false memory	Prior to this century 10-30% of schizophrenia-like patients had neurosyphilis
Chronic alcoholics suffer loss of gray matter, cognitive dysfunction, disorganization of thought and memory loss	Post-traumatic stress disorder
Special K, otherwise known as ketamine, causes a schizophrenia-like psychosis in healthy individuals and exacerbates the psychotic symptoms in schizophrenic patients, decreasing responsivity to environmental stimuli	Sleep deprivation impairs cognitive performance and causes activity shifts from temporal to parietal cortex on verbal learning tasks (Drummond et al., Nature, 2000)
PCP, or phencyclidine otherwise known as ‘Angel Dust’, causes both the positive and negative features of schizophrenia

How may we quantitatively measure schizophrenia?

Psychometric measurements

Thought disorder index in response to questions (TDI)

By a dysfunction in smooth pursuit eye movement (eye tracker)

Evoked potentials

Measuring a deficit in information processing, inhibitory and gating deficits are apparent in both human and animal models of schizophrenia, and this neurological deficit can be revealed by a loss of prepulse inhibition (PPI) of the 'startle' reflex. Such PPI deficits in schizophrenic patients are thought to be neural correlates of cognitive deficits such as 'thought disorder' and distractibility. For example the PPI of the eyeblink component of the startle reflex to a loud noise can be measured by electromyogram, an electrical measurement of muscle activity (Braff et al., Am.J.Psych., 1999).

In addition both a failure to inhibit the P50 auditory evoked response to repeated stimuli, and an increase in latency of the P300 cognitive event-related potential in response to an auditory oddball event (Noldy & Carlen, 1997), which are measured by electroencephalography (EEG) are features present in diagnosed schizophrenics.  It would be instructive to determine what proportion of diagnosed schizophrenics possess these deficits.

Brain Imaging

Changes in the structure and function of the brain may be measured non-invasively by changes in:

regional blood flow (functional Magnetic Resonance Imaging)

regional blood oxygen consumption (BOLD)

binding or localization of emitting tracer (Single Photon Emission Computed Tomography, Positron Emission Tomography)

Structural changes (Computed Axial Tomography)
 

In what way are the brains of schizophrenics different?

As schizophrenia is believed by many to reflect a disturbance in information processing, and specifically a failure to correlate and integrate contextually appropriate stored material (memory) as a function of sensory input, in other words an inability to effectively relate stored experience to current circumstance.  Indeed ‘paranoid’ and ‘non-paranoid’ schizophrenic subjects exhibit equivalent performances in tests realted to cognitive and intellectual functioning (Zalewski et al., Schizo.Bull., 1998). The general concept of a fundamental cognitive deficit in schizophrenia is unifying and takes into account a broad diversity of symptoms and possible causes by describing a functional consequence rather than defining a specific causality.

What regions of the brain may be affected in schizophrenia?

Mesolimbic areas including the amygdala and ventral striatum, believed to be important in imparting emotional 'coloring' to external stimuli, have been shown to be unusually active in schizophrenia, whilst the prefrontal cortex is unusually hypoactive during hallucinations, a symptom of the so-called ‘active phase of schizophrenia’.  In fact these patterns of differential activity may be seen by PET imaging even without stimulation, suggesting a constitute state of arousal typically observed in response to threat (Epstein et al., 1999). Brain imaging of responses to non-threatening, negative expressions such as disgust, or threatening facial expressions, such as fear or anger, suggest that a region called the amygdala specifically responds to threatening facial expressions, an area known to be important in the integration of the cognitive and emotional aspects of human behavior.  The amygdala has since been shown to have an enormous influence on dopamine release, thereby emotionally and motivationally 'coloring' a wide range of behaviors. It is suspected by some that the amygdala plays a role in mediating some of the symptoms of schizophrenia.

There is agreement that an area known as the associative frontal (including left dorso-lateral pre-frontal) cortex has both reduced blood flow and metabolic activity in 'never-been' medicated schizophrenics, as do the upfoldings (gyri) of the parietal and temporal cortex, all association areas essential in governing the high level cognitive functions implicit in social interaction and language. Further the prefrontal cortex has been shown to be an area consistently associated with the altered cognitive activity and attentional deficits in schizophrenics, consistent with an area involved in mediating transient working memory and processing information involved in thought, which is impoverished or disorganized in schizophrenics. However, the thalamic and cingulate cortical areas are hyperactive in schizophrenics, regions that are thought to be important in perception and communication.

The hippocampus serves as a thoroughfare for information arriving from sensory areas en route to higher cortical areas for further association and encoding, a seeming crucial junction box both in information processing and learning. In particular the hippocampus has been implicated as central in the formation of memory and learned behaviors, and in particular spatial memory for places and resources. Rats with lesions introduced into their ventral hippocampus showed less time spent in interaction and an enhanced aggression which was not attributable to anxiety. This effect however occurred only in young rats and not in those lesioned after weaning, indicating that damage to cortical integrative circuits sustained before or during the period of learned social behaviors can result in schizophrenic 'asociality' (Becker et al., Psychopharmacology, 1999). Furthermore lesioning of the hippocampus, which processes auditory information, results in a loss of filtering of auditory information presented in the form of paired clicks, as the electrical signal produced by the second click was not substantially attenuated in the lesioned animals. As with the PPI test, this suggests that filtering of auditory information is deficient, and may occur at the level of the hippocampus, which mediates, at least in part, the selective filtering of sensory information.

The brain functions, as do its individual units of information processing (neurons), as difference detectors, comparing two inputs, for example sensory input with stored memory, and subtracting the current (sensory) input from the past (stored) experience (which may for example be a recent or evoked memory), and projecting the difference in the form of a (non-linear) output. If there is no difference between a present stimulus and a past stimulus then the pattern may be said to be ‘expected’ and that there is relatively little that is new to report (from Bilder, Mannarcc, Conference 2000) and thus little information processing capacity is devoted (energy) within higher cortical centers (attention) as the information may not be projected as extensively to higher centers for processing. By this means, only changes in environment 'perceived as significant' are passed forward and unwanted background information is filtered out, although in schizophrenia it is this filtering that is apparently impaired.

Andreasen and colleagues (Biol.Psychiatry, 1999) postulate that the diverse symptoms of schizophrenia are due to a single disorder involving the misconnection of neural circuitry within the cortical-thalamic-cerebellar-cortical (CCTCC) circuit, which is critical in the synchronous firing of neuronal centers involved in the smooth co-ordination of mental processes. Andreasen proposes that when the synchrony of the CCTCC circuit is impaired the patient suffers from cognitive dysmetria, and it is this impairment of basic cognitive processes which defines the hallmark of schizophrenia. Hence many different disruptions of this circuit may produce a common phenotype, just as many different ways in which cells may fail to regulate their growth and survival might result in a cancer.

Andreasen has argued that their is connectivity between nodes (or clusters of neurons involved in processing) in the pre-frontal cortex, the thalamic nuclei and the cerebellum. Any fundamental disruption in the CCTCC circuit may result in a cognitive impairment or dysmetria, associated with a difficulty in prioritizing, processing, co-ordinating, and responding to sensory information. This, as has been long since demonstrated for the visual system, shows that the brain is not comprised of a series of clearly defined and discrete functional centers ascribed to specific functions such as memory or logical thought, but rather is comprised of diffuse aggregates of functionally associated neuronal clusters, or nuclei, which distribute and dynamically process information in parallel. Thus damage to the delicate microelectronic circuitry of the brain can readily disrupt the highest level brain functions such as language, intelligence and social behavior.  Difficulties in isolating a cognitive deficit to any one receptor or part of a circuit is difficult, as function is thus devolved, and all neurons are ultimately interconnected. Further, any given neuron may express upon its receiving surface receptors for as many as six or more different neurotransmitters. From these basic observations there is an implicit divergence of information flow, and the consequences of disrupting signaling via any one type of neurotransmitter has widespread consequences for information processing across and between many circuits.

