German Journal of Psychiatry

ISSN 1433-1055

Recent Advances in the Neurobiology of Schizophrenia

John Smythies

From the Division of Neurochemistry, Brain and Perception Laboratory, Center for Brain and Cognition, U.C.S.D. La Jolla, CA. 92093-0109, and the Department of Neuropsychiatry, Institute of Neurology, Queen Square. London. WC1N 3BG, e-mail smythies@psy.ucsd.edu


This paper reviews the latest research in the field of the neurobiology of schizophrenia. Particular emphasis is placed on the microanatomical studies showing loss of dendritic spines and loss of neuropil and the studies implicating abnormal redox functions at the glutamate synapse. Particular attention is paid to ketamine and whether it acts as an indirect agonist or an antagonist at the NMDA receptor. There is evidence that oxidative stress plays a role in the disease. The role of catecholamine o-quinones derived from dopamine, noradrenaline and adrenaline in the brain is reviewed. One of these (adrenochrome) was demonstrated forty years ago to be a psychotomimetic agent. Thus these o-quinones may play a role in the illness.

(German J Psychiatry 1998; 1 (2): 24-40) 

Received: July 2, 1998

Published August 26, 1998 

key words; schizophrenia, glutamate, catecholamine o-quinones, redox mechanisms, dendritic spines

Neuroanatomical studies

In recent years research into the biological basis of schizophrenia has focused on anatomical damage and the biochemical mechanisms that may underlie this. At the macroanatomical level there is general agreement that many cases, particularly of type II schizophrenia show enlarged ventricles and cortical atrophy, especially in the temporal lobes and prefrontal cortex (Nopoulos et al, 1995; Lim et al, 1996; Marsh et al, 1997; Ziparsky et al, 1997; Sullivan et al, 1998). Dissenting opinions have been voiced by Dwork (1997: except for ”enlarged lateral ventricles”) and Heckers (1997: no ”strong clinicopathological correlations”). This atrophy appears to be progressive over time in certain cases (DeLisi et al, 1997; Nair et al, 1997; Rapoport, 1997; Gur et al, 1998). Similar changes have been found in the normal siblings of schizophrenic cases (Seidman et al, 1997). A loss of cells in the dorsomedial nucleus of the thalamus has been reported by some (Pakkenberg, 1990; Jones, 1997; Lewis, 1997) but denied by others (Lesch and Bogerts, ; Jernigan et al, 1991: and see Weinberger, 1997). Portas et al (1998) found reduced connectivity between the thalamus and the cortex.

At the microanatomical level the most consistent findings have been a reduction of the neuropil together with a reduction in the number of dendritic spines in the cerebral cortex and striatum (Garey et al, 1995; Glans and Lewis, 1995; Holinger et al, 1995; Selemon et al, 1995, 1998; Roberts et al, 1995; Roberts et al, 1996; Goldman-Rakic and Selemon, 1997; Hirsch et al, 1997; Zaidel et al, 1997). Reports concerning disordered cytoarchitecture in the hippocampus have been conflicting (present - Arnold et al, 1997; Jönsson et al, 1997: absent - Akil and Lewis, 1997; Krimer et al, 1997). Akil and Lewis (1995) also report a reduction in all cortical layers of catecholaminergic axons and terminal boutons in the entorhinal cortex and prefrontal cortex. These microanatomical changes have been described as ”subtle” (Bogerts, 1997; DeLisi et al, 1997).

Neurochemical studies

The glutamate synapse

Earlier work in this field concentrated upon looking for abnormalities in the number or function of receptors for biogenic amines. Now the focus of studies has shifted towards the glutamate synapse and towards 'deeper' aspects of neuronal function such as post-synaptic cascades, the molecular mechanisms of synaptic formation, cohesion and elimination, transcription mechanisms, redox systems and others. Clearly the place to start looking today, in view of the microanatomical evidence listed earlier, is at the mechanisms that are responsible for synaptic growth and deletion, particularly on dendritic spines. It so happens that this system closely involves the glutamate synapse. Interest in the glutamate system arose because it was noted that drugs that act on the NMDA glutamate receptor, such as ketamine and PCP, at low dose produce a model schizophrenic-like psychosis. It would therefore be appropriate to start with an account of the relevant parts of this synapse.

Activation of the NMDA receptor opens a calcium channel which starts a number of post-synaptic cascades. Ca + ions activate a number of neurodestructive proteases and nucleases. They also activate the enzyme phospholipase A2 which converts membrane phospholipids into arachidonic acid (AA). AA in turn activates the enzyme prostaglandin H synthase, the rate-limiting step in prostaglandin synthesis. This activation releases a large amount of reactive oxygen species (ROS) including the superoxide anion and the freely diffusable molecule hydrogen peroxide. Ca++ also activates the enzyme nitric oxide synthase, which process also releases large quantities of ROS and freely diffusible nitric oxide, which, in its dominant nitric oxide radical form, is a pro-oxidant. The free diffusion of H2O2 and NO back into the glutamate synapse would have pro-oxidant neurotoxic effects if it were not balanced by antioxidant defenses. The principle antioxidant defenses at the glutamate synapse are (i) ascorbate which is released into the synapse by the Na+/K+ ATPase-dependent glutamate transporter in exchange for glutamate during the reuptake process which terminates glutamate action, (ii) carnosine which is released together with glutamate from the synaptic vesicle and (iii) probably glutathione. There is also a redox sensitive site on the NMDA receptor protein which upon oxidation down regulates the NMDAr thus serving as protective negative feedback to shut off the source of ROS and RNS. Thus an important factor in the plasticity of the synapse (i.e. whether it grows or is deleted) may be the redox balance inside the synapse between neurotoxic pro-oxidants and neuroprotective antioxidants.

Another important component of the redox balance is likely to be dopamine released from adjacent dopamine boutons-en-passage and diffusing into the glutamate synapse (Smythies, 1997a,b). Dopamine is a potent antioxidant as are all catecholamines. The antioxidant mechanism entails redox cycling between dopamine and dopamine quinone driven by free radical scavenging in one direction and reduction of the dopamine quinone by ambient antioxidants, such as ascorbate and glutathione, in the other direction. This may constitute a basic mechanism underlying learning and neural computation since dopamine release is contingent upon positive reinforcement being received by the organism. Thus dopamine release would tilt the redox balance towards the neuroprotective reductive side and would result in synaptic growth. Lack of dopamine would have the opposite effect. Another mechanism whereby dopamine can alter the redox balance of neurons is the fact that D2 receptor activation leads to increased synthesis of antioxidant proteins -probably superoxide dismutase (Sawada et al, 1998). It is of interest that one effect of nerve growth factor (also involved in synaptic plasticity) is to increase the antioxidant defenses of the neuron by three mechanisms (i) inducing the activity of the antioxidant enzymes glutathione peroxidase and catalase (Goss et al, 1997; Sampath and Perez-Polo, 1997), (ii) lowering ROS production by inhibiting mitochondrial respiration and arachidonic acid metabolism -both potent sources of ROS production (Dugan et al. 1997), and (iii) by inhibiting ROS production by a carpase-linked mechanism (Schulz et al, 1997).

However, the entry of dopamine into the glutamate synapse would carry a risk because, in conditions of reduced antioxidant cover, dopamine can be easily oxidized further than dopamine quinone, either spontaneously or by peroxynitrite (produced by the interaction of NO and the superoxide anion) to form cyclized dopamine o-quinones including the highly toxic free radical o-semiquinone (Smythies, 1997a,b; Smythies and Galzigna, 1998). This also applies to other catecholamines in the brain, namely noradrenaline and possibly adrenaline. The noradrenergic neurons in the locus coeruleus and the C1-C3 neurons in the medulla both contain neuromelanin (Bogert, 1981; Saper and Petito, 1982). However, Gai et al (1993) claim that it is mainly the non-adrenergic pigmented neurons (that presumably contain some other catecholamine) in the C1-C3 group that contain the neuromelanin. But this work was carried out in patients with advanced Parkinsonís disease and needs to be repeated with normal brains. So we can infer that the noradrenergic and dopamine neurons in the brain contain o-quinones, which are obligatory metabolic precursors of neuromelanin. But further work needs to be done on the adrenergic system before we can say that adrenochrome occurs in brain. It is of course possible that adrenaline may be oxidized in brain tissue to form adrenochrome but for some reason this does not lead to neuromelanin formation. One explanation for this may be that a major metabolite of adrenochrome is adrenolutin in which the 3 -OH group is replaced by =O. This cannot form dihydroxyindole which is the necessary precursor for neuromelanin formation. Adrenolutin (but not adrenochrome) has been reported to be present in normal plasma (Dhalla et al. 1989) but no one as yet has looked for it in the brain.

Adrenochrome has been shown to be a psychotomimetic agent (Hoffer et al, 1954, Schwartz et al, 1956; Taubman and Jantz, 1957; Grof, 1963). No such tests have yet been carried out on noradrenochrome or dopaminochrome. The C1-C3 group are thought to be concerned in stress responses and project to the medial thalamus (Phillipson & Bohn. 1994; Otake et al. 1995; Rico & Cavada. 1998) and substantia nigra (Nagatsu et al. 1998). Furthermore phenylethylanolamine N-methyl transferase activity in human brain was found to be high in the RF, hypothalamus and locus coeruleus, and intermediate in the SN, amygdala, septum, periacqueductal grey, and central thalamus (the medial thalamus was not looked at) in a report by Lew et al. 1977). Mefford et al (1978) report that adrenaline levels are high in the medial thalamus as well as the hypothalamus and septum. All this suggests that the medullary adrenergic system may not only be concerned with lower visceral functions in the brain as was once thought, but may powerfully modulate key limbic higher functions in particular those related to stress.

Direct evidence of catecholamine o-quinone production in brain is furnished by the detection of a metabolite of dopamine o-quinone -5-cysteinyl dopamine -by Carlsson et al, (1994). Levels of this compound are raised in the brain in schizophrenia indicating increased auto-oxidation of dopamine by the quinone pathway.

Intraventricular infusions of dopamine in humans every 3 weeks led to the development of paranoid delusions (but no hallucinations or thought disorder) that lasted 2 weeks after each infusion (Kulkarni et al., 1992). This may have been due to over-stimulation of dopamine receptors. It may also have been due to the neurotoxic effects of quinone metabolic products of the dopamine.

Direct studies of the glutamate synapse

Postmortem studies of glutamate receptors have yielded conflicting results:

(i) mRNAs for AMPA receptors subunits R1 and R2 have been reported by one group to be reduced in the hippocampus (Eastwood et al, 1997a), medial temporal lobe (Eastwood et al, 1997b) and in the subiculum and parahippocampal gyrus (Kerwin and Harrison, 1995). The same group also report altered AMPA receptor desensitization kinetics (changes in flip-flop ratios) in remaining R2 subunits (Eastwood et al, 1997a). They conclude that ”subtle, progressive excitotoxic damage may be involved.í (Eastwood et al, 1997b).

(ii) The same group report an increase in mRNAs for NR1 and NR2A (but not NR2B) subunits of the NMDA receptor in the hippocampus (Beckwith et al. 1995b). Another group (Humphries et al, 1995; Humphries et al, 1996; Hirsch et al, 1997) report a decrease in mRNAs for the NMDA R1 subunit in the superior temporal cortex in cognitively impaired but not unimpaired schizophrenics. Goff and Wine (1997) found that NMDArs have raised levels of 2D subunits, which would result in higher sensitivity to glutamate. They also found more unedited AMPArs, which would increase Ca++ inflow. This data would support increased excitotoxic damage in the disease.

In contrast, Meador-Woodruff et al (1997b) failed to find any abnormality in mRNAs for ionotrophic glutamate receptors in the prefrontal cortex, hippocampus, septum and striatum in schizophrenic brains. A loss of glutamate terminals in the hippocampus and polar temporal cortex (Deakin and Simpson, 1997) and of non-NMDArs in the hippocampus (Beckwith et al, 1995a) have also been reported.

Indirect studies of the glutamate synapse


This anesthetic drug is usually described as an antagonist at the glutamate receptor. Therefore, since it produces psychotic reactions at sub-anesthetic doses, schizophrenia has been attributed to underactivity at glutamate synapses. However, glutamate excitotoxicity, which has also been linked to schizophrenia, involves overactivity at glutamate synapses. This led Olner and Farber (1995) to suggest that an early over-activity of glutamate synapses might destroy GABAergic neurons, or NMDArs on their surface, and so lead to disinhibition of glutamate systems downstream. This overlooks the fact that GABArs are continually being synthesized and so a local destruction would have to be continually maintained in order to result in a chronic disease.

However, there is a simpler explanation. Ketamine at subanesthetic doses leads to increased glutamate release and subsequent increased stimulation of AMPA receptors (which open channels that allow ingress of Ca++ as well as Na+) as well possibly of NMDArs not blocked by ketamine at this lower dose -in other words it would act as an indirect AMPA/NMDA agonist at this low dose (Moghaddam et al, 1997; Moghaddam, 1997). Hoffman and McGlashan (1997) also point out that that the dose used in animals (0.5-50 mg/kg) to demonstrate NMDAr antagonism is much larger than the psychotomimetic dose used in humans (0.05-0.1 mg/kg). They suggest that the lesion in schizophrenia may be reduced cortical connectivity rather than receptor dysfunction.