A Diaspora of theories of the causation of schizophrenia

A plethora of theories have arisen to explain the deficits associated with schizophrenia including specific or ‘global’ changes in neurotransmission involving a given neurotransmitter, cell type or receptor, and a host of changes in brain function elicited by agents as diverse as stress, developmental aberrations and viral infection. These may be summarized as follows,
 

Changes in neurotransmitter systems

Other popular theories

Dopamine  Glutamate  Acetylcholine  Serotonin  GABA  Norepinephrine

Miswiring of the brain during development  An inherited disorder exacerbated by stress and hormonal changes  A transmissible viral infection Perinatal hypoxia  Autoimmune damage  A neurodegenerative disorder (such as Alzheimers, Parkinson's)  An inherited predisposition interacting with a overload of dietary proteins  The loss of tissue due to the neurotoxic effects excessive nerve transmission  Social stressors in urban settings  Depletion of certain fatty acids in cell membranes  Dietary Exorphins from milk

 

The Dopamine hypothesis

The central involvement of a deficit in dopamine function in schizophrenia is suggested by the observation that medications which alleviate the psychosis of schizophrenia such as chlorpromazine (Thorazine) act by antagonizing the actions of dopamine at its receptor, especially the D2 receptor. Bilder proposes that dopamine systems mediate the comparison of observed (perceived) and expected ('normal') patterns of events within resonant cortical circuits, measuring departures from ‘normality’ as deviations from patterns of expected resonance. By antagonizing dopamine receptors it is possible to block these perceived shifts, and the attendant projections of ‘nonexistent’ perceived events (hallucinations) during the active phase of schizophrenia.

Dopamine receptors are present in the prefrontal cortex (PFC), nucleus accumbens, striatum, hypothalamus and hippocampus, and are believed to mediate the motivational aspects of reward and reinforcement following dopamine (DA) release from projections from the ventral tegmental area into the striatum, nucleus accumbens and PFC which are under hippocampal influence. Further, drugs which increase dopamine by blocking its reuptake by the DA transporter into nerve terminals such as cocaine and amphetamine cause the positive symptoms of schizophrenia, such as increased locomotion, hallucination and other aspects of psychosis at high concentration.  Further, in 1995 Csernansky & Bardgett suggested that damage to hippocampal neurons, whose projections impinge upon dopaminergic terminals coming from the midbrain, might explain the anatomical and functional abnormalities in gating of sensory information observed in schizophrenia.

The contention that an excessive state of dopaminergic activity is present in schizophrenia has been demonstrated by Laruelle and colleagues who showed by SPECT imaging that acute challenge with the dopamine uptake inhibitor amphetamine caused a greater, although variable, increase in dopamine release from presynaptic terminals in the striatum of schizophrenics as measured by an increase in the occupancy of D2 receptors in schizophrenic patients relative to 'healthy' patients, indicating some manner of a dysfunction of dopamine regulation in these individuals (Laruelle et al., 1999).  However, this could only be observed during the active phase, when psychotic episodes are known to occur.  However, there was no difference noted in D2 receptor availability in the absence of amphetamine challenge (or during periods of remission), although amphetamine challenge stimulated a worsening or emergence of positive symptoms, suggesting that schizophrenics exhibit a dysregulation of striatal dopamine release (Abi-Dargham et al., 1998). However, there is a small, but significant increase both in D2 receptor density post-synaptically and in presynaptic DOPA decarboxylase activity (Laruelle, Quart.J.Nuclear Med. 1998).

As dopamine is held to modulate, or 'color', the tone of excitatory transmission through projections of the frontal and temporal cortex to the basal ganglia (e.g. striatum) and other areas, dopaminergic transmission is thought to be implicated in the deficit in information processing associated with the prefrontal cortex, the PFC having one of the highest concentrations of dopaminergic nerve terminals. It is believed that a high concentration of certain DA receptors interact with glutamate receptors to facilitate memory formation in the PFC (D1?). Professor Goldman-Rakic has argued that the 'derailed' train of thought associated with schizophrenia is due to a deficit in working memory, the executive function of the prefrontal cortex. As the prefrontal areas receive a high concentration of dopamine, and drugs that are effective in treating schizophrenia act on these dopamine receptors, such as clozapine, Professor Goldman-Rakic argues that enhanced dopamine levels ‘induced’ by clozapine act to improve thinking and memory. Perhaps this is the mechanism by which cocaine and ritalin (methylphenidate) enhance cognitive performance, attention and memory, by increasing availability of DA in the PFC through an inhibition of reuptake. If so, there must be a fine balance, as cocaine and other dopamine uptake inhibitors also cause the positive symptoms of schizophrenia at high doses.

The Glutamate Hypothesis

Much of the transmission of excitatory information in the brain occurs via the binding of glutamate to its receptors, and, directly or indirectly, the activity of most neurons in the brain are influenced by this excitatory amino acid. The blockade of one specific glutamate receptor, the NMDA receptor, which plays a critical role in the plasticity of nervous connections associated with learning and memory, appears to mimic certain symptoms of schizophrenia. Two of the more popular psychoactive drugs of the 1970's, phencyclidine ('Angel Dust') and ketamine ('Special K') specifically block NMDA receptors and cause hallucinations in humans, as well as stereotyped, repetitive behavior and social withdrawal in both rats and humans, thereby reproducing both the positive and negative symptoms present in schizophrenia. Ketamine, a dissociative anesthetic, causes a schizophrenia-like psychosis in healthy individuals and exacerbates the psychotic symptoms in schizophrenic patients, decreasing their apparent responsivity to environmental stimuli (Shiigi & Casey, Psychopharmacology, 1999).

In light of these observations, one theory which has been put forward is that schizophrenia results from a hypoactivity of glutaminergic transmission in the brain. A decrease in glutaminergic output from the hippocampus, coupled with the high levels of glutamate receptors present (particularly NMDA) in the anterior cingulate cortex, one of the principal targets of hippocampal glutaminergic output, may underlie some of the diminished cognitive aspects and processing deficits associated with schizophrenia. In contrast Professot Dan Javitt and colleagues have suggested that treatment with glycine, a co-transmitter essential for proper NMDA functioning, improves the negative symptoms of patients with schizophrenia (Heresco-Levy et al., 1999). Memory and other cognitive deficits in schizophrenic patients may be explained in part by reductions in transript (mRNA) for the glutamate receptor subunits NMDAR1, GluR1, GluR7 and KA1 mRNA levels in frontal cortex both in drug-free and drug-withdrawn schizophrenics (Sokolov, J.Neurochem., 1998).

The NMDA receptor has a key function in information processing as a coincidence detector implicated in the molecular basis of learning and memory, as converging and coincident signals must be received by a nerve cell bearing this receptor upon its receiving terminals, or dendrites, for its activation (see Eric Kandel, Principles of Neural Science).  Many have proposed that abnormalities in the functioning or expression of this receptor may underlie both a predisposition to and a manifestation of schizophrenia (Catts et al., Aus.& N.Z.J.Psych, 1997). Indeed mice genetically engineered to have a reduced level (5%) of NMDA receptor expression display social and sexual impairments in their interactions in addition to the stereotyped behaviors and increased motor activity of schizophrenia (Mohn et al., Cell, 1999), which could be ameliorated by antipsychotic drugs that antagonize both dopamine and serotonin receptors. In the social interaction test, an animal model of schizophrenia, PCP (a non-competitive NMDA antagonist) induces social isolation and stereotyped behavior in rats which could also be overcome by anti-psychotic drugs which act at DA receptors (Sams-Dodd,Neurosci & Biobehav.Rev, 1998). Indeed, a measurable disturbance in glutamatic and N-acetyl aspartic acid levels has been shown in unmedicated schizophrenics (Kishimoto et al., 1998).

The Acetylcholine Hypothesis

It is notable that the prevalence of smoking amongst schizophrenics is 3 times higher than in the general U.S. population (20-25%), as over 75% of schizophrenics smoke. Further, nicotene withdrawal may temporarily worsen schizophrenic symptoms, suggesting that nicotene may help to control psychotic symptoms. The specificity of nicotene in its action upon a subtype of 'fast' acetylcholine receptors, known for their mediation of rapid excitatory signals, especially within the presynaptic terminal, infers a central role for acetylcholine in the etiology of schizophrenia.

Cortical acetylcholine is known to mediate the detection, selection and processing of stimuli and associations, and may additionally play a role in the filtering and allocation of other processing resources for these attentional functions. Attention is impaired if increases in cholinergic tone are blocked either by increasing GABAergic activity or by removing cholinergic inputs. Nicotene modulates both the failure to see inhibition of the P50 auditory-evoked response to repeated stimuli and the dysfunction in smooth pursuit eye movement associated with schizophrenia. Indeed D2 (and D1) antagonists attenuate increases in cortical ACh release stimulated by dopamine release within the Nucleus Accumbens, increases which are mediated by GABAergic neuronal projections to the basal forebrain that control the excitability of basal forebrain cholinergic neurons ([NA] DA Þ {-} GABA Þ {-} ACh [BF]). As DA release is elevated in the Nucleus Accumbens during both the acute phase of schizophrenia and as a result of the action of psychoactive drugs, it is suspected that cholinergic tone in the forebrain is altered in schizophrenia (Sarter et al., Annals N.Y.Acad.Sci., 1999). Further this opens up the possibility of using nicotene as a treatment in schizophrenia, as it exhibits anxiolytic, attentional and cognitive benefits. Is schizophrenia attributable in part to a hypocholinergic deficit?

However, just as 'fast' nicotinic receptors may be implicated in schizophrenia, so may 'slow' acetylcholine receptors, inferred by the actions of clozapine which has a high affinity for these slow 'metabotropic' ACh receptors. This raises the possibility that the functional deficits in schizophrenia are attributable to changes in function of slow as well as fast receptors.

The Serotonin hypothesis

The action of clozapine, an atypical antipsychotic used in the treatment of individuals resistant to dopamine antagonists which is noted to have a high affinity for serotonin receptors, suggested that serotonin (5-HT) may also play a role in the etiology of schizophrenia.

Prozac (fluoxetine), an anti-depressant, as well as other serotonin reuptake blockers (SSRIs), are alleged to cause long-term deficits in memory, concentration and even mental disability, disrupting perceptions of reality and creating false memories (see Ann Blake Tracey, Prozac, Panacea or Pandora). Elevated levels of serotonin (5-HT) are found in schizophrenia, and SSRIs are alleged to have created an epidemic of suicide attempts (source: Prozac: Panacea or Pandora, by Ann Blake Tracey). Another potent serotonin-releasing agent, MDMA, otherwise known as ecstasy, causes hallucinations, memory deficits and other psychiatric symptoms affecting mood, cognition and anxiety (McGuire, 2000) which are related to changes in serotonergic function.

The GABA hypothesis

Disputes have arisen as to whether GABA receptor function is altered in schizophrenics from evidence obtained from binding studies (Abi-Dargham et al., Neuropsychopharm., 1999), although GABAergic projections are certainly involved in mediating the effects of dopamine released from the nucleus accumbens upon activity in the prefrontal cortex.

Benzodiazepines, which act to increase the efficacy of transmission through GABA receptors and which are used both as sedatives and in the treatment of anxiety, have also been shown to ameliorate the core positive symptoms of schizophrenia (Pato et al., 1989). Indeed the brains of cocaine addicts, who exhibit schizophrenic symptoms, are more sensitive to benzodiazepines than those of drug-free individuals, indicating a change in GABA pathways in these individuals (Am.J.Psych., 1998).  GABA receptors have further been shown to be important in the acquisition of behavioral sensitization to drugs that induce schizophrenia-like behaviors, such as metamphetamine.

Bogert's temporolimbic hypothesis suggests two phases, a first in which a preferential loss of GABA receptors bearing NMDA glutamate receptors occurs, making the brain effectively hypofunctional for NMDA receptors, and a second stage in which the neural circuits altered by the loss of these GABAergic neurons are activated in late adolescence, but are consequently dysfuntional.

Recent interest has focused upon the reelin gene (RELN) whose expression is decreased by 50% in the telencepahlic GABAergic interneurons of the PFC, temporal cortex, hippocampus & also the glutaminergic cerebellar granule cells in schizophrenic patients. Reelin’s signaling target, DAB1, is present in the neuroplasm of hippocampal & pre-frontal cortical pyramidal neurons as well as that of cerebellar Purkinje neurons (Impagnatiello et al., PNAS, 1998). Further a second generation of telencephalic (including PFC, temporal cortex & hippocampus) region RELN is expressed in the adult cortex by horizontal and bitufted GABAergic interneurons, and thus RELN mediated signaling, similar to that which is operational during development, may continue during adult neurogenesis. Further there are alterations in the level of GAD expression in GABAergic neurons in the PFC and changes in GABAA receptor density in the dentate gyrus and corticolimbic structures in schizophrenic patients (Impagnatiello et al., PNAS, 1998).

The anatomical and developmental theory of schizophrenia

Benes proposes that a developmental miswiring of dopaminergic inputs onto GABAergic neurons in the cortex occurs around birth (J.Psych.Res., 1997). Since the cortical dopamine system continues to mature until adolescence, the formation of misplaced connections during the normal ingrowth of dopaminergic fibres which occurs at this time, possibly exacerbated by stress, could trigger the onset of symptoms. Further evidence for a developmental onset comes from studies with rhesus monkeys irradiated with X-rays during fetal devlopment which resulted in no ill effects until puberty, when schizophrenia-like symptoms such as poor working memory and hallucinations began to emerge (Castner et al., Soc.for Neuroscience, 1998). This lends further weight to the theory of Professor Goldman-Rakic that fetal brain damage predisposes an individual to the onset of schizophrenia at puberty.

Andreasen and colleagues (Biol.Psychiatry, 1999) have postulated that the diverse symptoms of schizophrenia are in fact attributable to a single disorder linked by a neurodevelopmental mechanism that results in the misconnection of neural circuitry, and specifically within the cortical-thalamic-cerebellar-cortical (CCTCC) circuit which is critical in the synchronous firing of neuronal centers involved in the smooth co-ordination of mental processes. Andreasen proposes that when the synchrony of the CCTCC circuit is impaired, the patient suffers from cognitive dysmetria, and this impairment of basic cognitive processes defines the hallmark of schizophrenia.  Neuropathological changes occurring during the developmental stages of formation of the hippocampus has become a popular theory in predisposing an individual to schizophrenia, as the hippocampus is central in the processing, routing and filtering of sensory information which are known to be affected in schizophrenia (www.augsburg.edu/psych/vml/schizo.html). A loss of inhibitory neurons (GABA) appears to occur within the limbic lobe during development, concomitant with an infiltration of processes from excitatory neurons from elsewhere in the cortex, possibly predisposing to excitotoxicity.  It seems that losses of neurons (gray matter) are reported to occur in schizophrenia by many groups, especially from the hippocampus, the amygdala, the superior temporal gyrus, parahippocampal gyrus and thalamus (www.augsburg.edu/psych/vml/schizo.html), and the PFC has been reported to decrease in volume in some patients. Indeed David Lewis suggests that a specific part of the circuitry of the PFC, specifically the chandelier neuron axon cartridge which controls information processing within other neurons in the PFC, is specifically reduced by 40% in schizophrenia (PNAS, April 1998). The density of expression of GABA transporters in these chandelier neurons is also decreased by 40%, again within these chandelier axon cartridges, an attractive and functional description of a neuron with divergent outputs (Impagnatiello et al., PNAS, 1998).

However, a significant proportion of individuals diagnosed as schizophrenic do not show symptoms until very late in life, seeming to argue against an exclusively developmental basis for schizophrenia (Owen & Castle, Drugs and Aging, 1999). Andreasen and others have also proposed that an enlargement of the fluid filled ventricles of the brain may also be a feature of schizophrenia, although Staal and coworkers using computerized axial tomography demonstrated no correlation between the incidence of schizophrenia and ventricular enlargement, although it was predictive for the severity of symptoms (Schizophrenia Bulletin, 1999). Woods concluded that there is strong evidence AGAINST a classic neurodegenerative pathogenesis in schizophrenia, but that there is some support for prenatal developmental abnormalities and a loss of brain volume after the initial development of symptoms (Am.J.Psychiatry, 1998).

It may, however, be the case that the estimated 5% decrease in the volume of gray matter in the cortex may be due to a decrease in the number of connections between cells, including dendrites and chandelier axon cartridges, rather than primarily due to the loss of neurons or glia (Arch.Gen.Psych., 52, 1995). Thus the poverty of thought, attention and memory associated with schizophrenia may reflect a poverty of brain cell interconnections, due to the excessive pruning of these axonal and dendritic connections, a process that appears to be at its height during adolescence (after puberty), although many now believe that the process begins before birth.

Steroids and the two hit model of schizophrenia

Steroid hormones influence a wide range of physiological functions from reproduction, stress, immune and inflammatory responses to behavior, motor function and even cognitive performance (Rupprecht & Holsboer, 1999; Di Paolo, 1994). It has been proposed that there is a relationship between disrupted forebrain development and signaling by the steroid-like hormone retinoic acid, which is produced by a developmental layer of cells derived from neural crest known as the mesenchyme (within the anterior neural tube), responsible for the induction and differentiation of adjacent epithelia. It is this induction mediated via interaction between the retinoic acid-producing mesenchyme and and the anterior surface epithelium of the embryo that guides differentiation and PATHWAY FORMATION. It is thought that such a developmental flaw, either inherited or environmental, may constitute the "first hit" in the genesis of schizophrenia.