Low doses of ketamine increase 2-DG uptake in the limbic cortex and subcortex, whereas high doses reduce 2-DG uptake globally (Duncan et al, 1998). Low doses of ketamine also promote FOS-L1 induction in limbic cortex (but not in limbic subcortex), whereas high doses lead to a robust increase of FOS-L1 induction (Duncan et al, 1998). These workers suggest that ketamine may produce its psychotomimetic effect by two mechanisms (i) by the one suggested by Olney and Farber (1995) and (ii) by increasing glutamate release. Anesthetic doses of ketamine inhibit glutamate release. The hypothesis that the psychotomimetic effect of ketamine and PCP is due primarily to increased, not decreased, glutamatergic activity is supported by the observation that acute administration of PCP (i) increases the expression of COX-2 mRNA in rat retrosplenial cortex which indicates activation of the post-NMDAr cascade (COX-2 is a part of the PGH synthase complex) (Hashimoto et al, 1997). and (ii) increases the production of mRNA for glutamate dehydrogenase (Shimizu et al, 1997) which these authors suggest is compensatory for increased glutamate release. In monkeys PCP given acutely activates the mesoprefrontal dopamine system (Jentsch et al, 1998) due, these authors suggest, to a decrease in the inhibition of the dopamine system by glutamate. In contrast chronic administration of PCP inhibits DA turnover. Which of these effects is related to the psychotomimetic effects of PCP is unclear.

There is also data from research into the mode of action of antipsychotic drugs on this system to support the hypothesis of an initial over-activity of the glutamate system which could lead to ”subtle, progressive excitotoxic damage” which would result to later underactivity of this damaged system. However, this damage is to replaceable spines and neuropil not to irreplaceable neurons. Lidsky et al (1997) state that low doses of antipsychotic drugs enhance NMDA activity possibly (a) because they block dopamine presynaptic D2 receptors, leading to an increase in extracellular dopamine, which in turn would block glutamate reuptake, resulting in increased intrasynaptic glutamate levels and (b) because dopamine acting post-synaptically at D1 receptors enhances glutamate activated G-protein linked adenylate cyclase activation. This group claims that antipsychotics are NMDA antagonists only at high doses (Lidsky et al, 1997). Bannerjee et al. (1996) state that haloperidol and clozepine are potent augmentors (rather than antagonists) at the NMDAr. In contrast Ilyin et al. (1996) state that haloperidol is an NMDAr blocker (by a direct allosteric effect on the receptor protein) and only at very low doses may potentiate NMDAr activity. Coughenour et al (1997) also support the claim that haloperidol is a non-competitive allosteric antagonist at the NMDAr. Clearly, if antipsychotic agents are NMDA receptor blockers (at the relevant dose), then ketamine is hardly likely to act as an NMDAr antagonist in the production of its psychotomimetic effect..

A complication is introduced by Halberstadt (1995) who claims that haloperidol does not bind to NMDArs but to sigma receptors. Sharp (1997) states that PCP binds to NMDArs (which does not lead to an induction of c-fos production) and to sigma receptors (which results in abundant c-fos production in the cingulate, parietal, and piriform cortex, midline thalamus, hypothalamus, but not in the hippocampus). Thus the binding to sigma receptors might appear to be more important. Sharp (1997) further states that there are no known endogenous ligands for the sigma receptor and its normal physiological function is also unknown. One additional interesting datum is that sigma receptor antagonists (such as rimcazole) block PCP-induced stereotyped behavior and inhibit PCP-induced c-fos production.

Further support for the hypothesis that psychotic reactions are associated, at least at some stage, by over-activity rather than under-activity at NMDA receptors is the reported successful use of the NMDAr antagonist amantadine in the treatment of catatonic schizophrenia (Northoff et al, 1997). Kornhuber et al (1997 and Kroemer et al (1998) have stressed the therapeutic promise of low-affinity uncompetitive NMDA antagonists like amantadine and memantine in protection against glutamate toxicity. Ketamine increases cortical blood flow in the anterior cingulate and right inferior frontal lobe in both schizophrenics and normals and decreases it in the left middle temporal cortex only in schizophrenics (Lahti et al, 1997).

The mixed apoptotic/necrotic effect of chronic administration of PCP is prevented by pretreatment with clozepine (Johnson et al, 1998). The pattern of degeneration produced by PCP follows the distribution of mRNAs for the NR1 subunit of the NMDAr and of dopamine. These authors suggest that the toxic effects of PCP given chronically involves NMDAr overactivity.

To conclude this section, the evidence seems to support the hypothesis that schizophrenia, and the effects of psychotomimetic doses of ketamine, is associated with a shift in the balance of glutamate receptor function towards chronic local excitotoxic over-stimulation of the post-synaptic cascade, and/or the production of excessive amounts of ROS/neurotoxins by this cascade, leading to dynamic damage to the post-synaptic spines and their replacements and so a functional overall underactivity of the excitatory network results (loss of dendritic spines and functional synapses) (Benes, 1995). Based on neural net computer modeling Hoffman and McGlashan (1993) have pointed out that excessive pruning of dendritic spines and reduced cortical connectivity would lead to the formation of ”parasitic foci” in the non-linear dynamical attractor networks of the brain. This leads to bizarre outputs, functionally autonomous sub-populations, and the locking of some modules into cognitive outputs independent of the input, all of which in a real brain could underlie the symptoms seen in schizophrenia. EEG support for this hypothesis has been provided by Lutzenberger et al (1995).

The redox balance in schizophrenia

Studies of antioxidant systems in schizophrenia has produced the usual medley of conflicting results. In red blood cells SOD has been reported as lowered (Mahadik and Mukherjee, 1996) and raised (Abdalla et al, 1986; Reddy et al, 1991); GSHpx as lowered (Abdalla et al, 1986) and as normal (Mahadik and Mukherjee, 1996; Reddy et al, 1991); CAT as normal (Mahadik and Mukherjee, 1996) and as lowered (Reddy and Yao, 1996). Buckman et al (1990) report a strong negative correlation between brain atrophy and platelet GSHpx levels. They suggest the hypothesis that low GSHpx levels may constitute a vulnerability factor to oxidative stress. CAT activity in brain is low, and is located mainly in astrocytes. Therefore GSHpx (located mainly in neurons) is important. In the brain Loven et al (1996) found that Mn SOD activity was markedly raised (which would lead to excess production of hydrogen peroxide) in the temporal cortex and frontal cortex of a group of ”psychotic” patients on neuroleptics, but there was no change in Cu/Zn SOD activity. Levels of the blood antioxidants albumin, uric acid and bilirubin are reduced (Yao et al, 1998a,b) and total antioxidant capacity is low (Yao et al, 1998c). These changes are correlated with the clinical severity of the disease. There is evidence that TBARS, a marker of lipid oxidation, is raised in schizophrenia (Mahadik et al, 1998) and that superoxide production by neutrophils is raised (Melamed et al, 1998) both indicating the presence of increased oxidative stress.