Schizophrenia is extremely uncommon before adolescence and puberty, suggesting that the surge of altered steroid hormone biosynthesis associated with this stage of development, and possibly also those steroid hormones which are elevated in response to stress during these critical career-forming years of life, may also be implicated in the etiology of schizophrenia. Further, sex hormones have been shown to influence dopaminergic activity (Di Paolo, 1994). Such surges in hormone levels may constitute the "second hit" in schizophrenia, facilitating excitotoxicity or oxygen radical formation that leads to neuronal damage. Indeed stress is well known as a common precursor of the first episode of psychosis.

There is further evidence that altered levels of sex steroid hormones are associated with schizophrenia. Male schizophrenics were found to have higher levels of Lutenising Hormone (LH) and testosterone than healthy subjects, presenting a puberty-like profile, and female schizophrenics higher levels of LH and lower levels of estrogen, in effect a menopause-like profile (Kulkarni et al., Schizophrenia Res., 1996).

Schizophrenia: An inherited disordering of the mind?

Interest in an inherited causality for schizophrenia came from observations that schizophrenia often appeared to be clustered in families, an identical (monozygous) twin having a 40 to 50% chance of developing the illness, and a child of a schizophrenic parent around 10%. These rates are statistically high, but suggest neither classic Mendelian patterns of inheritance, nor exclude the effects of family or local environmental influences. A study of relatives of adoptees, in an attempt to minimize environmental influences, also found that schizophrenia is concentrated within biological families, the incidence of schizophrenia being slightly, but significantly elevated (5.1%) within the biological relatives of adopted schizophrenics (Kety & Ingraham, J.Psych.Res, 1992).  Psychiatric studies have suggested that schizophrenia is a disorder with multifactorial inheritance, i.e. involving many genes present in many different locations throughout the bank of human ‘chromosomal’ information, as schizophrenia does not follow simple Mendelian inheritance.

A disruption of genes that govern the neural crest-mediated, RA-dependent induction and differentiation in the forebrain such as Pax-6 & Gli-3 might be implicated in schizophrenia (LaMantia, Biol.Psych., 1999) and perhaps crucially, the secreted extracellular matrix protein reelin (RELN) may play a role in schizophrenia.  Linkage analysis of microsatellite regions in families with patterns of schizophrenia have revealed that genes predisposing susceptibility to schizophrenia may be present on chromosomes 1q, 5q, 6p, 8p, 13q, 15q, 18p and 22q (Shastry, Neurogenetics, 1999), one of which (15q, locus 14), has been associated with the a7 nicotinic receptor underlying the P50 deficit of schizophrenia (Adler et al., Biol.Psych.1999) . Regions on chromosomes 3, 9 and 20 have also been proposed to be candidates for schizophrenia genes (www.augsburg.edu/psych/vml/schizo.html). Thus not only may the many hundreds of genes involved in neuronal signaling and the development of the nervous system be potential factors in schizophrenia, but at least 8 chromosomal regions, each of which potentially may contain many genes which predispose to schizophrenia, have been variably associated with linkage analysis. This observation rather supports Andreasen's contention that any "misconnection of neural circuitry ... within the cortical-thalamic-cerebellar-cortical circuit which is ... involved in the smooth co-ordination of mental processes... when .... impaired, (causes) the patient (to) suffer from cognitive dysmetria". This variation in causality is further suggested by the observation that 2% of schizophrenics have microdeletions on chromosome 22(q11) which may be associated with altered speech and learning difficulties (Weinberger, Biol.Psych., 1999).  In addition, variations in the D5 receptor gene have been found in some (but not all) schizophrenics (Feng et al., Am.J.Med.Gen. 1998).  Schizophrenia may result from small so-called unstable expansions of repeating trinucleotide (CAG)n and (CGG)n 'triplet' microsatellite sequences associated with dominant genes associated with ataxia (a disorder of movement) such as Spinal Cerebellar Ataxia type 1 (SCA1, Fischer, Med.Hypoth. 1998). Intriguingly, such an expansion of a random repetition of the nucleotides at the beginning of a gene that encodes for a K+ channel (hKCa3) in one of the chromosome regions believed to be associated with schizophrenia, may be involved in the regulation (inactivation) of NMDA receptors (Li et al., BBRC, 1998).

Clearly the evolution of parallel processing within the neocortex in higher mammals, which requires a prolonged period of development ex utero before language and social function are fully developed (perhaps as long as seventeen years after birth in humans), leaves many potential avenues for disruption or injury, some of which we may refer to as schizophrenia. Alternatively, are schizophrenics an example of a previously advantageous polymorphism of form or function that is currently disadvantaged in the high information throughput, technocratic and intensively socially interactive society of today.  For example genes that protect against typhoid and malaria in 'single dose' are lethal in double dose in cystic fibrosis and sickle cell anemia respectively. Would an absence of sensory filtering have been advantageous to a neolithic hunter whose auditory and visual responses remained uninhibited to sounds and sights of predator or prey? Is schizophrenia an example of the 'Odyssian personality' which gives rise to an advantage in evolutionary adaptation in changing times (Rison, 1998)?

Other prevailing theories on the causation of schizophrenia

Five studies have suggested that being born or raised in an urban area is a risk factor for schizophrenia. E.Fuller Torrey and Yolken have proposed that an infectious agent transmitted through household crowding maybe responsible (Schizophrenia Bulletin, 1998). Even neurotrophic viruses have been suggested. Royce Waltrip believes that the Borna disease virus, an agent that was thought only to affect horse and sheep, causing brain inflammation through an immune response, is also a causative agent in schizophrenia. Waltrip and co-workers found antibodies to the Borna virus in 9 of 25 schizophrenic twins in a cohort NIMH study. Previous investigators have suggested that a first "hit" risk factor for schizophrenia may be viral infection in utero, although studies in Britain (Cannon et al., Br.J.Psychiatry, 1996) and the Netherlands (Takei et al., J.Psych.Res, 1995) indicate that exposure to the influenza virus during gestation poses no substantial risk for schizophrenia.

Other factors predisposing to schizophrenia include perinatal hypoxia, autoimmunity (Jones & Cannon, 1998). Dohan's Hypothesis, proposes that Schizophrenia is an inherited predisposition which interacts with a overload of dietary proteins such as casein, glutens or gliadins. In a potentially related finding, exorphins, morphine-like compounds produced from milk protein which are taken up into the brain, are elevated in 95% of autistic and schizophrenic children, especially b-casomorphin-7. In contrast Peet & Puri have proposed that schizophrenia is caused by a depletion of certain fatty acids in the membranes of nerve cells, symptoms which are ameliorated with dietary intake of EPA.

Other neurotransmitter systems, not all of which have been identified to date, may be involved. For example norepinephrine (NE) is proposed to a role in the induction of psychosis, and is further evidenced by the observation that a prenatal exposure of rats to amphetamines causes an increase in NE levels in the PFC. These observations are taken to be suggestive of a hyperactive NE system, resulting in psychotic behaviors (Nasif et al., Brain Res., 1999).

Other causative hypotheses take into account socio-developmental factors. Dysfunctional relations with, or absence of mother were thought by some to be schizophrenigenic, although this argument is now widely refuted. Social stressors in urban settings are thought to facilitate the onset of disease in vulnerable persons (www.ndmda.org/schiz.htm). Indeed the loss of neuronal and/or connective tissues in schizophrenic patients due to the neurotoxic effects of overtransmission of dopamine or excitatory amino acids (glutamate; www.augsburg.edu/psych/vml/schizo.html) may be attributable, in part if not in whole, to stress.

In conclusion Andreasen has demonstrated that there is connectivity between nodes (or clusters of neurons involved in processing) in the pre-frontal cortex, the thalamic nuclei and the cerebellum. Any disruption in this circuit may result in a cognitive impairment or dysmetria, leading to a difficulty in prioritizing, processing, co-ordinating and responding to information:- central deficits in schizophrenia. Specific neurochemical disruption involving the release or reception of the neurotransmitters serotonin, glutamate, dopamine, acetylcholine, norepinephrine or GABA may be sufficient to wholly or partially mimic the symptoms of schizophrenia. Thus schizophrenia may be regarded as a heterogeneous dysfunction of cognitive and sensory processing.

Schizophrenia: A contemporary epidemic?

Schizophrenia is a disabling condition with an age of onset which is earlier for men (15-25) than for women (25-35), with a lifetime prevalence of 1.3% within the U.S. population (NIMH, or 2-3 million Americans, of whom fewer than 1 in 5 recover fully. About half of all schizophrenics will attempt suicide at least once, 10-15% of whom will be successful. Schizophrenia has an attributed, estimated annual direct and indirect cost to U.S. of $30-48 bn, and there are related costs due to the high prevalence of substance abuse and cigarette smoking amongst schizophrenics. More intriguing and indicative for the possible role of environmental factors in the etiology of schizophrenia, is the epidemiology of the disease.  Specifically the question is whether the incidence of schizophrenia is rising (or falling) as a consequence of changes in lifestyle and work practices? Surprisingly there is little evidence available in the literature to reveal any such patterns, although one paper was found which predicted an incipient epidemic of schizophrenia amongst young black males, a high risk group within the U.S. population (Turns, Ann.Med.Psychol., 1980).

Who constitute high risk groups for schizophrenia?

Low socio-economic status has NOT consistently been shown to be a risk factor for schizophrenia although this remains contentious. Several high risk groups have been identified however, in addition to late adolescent males, especially blacks (Turns, 1980), and women during menopause, childbirth and pregnancy. Against a background prevalence of 1.3% for the general U.S. population (and approximately 1% in the U.K.), a recent follow-up study of mental health amongst non-German speaking immigrants indicated that 38.7% were schizophrenic, whilst only 8.3% were diagnosed as impaired at the time of entry, although this was admittedly seen as an overestimate due to language difficulties (Haasen et al., 1998).

Studies amongst the homeless in Germany have indicated that schizophrenia is significantly over-represented amongst both women (21.9%, Greifenhagen & Fichter, 1997) and men (12.4%, Fichter et al., 1997). These studies were the lowest estimates available, and likely an underestimate as some studies found that between a third and two-thirds of the homeless population were afflicted by schizophrenia. Intriguingly, whilst the rates for effective psychoses were low among men in Greenland, a possible model for 'social' isolation in comparison to the Danish mainland, rates for schizophrenia and suicide were found to be very high (Lynge et al., 1999).

Do psychoactive drugs cause or merely mimic schizophrenia?

Although it is widely accepted that whilst drugs which act by ‘blocking’ NMDA receptors (e.g. PCP, ketamine), dopamine transporters (DAT; cocaine/metamphetamine) and serotonin transporters (prozac, MDMA) mimic in part or in whole the symptoms of schizophrenia, it is 'said' that they do not cause schizophrenia as their actions are transient, lasting only for the duration of drug action, cocaine for example having a half-life of only some 6 minutes. However, this presupposes that there is neither a progressive augmentation in their action (behavioral sensitization) which may eventually become sustained in the absence of drug, and secondly that the drugs themselves do not cause functional neurotoxic damage at these self-same sites of action which are sufficient to induce the ‘schizophrenia-like’ symptoms.

However behavioral sensitization is seen in both humans and animals exposed to metamphetamine, especially in regard to hallucinations, suggesting a prolonged change in the neurochemical balance within the brain (Ito, Hokkaido J.Med., 1999). Amphetamine especially induces psychosis after prolonged, frequent high dose exposure. Further, drugs which increase dopamine levels by blocking its reuptake by the DA transporter into nerve terminals, such as cocaine and amphetamine, cause positive symptoms of schizophrenia such as increased locomotion, hallucination and other psychotic states at high concentration. A clear correlation between the degree to which cocaine blocks this transporter and a cocaine abuser's euphoric feelings has been demonstrated, at least half of these transporters having to be blocked in order for the user to perceive cocaine's euphoric effects (Volkow, Nature, 1998). Ritalin (methylphenidate), a stimulant sharing a molecular mechanism of action with cocaine at the level of the DAT transporter, was administered to both cocaine addicts and non-users in PET studies. The cocaine (ab)users showed reduced dopamine responses to Ritalin in the striatum, a region linked to motivation and reward, and an abnormal increase in the DA response in the thalamus associated with intense experiences of cocaine cravings in addicts, not observed in the control group. Repeated exposure to cocaine causes long-term changes in behavior ranging from addiction to behavioral sensitization which are related to the nigrostriatal system of the basal ganglia, of which the striatum is a part. Chronic cocaine application causes alterations in the inducibility of bZIP transcription factors, immediate early gene expression (cFos) and changes in the expression of ensembles of striatal neurons which express these proteins, suggesting network level adaptations and a functional reorganization of these basal ganglia circuits (Moratalla et al., Neuron, 1996).

Cocaine, which is both a local anesthetic and vasoconstrictor, reaches the brain within minutes and produces a fast acting and short-lived period of euphoria mediated by an elevation of DA levels followed by a dysphoric 'crash' with depression, anxiety, craving and fatigue. Repeated doses of cocaine lead to the constriction of blood vessels in the brain and may at high doses cause brain hemorrhage, heart failure or stroke. There are more than an estimated 2 million cocaine addicts in the U.S. and 3.8 million users (NHSDA www.usdoj.gov/dea/concern/cocaine.htm). Perhaps more concerning, 4.7 million Americans have tried metamphetamine in their lifetime (otherwise known as speed, ice or crystal). Amphetamine was first marketed as Benzedrine in the 1930s when it was used to treat ADHD, and during WWII methamphetamine (Methedrine) and dextroamphetamine (Dexedrine) were used to motivate troops. Methamphetamine, or meth, is preferred by many drug-users as it produces a more gradual and sustained euphoric effect (a ‘cool smoke’) than crack cocaine (which results in a ‘hot smoke’). Further it is cheaper to purchase as it is produced in bulk by over 1,600 reported metamphetamine labs throughout Mexico and the U.S. (DEA figures, www.usdoj.gov/dea/concern/meth.htm). Use must rise with supply, as supply rises to meet demand, and there has been an exponential rate of increase in ‘meth’ lab seizures throughout the 90s.  Does this not suggest an epidemic of schizophrenia-like symptoms?

Chronic use of methamphetamine produces a psychosis that resembles schizophrenia, characterized by paranoia, picking at skin, preoccupation with one's own thoughts and hallucinations. Disorganized and violent behavior is often seen amongst chronic abusers. The long term changes seen in methamphetamine users may have a molecular basis, and indeed drugs such as PCP and cocaine induce lasting changes in the patterns of gene expression which may last for weeks following drug withdrawal. For example a single dose of PCP alters the neurochemistry of the anterior cingulate cortex and changes patterns of c-Fos expression (an immediate early transcription factor) in the striatum (Turgeon & Roche, Neuroscience, 1999). Repeated amphetamine exposure has been shown to alter DA systems and to induce behaviors reminiscent of both the positive and negative symptoms of schizophrenia in primates. Indeed, behavioral sensitization to amphetamines was present after 5 days of chronic exposure and persisted for as long as 28 months after withdrawal (Castner & Goldman-Rakic, Neuropsychopharm., 1999). Monkeys treated with PCP twice daily for 2 weeks displayed sustained deficits in tasks requiring PFC function. This repeated exposure to PCP caused a reduction in both the basal and evoked utlilization of DA in the dorsolateral PFC, consistent with observations in schizophrenic patients (Jentsch et al., Science, 1997).

Do psychoactive drugs cause brain damage?

It is well established that repeated treatment with psychostimulant drugs produces changes in brain and behavior that far outlast their initial neuropharmacological actions. These changes contribute to the development of dependence and of addiction and psychosis. A range of tests on chronic abstinent cocaine users and 'drug-free' controls revealed that cocaine caused reduced executive functioning, visuoperception, psychomotor speed and manual dexterity (Bolla et al., J.Neuropsych. Clin. Neurosci, 1999). Another study showed that cocaine abusers had deficits in attention, concentration, new learning, visual and verbal memory, word production and visuomotor integration (Strickland et al., J.Neuropscyh.Clin.Neurosci., 1993), consistent with persistent decrements of cognitive function, as occur in schizophrenia. Chronic cocaine abuse may be a neuropsychiatric syndrome, causing changes which include EEG abnormalities, seizures and a decrements in neurobehavioral performance, in addition to the acute psychotic and paranoid states associated with administration and the depression associated with withdrawal. Cadet and Bolla (Synapse, 1996) propose that chronic cocaine use is an example of a ‘disconnection syndrome’. Further, the vasoconstriction that cocaine causes leads to sustained hypoperfusion and ischaemic damage in brain regions, leading to significant cerebral hypoperfusion in the cortex (Strickland et al., J.Neuropscyh.Clin.Neurosci., 1993).