Synaptic associated proteins

The suggestion that schizophrenia may be associated with synaptic malfunction or damage has led to studies of synaptic-associated proteins in post-mortem brains. Reduced levels of synaptophysin have been reported in the prefrontal cortex (Karson et al, 1997; Glantz and Lewis, 1997), and in association cortex (Perrone-Bizzozero et al, 1996) but also denied Browning et al (1993) who reported instead reduced levels of synapsin. Levels of mRNAs coding for synapsin 1A and 1B and synaptophysin have been reported to be raised in the left superior and middle temporal cortex Tcherepanov and Sokolov, 1997). Levels of the synaptic vesicle protein rab3a have been reported to be reduced in the left but not the right thalamus (Blennow et al. 1996) associated with decreased synaptic density. Levels of the neural cell adhesion molecule N-CAM 105-115-kDA are raised in the hippocampus and prefrontal cortex (Vawter et al, 1998). In a study of monozygotic twins discordant for schizophrenia (Poltorak et al, 1997), the schizophrenic twin showed higher CSF levels of N-CAM and lower levels of L1 antigen, with no change in contractin levels. Another study (Honer et al, 1997) N-CAM and syntaxin levels were both reported to be raised. As the latter is found only in conjunction with excitatory terminals, the authors suggest that this finding indicates increased glutamate activity in the cingulate cortex. Cotter et al (1997) report an increase in the expression of non-phosphorylated MAPs in the subiculum suggesting an abnormal assembly of cytoskeletal proteins. GAP-43 levels have been reported to be raised in association cortex (Perrone-Bizzozero et al, 1996) but their mRNAs reduced in selected areas (Eastwood and Harrison, 1998). This protein is involved in the initial establishment and later reorganization of synaptic connections. Similar complexities are revealed by Thompson et al (1998) who measured levels of the synaptosomal associated protein SNAP-25 and found levels to be decreased in the inferior temporal cortex and prefrontal cortex (area 10), increased in the prefrontal cortex (area 9) and normal in area 17.

In view of these conflicting results and the early state of this work it would be premature to try to draw any conclusions. However it is clearly a field of great promise.

NAA/creatinine ratios

NAA/creatine and NAA/choline ratios as obtained by proton magnetic resonance spectroscopy gives a measure of neuronal damage in the living human. These ratios have been reported to be reduced in various brain areas (Bertolino et al, 1996, 1998; Yurgelun-Todd et al, 1996). However, Lim et al (1998) found that in cortical grey matter the NAA signal was normal but the grey matter volume was reduced, whereas in cortical white matter it was the other way round. They suggested that their results indicated abnormal axonal connections.

Neural development

There is considerable evidence that risk factors for schizophrenia include brain insults during gestation, such as maternal viral infections, starvation, obstetric complications, etc. (see excellent reviews by Wright et al, 1995; Chua and Murray, 1996; Wyatt 1996; and Turner, 1997). Schizophrenia is often accompanied by minor physical abnormalities and abnormal dermatoglyphics (Buckley, 1998).



The literature on alleged abnormalities of DA receptors in schizophrenia is vast and full of contradictions. Halberstadt (1995) says that there is no reliable evidence for the dopamine hypothesis. It seems that previously claimed increases in striatal D1 and D2 receptors were probably due to neuroleptic medication (Knable et al, 1994; Reynolds 1995; Hietala and Syvälahti, 1996), and that D3 and/or D4 receptors may be normal (Lahti et al, 1996; Reynolds and Mason 1994; Helmeste et al, 1996). Previous claims that D4 receptors are increased (Seeman et al, 1993; Marzella et al, 1997) have been criticized on methodological grounds (Meador-Woodruff et al, 1997a) One recent study (Joyce et al 1997) reported that D3 receptors in schizophrenic subjects drug free for one year were increased in the target area of the mesolimbic tract together with an altered laminar distribution of D2 receptors in the temporal lobe. One study actually reported a reduction of D1 receptors in the prefrontal cortex (but not the striatum) related to the severity of negative symptoms (Okubo et al, 1997). Meador-Woodfruff et al (1997a) found a marked reduction of mRNAs for D3 and D4 receptors in orbitofrontal cortex. Opeskin et al, 1996) found that D2 second messenger systems (PKC and adenylate cyclase) were not altered in the striatum in schizophrenia. Sigma receptors however may be reduced (Helmeste et al, 1996).

One group (Goldsmith et al, 1997; Joyce et al, 1997) has reported abnormal detailed cytoarchitectural pattern of D2 receptors in the perirhinal cortex and temporal lobe (but not hippocampus).

Since receptor molecules are continually being replaced, any chronic abnormality in receptor numbers or function is likely to reflect a disorder in the dynamic mechanism of receptor production and matching to loading, including protein synthesis, nuclear transcription, second messengers, etc. Furthermore, even if receptor numbers are found to be increased, or decreased, this may well represent secondary changes to a primary disturbance in some more basic mechanism.


There have also been preliminary and often conflicting claims of malfunction in various other systems - serotonin receptors (Hashimoto et al, 1993; Simpson et al, 1996; Abi-Dargham et al, 1997; Burnet et al, 1996; Gurevich et al, 1997; Hernandez and Sokolov, 1997); the cholinergic system (Garcia-Rill et al, 1995; Dean et al, 1996; Leonard et al, 1996; Karson et al, 1996); mitochondria (Cavelier et al 1995; Whateley et al, 1996a,b); GABA systems (Beasley et al, 1997; Kalus et al, 1997); various polypeptides (e.g. CCK (Bachus et al, 1997), neurotensin (Wolf et al, 1995) and chromgranin (Miller et al, 1996)); melatonin (Monteleone et al, 1997): nitric oxide synthase (Karson et al, 1996); and phospholipids (Gattaz et al, 1987; Keshavan et al, 1993; Peet et al, 1994; George and Spence, 1996; Horrobin, 1996); Yao and Kammen, 1996; Katila et al, 1997; Ross et al, 1997; Volz et al, 1997). Much research has been directed at cytokines and possible autoimmune reactions. Naudin et al (1997) conclude that increased levels of IL-6 are widely accepted but the jury is still out on reported increased levels of TNF. This may reflect a genetic background (Naudin et al, 1997) or a non-specific stress response (Frommberger et al, 1997). Several reports on other cytokines await confirmation. There have also been some preliminary reports of abnormal neuromelanin in schizophrenic brains (see Smythies, 1996 for details). In view of the preliminary and inconsistent nature of all these reports, promising as they are, it is too early to evaluate them.

The transmethylation and one-carbon cycle hypotheses of schizophrenia and affective disorders have recently been reviewed elsewhere (Smythies et al, 1997). The key finding is that enzymes of the one-carbon cycle (MAT and SHMT) are impaired in schizophrenia that would be expected to lead to defective transmethylation mechanisms. It is noteworthy that O-methylation of catecholamine o-hydroquinones is a mechanism that prevents the formation of the toxic free radical o-semiquinone.


This review suggests that the most promising area for future research in schizophrenia are the mechanisms by which abnormal function at the glutamate synapse leads to excessive spine pruning, and loss of neuropil and inter-neural connectivity. These mechanisms may include oxidative stress, the production of neurotoxic catecholamine o-semiquinones, and the loss of trophic factors. These lesions may result in disorders in related mechanisms such as cell-adhesion factors, membrane lipids, receptors, etc.. The following risk factors are suggested (numbers (i)-(iii) have been reported to be present in schizophrenia): -

(i) Reduced antioxidant defenses leading to increased ROS attack on synaptic structures and increased oxidation of catecholamines to form neurotoxic o-quinones.