Which brain regions are implicated in schizophrenia & drug neurotoxicity?

Volkow's group in 1998 showed that cocaine addicts have evidence of persistent damage to their brain chemistry, their brains being more susceptible both to seizures and sleep abnormalities. Volkow’s group showed that the brains of cocaine addicts were more sensitive to drugs which enhance GABAergic activity because of damage to these GABA pathways which transmit pleasure signals to other regions of the brain.

Whilst neither amphetamine or cocaine have been shown to cause neurotoxicity in the nucleus accumbens (Xu et al., Brain Res., 2000), mice engineered to express higher levels of DAT transporters (THDAT mice), whilst habituating more rapidly to novel environments and displaying an enhanced reward in response to cocaine, show 50% greater losses in dopaminergic neurons in response to MPTP toxin treatment than controls, indicating that dopaminergic neurodegeration occurs in response to substance abuse (Donovan et al., 1999). The appearance of decreased N-acetyl compounds in the frontal cortex of abstinent cocaine abusers is further indicative of sustained neuronal injury in this region (Chang et al, Am.J.Psych., 1999), and even sub chronic cocaine administration for 5 days results in a pronounced degeneration in the lateral habenula (LHB) and its primary efferent tract (output) the fasciculus retroflexus (Ellison, 1992).

Immunostaining revealed a marked decrease in the density of GABAergic, but not glutaminergic, nerve terminals in the lateral habenula (LHB), but not in the nucleus accumbens, suggesting an exquisite sensitivity of this specific neuronal population. It is suggested that a decrease in inhibitory GABA activity leads to increased excitatory transmission through LHB glutaminergic neurons and a resulting neurotoxicity within and consequent degeneration of the fasciculus retroflexus (Meshul et al., Synapse, 1998). The habenula is the chief relay nucleus of the descending dorsal diencephalic (DDD) system which is an important link between limbic and striatal forebrain and lower diencephalic/mesencephalic centers. The DDD system has functional connections by which to modulate sensory GATING through the thalamus (sensory), pain gating through the central gray and raphe (pain), and motor stereotypies and reward mechanisms through the the substantia nigra and VTA. Lesions to the habenula alter a variety of behaviors, and damage to this habenula pathway constitutes an excellent candidate for producing behaviors which occur during psychosis (Ellison, Brain Res.Revs., 1994). At recreational doses, metamphetamine causes a decrease in striatal DAT transporter density in primates, indicative of a loss of DA neuron axonal terminals, which were further depleted at higher doses (Villemagne et al., J.Neurosci, 1998). Further, continuous amphetamine (but not cocaine) administration is neurotoxic to DA innervations in the caudate nucleus (Ellison, Brain Res.Rev., 1994).

Ecstacy, or 3,4 methylenedioxymethamphetamine (MDMA), evokes both a ‘calcium-independent’ release of brain monoamines (i.e. serotonin, dopamine, norepinephrine, Johnson et al., 1986) and inhibits their inactivation by reuptake into nerve terminals (Steele et al., 1987).  At sufficient concentration MDMA may cause a depletion of serotonin (5-HT) transporters ranging from 44% in the pons to 89% in the occipital cortex, indicative of widespread damage to serotoninergic neurons in these regions (Scheffel et al., Synapse, 1998). Whilst some regions recovered after 9 months e.g. hypothalamus, others areas such as the neocortex did not appear to recover from what appears to be a loss of serotoninergic axonal terminals (neuronal outputs).

Even though no apparent neurotoxicity is apparent in the nucleus accumbens, repeated application of cocaine or amphetamine causes alterations in the morphology of dendrites and dendritic spines, increasing both dendritic branching and spine density (synaptic contacts), thus reorganizing patterns of synaptic connectivity in the nucleus accumbens and prefrontal cortex (Robinson & Kolb, Eur.J.Neurosci., 1999). In addition cocaine inhibits neuronal differentiation in PC12 cells in response to Nerve Growth Factor (NGF, Zachor et al., Mol.Gen.Metab., 1998), and cocaine further causes programmed cell death (apoptosis) in embryonic neuronal precursor cells, which may be suggestive of a more general process of reorganization of plasticity and connectivity.

Telling insights from animal models of schizophrenia

"The absence of an animal model that accurately approximates schizophrenia limits current research into the pathophysiology of this disorder" (O'Donnell & Grace, 1999)

Normally the presentation of a weak stimulus immediately before a stimulus which is sufficient to startle a rat will lead to a decrease in the magnitude of the resultant startle response, a phenomenon termed prepulse inhibition (PPI). This provides a measurement of sensori-motor gating which is also deficient in schizophrenia patients. Intriguingly isolating rats from weaning to adulthood also causes this deficiency in the PPI response and hyperactivity, without apparent evidence for a genetic predisposition, as it occurred regardless of the breeding strain used. However the PPI deficits induced by isolation only emerged during or after puberty, in contrast to the hyperactivity (Bakshi & Geyer, Physiology and Behavior, 1999).  Moreover these effects persisted after the cessation of isolation (Domeney & Feldon, Pharm, Biochem & Behav., 1998). Even a short stressful life event, such as a 24 hour maternal deprivation, was sufficient to introduce the reduction in the PPI of the startle reflex observed in schizophrenics. However this effect was not seen until puberty, suggesting that the action of stress steroid hormones may combine with those of sex steroid hormones to alter cortical development at this time (Ellenbrook et al., Schizophrenia Research, 1998). Thus even early life events may have a profound influence on information processing and social functioning. Perhaps pertinent is the observation that schizophrenics accommodated within the community rather than within the asylum suffer more relapses in a high ‘expressed emotion’ environment wherein they receive negative criticism, overinvolvement by certain members of the family, expressed hostility, and prolonged contact with such individuals (Green, www.priory.com/schizo.htm).

The hippocampus has been implicated as central in the formation of memory and learned behaviors and in particular spatial memory for places and resources. Rats with neonatal lesions in their ventral hippocampus, but not medial PFC (Lipska et al., 1998), showed less time spent in interaction and an enhanced level of aggression, which was not due to anxiety. This effect however occurred only in young rats and not in those lesioned after weaning, indicating that damage to cortical integrative circuits sustained before or during the period of learned social behaviors can result in schizophrenia-like 'asociality' (Becker et al., Psychopharmacology, 1999). The causation of this damage need only extend as far as the expression of a given gene, as mice expressing only 5% of normal levels of an NMDA receptor subunit show the impaired social and sexual functioning and stereotyped behaviors believed to be related to schizophrenia. Introduction of PCP induces stereotyped behavior and social withdrawal in rats, the animal behavioral correlate of schizophrenia, which was similarly alleviated by DA anti-psychotics (Sams-Dodd, Rev.Neurosci., 1999).

The slow decline in condition (prodromal phase) preceding of schizophrenia lasts several years (Hafner et al., Acta Psych.Scand., 1999) and social disability emerges 2-4 years prior to psychiatric admission. It has yet to be proven beyond doubt that the cognitive decline, deficit in PPI and other deficits present in schizophrenia occurs prior to, concomitant with, or as a result of social decline and isolation.
 
 

An alternative theory for the causation of schizophrenia:

The four 'S"s: Stress, steroids, solitude and sensory deprivation

Stress & Steroids

It is held that stress precipitates the positive psychotic symptoms of schizophrenia in many sufferers, and stress has been noted to precipitate positive symptoms in schizoid personality disorder sufferers who normally display only the negative symptoms of schizophrenia (Sverdlov, 1998). Indeed stress is a common precursor of the first episode of psychosis following a long prodromal phase where only negative symptoms are seen.

Stress induces the release of neuroactive steriods such as corticosterone from the hypothalamic-pituitary-adrenal axis, which like sex steroids including progesterone, have profound modulatory actions upon the function and expression of receptors and processes involved in the nervous transmission and processing of information. For example Cho and Little (Neuroscience, 1999) showed that perfusing slices from the ventral tegmental area, an area implicated in drug dependence and reward, with the steroid hormone corticosterone, released in response to stress,  caused an increase in sensitivity of the activity of dopamine-releasing neurons to the three 'fast' glutamate receptor subtypes AMPA, kainate and NMDA.