(ii) Impaired function of COMT leading to increased levels of neurotoxic catecholamine o-semiquinones.

(iii) Defects in the synthesis of neuromelanin.

(iv) Impaired function of the enzyme DT-diaphorase (Segura-Aguilar, personal communication), which converts aminochromes to the nontoxic o-hydroquinones and so inhibits the formation of the o-semiquinone..

(v) Excess action of the cytochrome P450 enzymes that synthesize catecholamine o-semiquinones.

Research programs suggested include studies on: -

(i) the status of neuromelanin in the catecholaminergic neurons in the SN, LC and C1-C3 groups of neurons in the brain in schizophrenia.

(ii) Determining in normal brains if the pigmented neurons of the C1 and C3 groups in the medulla are adrenergic or noradrenergic.

(iii) the details of where catecholamine o-quinones are synthesized in the brain and further details of the pathways involved.

(iv) a search for further metabolites on the neuromelanin pathway, particularly 5,6-dihydroxyindoles and their O-methylated metabolites, as well as 5-cysteinyl and 5-glutathionyl derivatives, in the brain and body fluids and their status in schizophrenia. If the C1 & C3 adrenergic neurons in the medulla do not produce neuromelanin, it would be worth while to see if they do or do not contain 5-cysteinyl adrenaline, or adrenolutin derived from adrenaline and any 0-methylated o-quinone metabolites.

(v) further studies on the enzymology, pharmacology, psychopharmacology, and physiology of catecholamine o-quinones and their metabolites.

(vi) further studies of redox mechanisms at the glutamate synapse and their possible role in normal and abnormal synaptic plasticity.

(vii) further exploration of the role of the adrenergic projection to the medial thalamus and its possible relationship to the action of neuroleptics at this site (Cohen and Wan, 1995).

(viii) further studies of the mechanism of the antioxidant properties of catecholamines.

It is further suggested that any clinical studies should be carried out according to the guide lines laid out by Stevens (1997).


Abdalla DSP, Monteiro HP, Oliveira JAC, Bechara EJH. Activities of superoxide dismutase in schizophrenic and manic-depressive patients. Clin.Chem. 1986; 32: 805-807.

Abi-Dargham A, Larvelle M, Aghajanian GK, Charney D, Krystal J. The role of serotonin in the pathophysiology and treatment of schizophrenia. J.Neuropsychiat.Clin.Neurosci. 1997; 9: 1-17.

Akil M, Lewis DA. The catecholaminergic innervation of the human entorhinal cortex: alteration in schizophrenia. Abst.Soc.Neurosci. 1995; 21:238.

Akil M, Lewis DA. Cytoarchitecture of the entorhinal cortex in schizophrenia. Amer.J.Psychiat. 1997; 154: 1010-1012.

Arnold SE, Ruscheinsky DD, Han l-Y. Further evidence of abnormal cytoarchitecture of the entorhinal cortex in schizophrenia using spatial point pattern analysis. Biol.Psychiat. 1997; 42: 639-647.

Bachus SE, Hyde TM, Herman MM, Egan MF, Kleinman JE. Abnormal cholecystokinin mRNA levels in entorhinal cortex of schizophrenics. J.Psychiat.Res. 1997; 31: 233-256.

Banerjee SP, Zuck LG, Yablonsky-Alter E, Lidsky TI. Glutamate agonist activity: implications for antipsychotic drug action and schizophrenia. NeuroReport 1996; 6, 2500-2504.

Beasley CL, Reynolds GP. Parvalbumin-immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics. Schiz.Res. 1997; 24: 349-355.

Beckwith JP, McLaughlin DP, Stefanis N, Eastwood S, Harrison PJ, Kerwin RW. Expression of neurodevelopmentally specific isoforms of non-NMDA mRNAs in the hippocampus of schizophrenics. Schiz.Res. 1995a; 15:53-54.

Beckwith JP, Stefanis NC, McLaughlin DP, Kerwin RW. The expression of NMDA receptor subunits in schizophrenia post-mortem human hippocampus. Schiz.Res. 1995b;15:54.

Benes FM. Development of the glutamate, GABA, and dopamine systems in relation to NHR-induced toxicity. Biol.Psychiat. 1995; 38:783-787.

Bertolino A, Nawroz S, Mattay VS, Barnett AS, Duyn JH, Moonen CT, Frank JA, Tedeschi G, Weinberger DR. Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic spectroscopic imaging. Amer.J.sychiat. 1996; 153:1554-1563.

Bertolino A, Callicott JH, Elman I, Mattay VS, Tedeschi G, Frank JA, Breier A, Weinberger DR. Regionally specific neuronal pathology in untreated patients with schizophrenia: a proton magnetic resonance spectroscopic imaging study. Biol.Psychiat. 1998; 43:641-648.

Blennow K, Davidsson P, Gottfries C-G, Ekman R, Heilig M. Synaptic degeneration in thalamus in schizophrenia. Lancet 1996; 348:692-693.

Bogerts B. A brain stem atlas of catecholaminergic neurons in man, using melanin as a natural marker. J.Comp.Neurol. 1981;197:63-80.

Bogerts B. The temporolimbic system theory of positive schizophrenic symptoms. Schiz.Bull. 1997;23:423-435.

Browning MD, Dudek EM, Rapier JC, Leonard S, Freedman R. Significant reductions in synapsin but not synaptophysin specific activity in brains of some schizophrenics. Biol.Psychiat. 1993;34:529-535.

Buckley PF. The clinical stigmata of aberrant neurodevelopment in schizophrenia. J.Nerv.Ment.Dis. 1998;186:79-86.

Buckman TD, Kling A, Sutin MS, Steinberg A, Eiduson S. Platelet glutathione peroxidase and monoamine oxidase activity in schizophrenia with CT scan abnormalities: relation to psychosocial variables. Psychiat.Res. 1990;31:1-14.

Burnet PW, Eastwood SL, Harrison PT. 5-HT1A and 5HT2A receptor RNAs and binding site densities are differentially altered in schizophrenia. neuropsychopharmacology 1996;15:442-455.

Carlsson A, Waters N, Hansson LO Neurotransmitter aberrations in schizophrenia: new findings. In: Fog R: Gerlach J: and Hemmingsen R. (eds). Schizophrenia. An Integrated View. Copenhagen: Munksgard; 1994.

Cavalier L, Jazin EE, Eriksson I, Prince J, Bave U, Oreland L, Gyllensten U. Decreased cytochromec oxidase activity and lack of age-related accumulation of mitochondrial DNA deletions in the brains of schizophrenics. Genomics 1995;29:217-224.

Chua SE, Murray RM The neurodevelopmental theory of schizophrenia: evidence concerning structure and neuropsychology. Ann.Med. 1996;28:547-555.