These pacemaker neurons release DA into the prefrontal cortex and nucleus accumbens as part of the neural mechanisms of reward and pleasure, and this increased sensitivity to glutamate is observed within 15 minutes of application of corticosterone, showing that stress can rapidly modulate neuronal activity and make neurons exquisitely sensitive to glutamate-mediated excitotoxicity. Indeed Gardner and others have proposed that mammals seek to maintain elevated DA levels within the Nucleus Accumbens, released from projections arising within the VTA, as a reinforcement of a positive activity, behavior or environment. Stress is catabolic, and pleasure, resulting in an elevation DA levels in the Nucleus Accumbens, PFC and hypothalamus is anabolic. So sex, food and social reward (for achievement or as a result of desirable or gainful behavior) can be argued to represent 'trophically' advantageous behaviors, and their reinforcement is mediated, at least in part, by enhanced activity within the dopaminergic system. However, this pleasure-seeking or reward behavior may be mimicked or bypassed by the use of psychoactive compounds which mimic or 'short-circuit' this enhancement of DA release, or else by abuses of food, video games or sexual activities, features of the densely-populated and technologically 'enriched' modern city environment.

A increase in the functional weighting of excitation through glutamate receptors over inhibition through GABA and glycine receptors leads to an increase, both directly and indirectly, in levels of intracellular calcium, the universal signal of intracellular excitability. Excess calcium entry into the cell, which may occur due to cerebral ischaemia (loss of oxygen), head injury, excitotoxic drugs or even excessive nerve cell activity, causes damage to nerve cells and their connections (terminals), and at very high levels can even cause their death. Hence extreme stress as a result of traumatic life events or as a process of active social isolation, either alone or in combination with psychoactive drugs and possibly excessive excitatory transmission, may lead to the damage of intricate neuronal circuits and hence of cognitive processing and behavior.

Excitotoxicity may in part explain the cognitive and functional decline observed in schizophrenia, but may not be the only possible explanation for a decline in the degree of neuronal arborization (dendrites and axons) which have been suggested to occur in schizophrenia, and accordingly further experimental evidence must be afforded in support of this model.

Solitude & Sensory deprivation: the activity dependence of survival

Neurons extend processes during development and repair which are guided by factors to their programmed targets by molecules secreted from their target cells known as neurotrophins. However, the establishment of functional neuronal connections requires the secretion of signals from the outgrowing axon terminals. Indeed this process has been shown to occur even in the absence of synaptic signaling, as mice that that lack the synaptic protein munc 18-1, essential for the release of neurotransmitters, nethertheless form 'normal' layered structures, fiber pathways and morphologically defined synapses during development (Verhage et al., Science, 2000). However, in the absence of functional synaptic transmission, the neurons in this 'knockout' mouse undergo programmed cell death (apoptosis), leading to widespread neurodegeneration. Thus neurons require activity (neurotransmission) to survive, and if such activity is absent they will die as part of a pruning process that maintains only those neuronal connections which are useful, i.e. functional, perhaps only a fraction of the number that are originally formed. Thus there exists a dual influence of neuron upon target, and of target upon neuron, by the release of neurotrophic factors such as Nerve Growth Factor (NGF). Thus there is a both a genetically-programmed and use-dependent refinement of connections in the nervous system during development, and the more sophisticated cortical circuits associated with information processing, language and higher social functioning which emerge both later in evolution and during development, require functional validation for the establishment of their final patterns of connectivity (Shatz, 1997).

Dr.Fred Gage and co-workers have shown that new cell growth continues to occur in the hippocampus in patients aged from 55 to 70, and in fact new cells are constantly being generated within the hippocampus and neocortex of adult monkeys (Gould et al., 1999). Further it has been shown that associative learning enhances adult neurogenesis in the hippocampus in rats (Gould et al., 1999), whilst stress, via the action of glucocorticoid steroid hormones, in contrast inhibits neurogenesis in the hippocampus and causes an increase of potentially neurotoxic glutamate release within the hippocampus (Gould & Tanapat, 1999).

Brain cells in most people do not in fact die when we age (excepting senile dementia, Alzheimer’s etc..), rather the number of connections that they form diminishes, and this connectivity is believed to correlate with a neuron’s "computational power", and is enhanced in response to growth factors called neurotrophins which are released when neurons are stimulated (McAllister et al., 1996), for example by new learning. Contextual learning in the hippocampus has been demonstrated to evoke the release of neurotrophin (BDNF), thereby increasing the extent of arborization of dendrites and thereby the potential computational power of the circuits involved (McAllister et al., 1996). Conversely, removing neurotrophins causes dendrites to atrophy, which suggests that a lack of brain activity causes a loss of computational activity and mental decline (Katz, McAllister & Lo). In fact neurotrophins help to maintain our intelligence and mental function via their release from active neurons, although it might be noted that neurons may be activated by a range of stimuli from sound through thought to smell and emotion. Thus sensory and social deprivation may cause a loss of computational power in regions of the brain involved in sensory processing, language and higher social intelligence, with the attendant consequences of social decline and lost opportunity.

Such is the degree of plasticity present in the nervous system for the growth and regeneration of new cells and processes, that even after the loss of sight or even actual regions of the brain, function can be restored or replaced in whole or in part by other regions in a time and use-dependent manner. For example monkeys who lose part of their brains involved in the control of fine finger touch and manipulation recover this function in neighboring areas over time with use in areas that previously had no such attributed function (Xerri et al., 1998). Similarly, people who lose their sight after development show a shift in functional activation of their visual cortex from sight towards somatosensory touch upon learning Braille.

As stated before, it may be the case that the interpretations of an estimated 5% decrease in the volume of gray matter in the cortex observed in schizophrenia may be attributable to a decrease in the number of connections between cells, such as the dendrite and chandelier axon cartridge, rather than primarily a loss of neurons or glia per se (Arch.Gen.Psych., 52, 1995). The poverty of thought, attention and memory associated with schizophrenia may reflect an acquired and progressive impoverishment of brain cell interconnections, due to an excessive loss or pruning of axonal and dendritic connections.
 

In search of an explanation for schizophrenia: Mice, men or the mind?

Each model of study the mind, the brain and the animal model affords advantages and disadvantages, in effect forcing a pronged approach to the study of multifactorial traits such as schizophrenia or depression.
 

Advantages	Disadvantages
Mice allow genetic manipulation and the rapid expression of traits ‘Men’ allow linkage analysis and DNA testing of defined psychological profiles determined by psychometric parameters The ‘mind’ allows the study of the dynamic functioning of the brain in response to fixed stimuli, measured by imaging or electrically evoked potentials	The human mind does not allow an easy examination of the underlying molecular, genetic or biochemical causations of mental 'illness' Men are a heterogeneous and poorly controlled mixture of environment, experience and inheritance Mice do not sell stocks and shares, pass stressful examinations or manage their finances, but they do behave...socially and trophically

 

A transgenic solution?

Much insight into the mechanisms of neural signaling has been gained from transgenic animals, i.e. those which have been genetically altered to change the amount or sequence of a given gene is expressed. For example mice that have been genetically altered to express only 5% of an NMDA glutamate receptor gene (NR1) exhibit the social and sexual impairments, stereotyped behaviors and increased motor activity typical of schizophrenia (Mohn et al., 1999). Perhaps but fortune rather than deliberation, knock-out mice lacking a gene that synthesizes neuronal nitric oxide (NO, nitric oxide synthase, NOS), an intended animal model for stroke, became socially aggressive and lacked normal patterns of social interaction, forcibly mating with unreceptive females and killing cage mates.

The problem with transgenics is that any mutation might conceivably affect development as well as function in the adult animal, and these are often difficult to distinguish. A further dilemma is that mental ‘illness’ is already known to be an example of multi-factorial inheritance, and a plethora of potential genes may likely be involved in schizophrenia and related disorders and that these alterations may be very subtle and inter-linked, making ‘black-and-white’ knockouts in mice a debatable model for mental illness, regardless of their scientific usefulness.

Gene expression

A great number of gene products have been implicated in schizophrenia, which may be modulated at many levels, from mutations that affect their final form or their level of expression to genetic and epigenetic factors such as satellite repeats, chromosomal recombinations, acquired gene silencing through methylation, and aneuploidy, an altered number of chromosomes in a given cell. These are all changes at the fundamental DNA level of encoding and exclude variations in functional gene expression at the level of expression or processing of the genetic transcript (RNA) or its final product, the protein. Even though we can now more finely control expression, the sheer array of possible targets and the variety that may stem from changes in RNA or protein processing possibly from an apparently unrelated gene, means that it may be easier to work backwards...

At what levels do we study genes, and by what do we measure when we look at genes at different levels, and do we lose any information in the process? The completion of the human genome project will give us a map of the location and the sequence of all the genes in the human genome. This will allow us to study variety in human polymorphisms, chromosomal rearrangements and mutations.