Cohen BM, Wan W. The thalamus as a site of action of antipsychotic drugs. Amer.J.Psychiat. 1995; 153:104-106.

Cotter D, Kerwin R, Doshi B, Martin CS, Everall IP. Alterations in hippocampus non-phosphorylated MAP2 protein expression in schizophrenia. Brain Res. 1997; 765:238-246.

Coughenour LL, Cordon JJ. Characterization of haloperidol and trifluperidol as substrate-selective N-methyl-D-aspartate (NMDA) receptor antagonists using [3H]TCP and [3H]ifenprodil binding in rat brain membranes. J.Pharmacol.Exp.Therap. 1997; 280”584-592.

Deakin JF, Simpson MD. A two-process theory of schizophrenia: evidence from studies of post-mortem brains. J.Psychiat.Res. 1997;31:277-295.

Dean B, Crook JM, Opeskin K, Hill C, Keks N, Copolov DL. The density of muscarinic MI receptors is decreased in the caudate-putamen of subjects with schizophrenia. Mol.Psychiat. 1996; 1:54-58.

DeLisi LE, Sakuma M, Tew W, Kushner M, Hoff AL, Grimson R. Schizophrenia as a chronic active brain process: a study of progressive brain structural change subsequent to the onset of schizophrenia. Psychiat.Res. 1997; 74:129-140.

Dhalla KS, Ganguly PK, Ropp H, Beamish RE, Dhalla NS. Measurement of adrenolutin as an oxidative product of catecholamines in plasma. Mol.Cell Biochem. 1989; 87:85-92.

Dugan LL, Creedon DJ, Johnson EM Jr., Holtzman DM. Rapid suppression of free radical formation by nerve growth factor involves the mitogen-activated protein kinase pathway. Proc.Nat.Acad.Sci. USA 1997;94:4086-4091.

Duncan GE, Moy SS, Knapp DJ, Mueller RA, Breese GR. Metabolic mapping of the rat brain after subanesthetic doses of ketamine: potential relevance to schizophrenia. Brain Res. 1998; 787:181-190.

Dwork AJ. Postmortem studies of the hippocampal formation in schizophrenia. Schiz.Bull. 1997;23:385-402.

Eastwood SL, Harrison PJ. Hippocampal and cortical growth-associated protein-43 messenger RNA in schizophrenia. Neuroscience 1998;86:437-448.

Eastwood SL, Barnet PWJ, Harrison P. GluR2 glutamate receptor subunit flip and flop isoforms are decreased in the hippocampal formation in schizophrenia: a reverse transcriptase-polymerase chain reaction (RT-PCR) study. Mol.Brain Res. 1997a; 44:92-98.

Eastwood SL, Kerwin RW, Harrison P. Immunographic evidence for a loss of -amino-3-hydroxy-5-methyl-4-isoxazole-proprionate-preferring non-N-methyl-D-aspartate glutamate receptors within the medial temporal lobe in schizophrenia. Biol.Psychiat. 1997b; 41: 636-643.

Frommberger WH, Bauer J, Haselbauer P, Fräulin A, Riemann D, Berger M. Interleukin-6-(IL-6) plasma levels in depression and schizophrenia; comparison between the acute phase and after remission. Eur.Arch.Psychiat.Clin.Neurosci. 1997;247:228-233.

Gai W-P, Geffen LB, Denoroy L, Blessing WW. Loss of C1 and C3 epinephrine-synthesizing neurons in the medulla oblongata in Parkinsonís disease. Ann.Neurol. 1993;33:357-367.

Garcia-Rill E, Biedermann JA, Chambers T, Skinner RD, Mrak RE, Husain M, Karson CN. Mesopontine neurons in schizophrnia. Neuroscience 1995;66:321-335.

Garey LJ, Ong WY, Patel TS, Kanami M, Davis A, Hornstein C, Bauer M. Reduction in dendritic spine numbers on cortical neurons in schizophrenia. Abst.Soc.Neurosci. 1995;21:236.

Gattaz WF, Köllisch M, Thuren T, Virtanen JA, Kinnunen PKJ. Increased plasma phospholipase-A2 activity in schizophrenic patients: reduction after neuroleptic therapy. Biol.Psychiat. 1987;22:421-426.

George TP, Spence MW. Alterations of membrane phospholipid metabolism in patients with schizophrenia assessed by phosphorus magnetic resonance spectroscopy. Arch.Gen.Psychiat. 1996;53:1065-1066.

Glantz LA, Lewis DA. Assessment of spine density on layer III pyramidal cells in the prefrontal cortex of schizophrenic patients. Abst.Soc.Neurosci. 1995; 21:239.

Glantz LA, Lewis DA. Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Arch.Gen.Psychiat. 1997; 54: 660-665 & 943-952.

Goff DC, Wine L. Glutamate in schizophrenia: clinical and research implications. Schiz.Res. 1997;27:157-168.

Goldman-Rakic PS, Selemon LD. Functional and anatomical aspects of prefrontal pathology in schizophrenia. Schiz.Bull. 1997;23:437-458.

Goldsmith SK, Shapiro RM, Joyce JN. Disrupted pattern of D2 dopamine receptors in the temporal lobe in schizophrenia. A postmortem study. Arch.Gen.Psychiat. 1997;54 :649-658.

Goss J, Taffe KM, Kochanek PM, DeKosky ST. The antioxidant enzymes glutathione peroxidase and catalase increase following traumatic brain injury in the rat. Exp.Neurol. 1997;146:291-294.

Grof S. Clinical and experimental study of central effects of adrenochrome. J. Neuropsychiat. 1963;5:33-50.

Gur RET, Cowell P, Turetsky BI, Gallacher F, Cannon T, Bilker W, Gur RC. A follow-up magnetic resonance imaging study of schizophrenia. Relationships of neuroanatomical changes to clinical and neurobehavioral measures. Arch.Gen.Psychiat. 55, 145-152.

Gurevich EV, Joyce JN. Alterations in the cortical serotoninergic system in schizophrenia; a postmortem study. Biol.Psychiat. 1997;42:529-545.

Halberstadt AL. The phencyclidine-glutamate model of schizophrenia. Clin.Neuropharmacol. 1995; 18:237-249.

Hashimoto K, Minabe Y, Iyo M. Expression of cyclooxygenase-2 mRNA in rat retrosplenial cortex following administration of phencyclidine. Brain Res. 1997:762:259-263.

Hashimoto, T, Kitamura N, Kajimoto Y, Shirai Y, Shirakawa, Mita T, Nishino N, Tanaka C. Differential changes in serotonin 5-HT1a and 5-HT2 receptors binding in patients with chronic schizophrenia. Psychopharmacology 1993; 112:S35-S39.

Heckers S. Neuropathology of schizophrenia: cortex, thalamus, basal ganglia, and neurotransmitter-specific projection systems. Schiz.Bull. 1997;23:403-421.

Helmeste DM, Tan SW, Bunney WE Jr. Potkin SG, Jones EG. Decrease in sigma but no increase in striatal dopamine D4 sites in schizophrenic brains. Eur.J.Pharmacol. 1996; 314:R3-R5

Hernandez I, Sokolov BP. Abnormal expression of serotonin transporter mRNA in the frontal and temporal cortex of schizophrenics. Mol.Psychiat. 1997; 2:57-64.

Hietala J, Syrälahti E. Dopamine in schizophrenia. Ann.Med. 1996; 28: 557-561.

Hirsch SR, Das I, Garey LJ, de Belleroche J. A pivotal role for glutamate in the pathogenesis of schizophrenia, and its cognitive dysfunction. Pharmacol.Biochem.Behav. 1997;56:797-802.

Hoffer A, Osmond H, Smythies JR. Schizophrenia. A new approach. Part II. J.Ment.Sci. 1954;100:29-45.

Hoffman RE, McGlashan TH. Parallel distributed processing and the emergence of schizophrenic symptoms. Schiz.Bull. 1993; 19: 119-140.

Hoffman RE, McGlashan TH. N-methyl-D-aspartate hypofunction in schizophrenia could arise from reduced cortical connectivity rather than receptor dysfunction. Arch.Gen.Psychiat. 1997; 54:57-580.

Holinger GD, Rosen GD, Galaburda AM. Decreased neuronal density in supragranular layer of area TPT of the superior temporal gyrus in schizophrenia. Abst.Soc.Neurosci. 1995;21:238.

Honer WG, Falkai P, Young C, Wang T, Xie J, Bonner J, Hu L, Boulianne GL, Luo z, Trimble WS. Cingulate cortex synaptic terminal proteins and neural cell adhesion molecule in schizophrenia. Neuroscience 1997;78:99-110.

Horrobin DF. Schizophrenia as a membrane lipid disorder which is expressed throughout the body. Prost.Leuk.Essent..Fatty Acids 1996; 51:3-7.

Humphries C, Mortimer A, Hirsch S, de Belleroche J. NMDA receptor mRNA correlation with antemortem cognitive impairment in schizophrenia. NeuroReport 1996;7:2051-2055.

Humphries CR, Virgo L, Mortimer A, Barnes T, Hirsch S, de Belleroche J. The expression of the N-methyl-D-aspartate receptor subunit NR-1 is decreased in schizophrenia. Schiz.Res. 1995;15:60-61.

Ilyin VI, Whittemore ER, Guastella J, Weber E, Woodward RM. Subtype-selective inhibition of the N-methyl-D-aspartate receptor by haloperidol. Mol.Pharmacol. 1996;50:1541-1550.

Jentsch JD, Elsworth JD, Taylor JR, Redmond DE Jr., Roth RH. Dysregulation of the mesoprefrontal dopamine neurons induced by acute and repeated phencyclidine administration in the nonhuman primate: implications for schizophrenia. Adv.Pharmacol. 1998;42:810-814.

Jernigan TL, Zisook S, Heaton RK, Moranville JT, Hesselink JR, Braff DL. Magnetic resonance imaging abnormalities in lenticular nuclei and cerebral cortex in schizophrenia. Arch.Gen.Psychiat. 1991;48:881-890.

Johnson KM, Phillips M, Wang C, Kevetter GA. Chronic phencyclidine induces behavioral sensitization and apoptotic cell death in the olfactory and piriform cortex. J.Neurosci.Res. 1998;52:709-722.

Jones EG. Cortical development and thalamic pathology in schizophrenia. Schiz.Bull. 1997;23:483-501.

Jönsson Sa, Luts A, Guldberg-Kjaen N, Brun A. Hippocampal pyramidal cell disarray correlates negatively to cell number: implications for the pathogenesis of schizophrenia. Eur.Arch.Psychiat.Clin.Neurosci. 1997; 247:120-127.

Joyce JN, Goldsmith SG, Gurevich EV. Limbic circuits and monoamine receptors: dissecting the effects of antipsychotics from disease processes. J.Psychiatr.Res. 1997;31:197-217.

Kalus P, Senitz D, Beckman H. Altered distribution of parvalbumin-immunoreactive local circuit neurons in the anterior cingulate cortex of schizophrenic patients. Psychiat.Res. 1997;75:49-59.

Karson CN, Griffin WS, Mrak RE, Husain M, Dawson TM, Snyder SH, Moore NC, Sturner WQ. Nitric oxide synthase (NOS) in schizophrenia: increases in cerebellar vermis. Mol.Chem.Neuropathol. 1996;27:275-284.

Karson CN, Mrak RE, Husain MM, Griffin WS. Decreased mesopontine choline acetyltransferase levels in schizophrenia. Mol.Chem.Neuropathol. 1996;29:181-191.

Katila H, Appelberg B, Rim -n R. No difference in phospholipase-A2 activity between acute psychiatric patients and controls. Schiz.Res. 1997;26:103-105.

Kerwin RW, Harrison P. Loss of non NMDA receptors in medial temporal lobe -a robust neurochemical finding: autoradiographical, gene expression and immnochemical findings. Schiz.Res. 1995;15:62.

Keshavan MS, Mallinger AG, Pettegrew JW, Dipple C. Erythrocyte membrane phospholipids in psychiatric patients. Psychiat.Res. 1993;49:89-96.

Knable MB, Hyde TM, Herman MM, Carter JM, Bigelow L, Kleinman JE. Quantitative autoradiography of dopamine-D1 receptors, D2 receptors, and dopamine uptake sites in postmortem striatal specimens from schizophrenic patients. Biol.Psychiat. 1994;36:827-835.

Kornhuber J, Weller M. Psychotogenicity and N-methyl-D-aspartate recepror antagonism: implications for neuroprotective pharmacotherapy. Biol.Psychiat. 1997;41:130-134.

Krimer LS, Herman MM, Saunders RC, Boyd JC, Hyde TM, Carter JM, Kleinman JE, Weinberger DR. A qualitative and quantitative analysis of the entorhinal cortex in schizophrenia. Cerebral Cortex 1997;7:732-739.

Kroemer RT, Koutsilieri E, Hecht P, Liedl KR, Riederer P, Kornhuber J. Quantitative analysis of the structural requirements for blockade of the NMDA receptor at the PCP binding site. J.Med.Chem. 1998;41:393-400.

Kulkarni J, Horne M, Butler E, Keks N, Copolov D. Psychotic symptoms resulting from intraventricular infusion of dopamine in Parkinsonís disease. Biol.Psychiatr. 1992;31:1225-1227.

Lahti AC, Holcomb HH, Weiler MA, Corey PK, Zhao M, Medoff D, Tamminga CA. Effects of ketamine on behavior and CBF in schizophrenic and normal individuals. Biol.Psychiat. 1997;41:16S.

Lahti RA, Roberts RC, Conley RR, Cochrane EV, Mutin A, Tamminga CA. D2-type dopamine receptors in postmortem human brain sections from normal and schizophrenic subjects. NeuroReport 1996;7:1945-1848.