This however does not tell us how disease or change may arise by a variability in the expression in the gene. For that we have to go to the basic message and study the expression and sequence of the RNA that must be first synthesized before protein can be made.
 

The importance of environment to development and function

The prevailing research provocatively suggests that an enriched social environment is necessary for the development of 'normal' behavior and enhanced cortical thickening, as rats isolated after weaning develop behaviors reminiscent of schizophrenia and mice bred in enriched environments show both an increased cortical thickening and a greater number of hippocampal neurons (Kemperman et al., 1997). Indeed Romanian orphans raised in an isolated and impoverished environment showed a level of development that was so markedly retarded as to raise the question as to whether schizophrenia with its attendant loss of cognitive function is not a mild manifestation of an activity-dependent developmental disorder caused by social and sensory deprivation.

Why should social contact be so important in cognitive performance, decision-making and the processing of sensory stimuli? The answer may be suggested in the formation of ocular dominance columns in the visual cortex which is itself dependent upon neural activity which is visually driven (Hubel and Wiesel, 1998). By depriving one eye of visual information for several weeks during an early critical period of development (monocular deprivation) there was a marked change in the patterns of activation in the primary visual cortex. Cells in layer IV of the visual cortex were now activated only by input from the eye that had remained open, even if the other eye was still functional in the detection and transmission of light signals. In other words a constant sensory input from both eyes is required for the correct development of binocular processing of light information and the attendant orderly patterning of brain cells in the visual cortex. Anatomically, the terminal arbors of the axons of the lateral geniculate nucleus which were supplied by the uncovered eye were considerably more extensive than those supplied by the deprived eye. As an explanantion for this phenomenon it has been found that there is an activity-dependent release of neurotrophic factors by cortical neurons and that this may affect the pattern and extent of wiring in the visual cortex. In fact this competitively-based loss of function from the covered eye could be specifically overcome by localized infusion with the neurotrophin NT-4 (Riddle et al., 1995).

In plasticity there is hope. If sight is lost after its development the areas of the cortex attributed to vision show considerable plasticity in that they remodel from being activated primary by visual information, to being activated by another sensory input, somatosensory touch, an acquired plasticity, (learnt) from the acquisition of Braille reading skills. Similarly social engagement and other high level forms of play and linguistic interaction, which constitute 'higher' primate behaviors and which are associated with the evolutionary enlargement of the forebrain and association cortex, must not only be acquired through development, but must be used or else they may diminish. Neurons form connections in response to stimulation, at least in part induced by the activity-dependent release of neurotrophins, and if these 'activity-dependent' neuronal wiring patterns are not induced by sensory input they may not form (Romanian orphans), and if they are not maintained they may diminish or be ‘functionally’ lost (schizophrenia?). Another possibility is that stress or information 'overloading' (excessive activity) may cause damage to the neuronal processes of these cortical and subcortical structures resulting in cognitive disruption and a loss of social functioning, concentration, disrupted speech etc.

Breeding a natural animal model for schizophrenia ....(and deciphering the changes)

"...the genetic dissection of quantitative behavioral traits, such as mood, personality and intelligence..pose new problems for gene cloning experiments...one way forward is by using animal models...and an efficient strategy for detecting sequences that give rise to quantitative behavioral traits can be devised in the mouse" (Flint & Corley, 1996).

There are almost certainly changes in the patterns of genes expressed underlying mental disorders such as depression or schizophrenia. It has been known by generations of animal breeders that specific behavioral characteristics may be bred into domestic animals such as dogs, sheep or horses. The same strategy has been used, for example, to breed rats that are chronically depressed in their responses to painful stimuli, or mice that are unusually aggressive (e.g. the C57 strain).

Good breeding is as old as human society itself, but at four or five generations per century (or fewer), humans can barely keep up with changes in their environment! Mice in contrast have the advantage that they reproduce as quickly as three generations per year, allowing specific characteristics to be rapidly selected for. As there are believed to be fundamental patterns of behavior that are conserved across all mammalian species, including mice and humans.  A research program might ask whether ‘equivalent’ socially dysfunctional animal behaviors such as poor grooming, social withdrawal or dysphoria (all criteria for schizophrenia) may arise from the social environment, or purely as a result of the animal’s genetic background.

Breeding an imperfect mouse

Mice may therefore be housed in either enriched (toys, terrain, mazes and plants) or featureless environments (a plain cage) and assessed for their social ranking behavior in both environments, and bred according to their specific behavioral characteristics. Mice that succeed and mice that do not succeed in each environment (as defined below) may be interbred, especially according to whether they display anti-social dominant (aggression) or sub-dominant behaviors (withdrawal) or sociable dominant/subdominant behavior.  These behaviors may be assessed as poor grooming, aggressive behavior, a lack of environmental ‘opportunism’, withdrawal, persistent unwanted behaviors (e.g. mounting an unreceptive female) etc. After ten generations, the behavioral responses of the eleventh generation litters, raised either in isolation or communally, may be tested in response to their introduction to a novel environment or to new individuals.

Behaviors that may be selectively bred for include aggression, withdrawal, poor grooming, anxiety, dominance and environmental niche colonizing capacities (e.g. the exploitation of a new area within a ‘cage’ accessible only by swimming or climbing). As additional 'control', mice that have been acutely isolated, or kept in impoverished environment or within overcrowded conditions for one generation (from original strain) will be used to dissect genes that change in expression over one lifetime from changes that associated with 'genetic drift' due to selective breeding (within or between strains).

Their behaviors will be assessed in response to each of the breeding populations to see if the nature of the individuals from each selected breeding population affects or predicts their specific behaviors. Where there are reproducible differences in behaviors between the breeding extremes (socially dominant, socially recessive or poorly groomed etc.) the nervous tissue from the eleventh generation post-mortem will be exposed to two dimensional gel electrophoresis to ascertain whether there are any quantitative differences in the amounts of proteins (levels of gene expression), properties (gene processing) or sequence (mutations or polymorphisms) present in the brain that may be associated with changes in brain function and behavior. A negative finding may support the contention that there is no genetic basis for social dysfunction or rejection, instead supporting the argument that such behaviors are 'learnt' or conditioned by the animal's social environment.

This research will thus address the eugenic basis (‘good genes’) for social dominance hierarchies and breeding patterns when compared to unselected breeding populations which have been allowed to breed undisturbed within an enriched or an impoverished (featureless) environment. The associated behavioral studies described above will seek to establish patterns of eleventh generation mouse behavior under the four environmental conditions chosen (enriched and crowded vs.enriched and sparsely-populated vs. impoverished and crowded vs. impoverished and sparsely-populated), for mice that have been selectively bred for extreme social characteristics and for 'control' mice that have been taken from the 'normal' (wild-type) breeding population.

It is hoped that these studies will ascertain whether aspects of environment, for example housing density (stress from overcrowding) or an impoverished environment, may trigger antisocial or aggressive behaviors in mice from each of the selectively bred stocks, and to determine which of these behaviors, if any, may be inherited, if so to what extent in each of the selectively bred populations.

Proteonomic analysis of the inheritance of behavioral traits

After breeding and exposing both control animals and specially bred animals to certain environments, the patterns of expression of the mouse genome in relation to its environment, the cell’s ‘protein complement’, will be determined with new proteonomic technologies screening, as the protein is the final functional manisfestation of a gene in response to a cell's interaction with its global environment.

Firstly, the various regions of the brain are separated, then the regions of the cells therein are separated into nuclear, soluble, membrane and other subcellular fractions. The proteins so isolated may be run and separated in two further dimensions, firstly by an electrical field across a gradient of pH to separate the proteins by virtue of their inherent net electrical charge. The proteins may then be further separated in a fourth dimension by denaturing them in a detergent which confers an equal distribution of negative charge (SDS + DTT) and then allows them to separate according to physical size, the largest moving the most slowly within the imposed electrical field.

This results in a gel showing the relative abundance, size and charge of each protein by region and cellular compartment. By comparing gels it is possible to see what has changed between animals that have been differentially bred and treated. The proteins that have changed in their properties or abundance can be extracted and sequenced to determine their differences in genetic sequence and post-translational modifications.  Hence we may be able to infer whether an individual's response to and success within an environment, isolated or densely-populated, engaging or Spartan, is 'indelibly inscribed' within his or her genes, or whether even an animal from 'inferior' stock may, by virtue of its intercation with its environment, be able to 'succeed' irrespective of inherited traits that appear to predict otherwise.