Leonard S, Adams C, Breese CR. Nicotinic receptor function in schizophrenia. Schiz.Bull. 1996;22:431-433.

Lesch A, Bogerts B (1984) The diencephlon in schizopphrenia: evidence for reduced thickness of the periventricular grey matter. Eur.Arch.Psychiat.Clin.Neurosci. 1984;234:212-219.

Lew JY Matsumoto Y, Pearson J, Goldstein M, Hökfelt T, Fuxe K. Localization and characterization of phenylethanolamine N-methyl transferase in the brain of various mammalian species. Brain Res. 1977;119:199-210.

Lewis DA. Schizophrenia and disordered neural circuitry. Schiz.Bull. 1997;23:529-531.

Lidsky TI, Yablonsky-Alter E, Zuck LG, Banerjee SP. Antipsychotic drug effects on glutamatergic activity. Brain Res. 1997;764:49-52

Lim KO, Tew W, Kushner M, Chow K, Matsumoto B, DeLisi LE. Cortical grey matter volume deficit in patients with first episode schizophrenia. Amer.J.Psychiat. 1996;153:1548-1553.

Lim KO, Adalsteinsson E, Spielman D, Sullivan EV, Rosenbloom MJ, Pfefferbaum A. Proton magnetic resonance spectroscopic imaging of cortical gray matter and white matter in schizophrenia. Arch.Gen.Psychiat. 1998;55:346-352.

Loven DP, James JF, Biggs L, Little KY. Increased manganese-superoxide dismutase activity in postmortem brains from neuroleptic-treated psychotic patients. Biol.Psychiat. 1996; 40:230-232.

Lutzenberger W, Stevens A, Bartels M. Do schizophrenics not differentiate between percepts and imagination? An EEG study using dimensional analysis. Neurosci.Lett. 1995; 199:119-122.

Mahadik SP, Mukherjee S. Free radical pathology and antioxidant defenses in schizophrenia: a review. Schiz.Res. 1996;19:1-17.

Mahadik SP, Mukherjee S, Schaffeer R, Correnti EE, Mahadik JS. Elevated plasma lipid peroxides at the onset of nonaffective psychosis. Biol.Psychiat. 1998;43:674-679.

Marsh L, Harris D, Lim KO, Beal M, Hoff AL, Minn K, Csernansky JG, DeMent S, Faustman WO, Sullivan EV, Pfefferbaum A. Structural magnetic resonance imaging abnormalities in men with severe chronic schizophrenia and an early age of clinical onset. Arch.Gen.Psychiat. 1997;54:1104-1112.

Manzella PL, Hill C, Keks N, Singh B, Copolov D. The binding of both [3H] nemonapride and [3 H] raclopride is increased in schizophrenia Biol.Psychiatr. 1997;42:648-654.

Meador-Woodruff JH, Haroutunian V, Powchik P, Davidson M, Davis KL, Watson SJ. Dopamine receptor transcription expression in striatum and prefrontal and occipital cortex. Focal abnormalities in orbitofrontal cortex in schizophrenia. Arch.Gen.Psychiat. 1997a;54:1089-1095.

Meador-Woodruff JH, Healy DJ, Haroutanian V, Davidson M, Powchik P, Davis KL, Watson SJ. Ionotopic glutamate receptors in schizophrenic brain. Biol.Psychiat. 1997b;41:66S-67S.

Mefford J, Oke A, Keller R, Adams RN, Jonsson G. Epinephrine distribution in human brain. Neurosci.Lett. 1978;9:227-231.

Melamed Y, Sirota P, Dicker DR, Fishman P. Superoxide anion production by neutrophils derived from peripheral blood of schizophrenic patients. Psychiat.Res. 1998;77:29-34.

Miller C, Kirchman R, Troger J, Savia A, Fleischhacker WW, Fischer-Colbrie R, Benzer A, Winkler H. CSF of neuroleptic-naive first-episode schizophrenic patients: levels of biogenic amines, substance P, and peptides derived from chromogranin A (GE-25) and secretogranin II (secretoneurin). Biol.Psychiat. 1996;39:911-918.

Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J.Neurosci, 1997;17:2921-2927.

Monteleone P, Natale M, La Rocca A, Maj M. Decreased nocturnal secretion of melatonin in drug-free schizophrenics: no change after subchronic treatment with antipsychotics. Neuropsychobiology 1997;36:159-163.

Nagatsu I, Ikemoto K, Takeuchi T, Arai R, Karasawa N, Fujii T, Nagatsu T. Phenylethanolamine-N-methyl transferase immunoreactive nerve terminals afferent to the mouse substantia nigra. Neurosci.Lett. 1998;245:41-44.

Nair TR, Christensen JD, Kingsbury SJ, Kumar NG, Terry UM, Garver DL. Progression of cerebroventricular enlargement and the subtyping of schizophrenia. Psychiat.Res. 1996;74:141-150.

Naudin J, Capo C, Giusano B, Mège JC, Azorin JM. A differential role for interleukin-6 and tumor necrosis factor in schizophrenia? Schiz.Res. 1997;26:227-233.

Northoff G, Eckert J, Fritze J. Glutamatergic dysfunction in catatonia? Successful treatment of three acute akinetic catatonic patients with the NMDA antogonist amantadine. J.Neurol.Neurourg.Psychiat. 1997;62:404-406.

Nopoulos P, Torres I, Flaum M, Andreasen NC, Ehrhardt JC, Yuh WT. Brain morphology in first-episode schizophrenia. Amer.J.Psychiat. 1995;152:1721-1723.

Okubo Y, Suhara T, Suzuki K, Kobayashi K, Inoue O, Terasaki O, Someya Y, Sassa T, Sudo Y, Matsushima E, Iyo M, Tateno Y, Toru M. Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature 1997;385:634-636.

Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia. Arch.Gen.Psychiat. 1995;52:998-1007.

Opeskin K, Dean B, Pavey G, Hill C, Keks N, Copolov D. Neither protein kinase C not adenylate cyclase are altered in the striatum from subjects with schizophrenia. Schiz.Res. 1996; 22:159-164.

Otake K, Ruggiero DA, Nakamura Y. Adrenergic innervation of forebrain neurons that project to the paraventricular nucleus in the rat. Brain Res. 1995;697:17-26.

Pakkenberg B. Pronounced reduction of total neuron number in mediodorsal thalamus and nucleus accumbens in schizophrenia. Arch.Gen.Psychiat. 1990;47:1023-1028.

Peet M, Langharne JDE, Horrbin DF, Reynolds GP. Arachidonic acid: a common link in the biology of schizophrenia. Arch.Gen.Psychiat. 1994;51:665-666.

Perrone-Bizzozero NI, Sower AC, Bird ED, Benowitz LI, Ivins KJ, Neve RL. Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia. Proc.Nat.Acad.Sci. USA. 1996;93:14,182-14,187.

Phillipson OT, Bohn MC. C1-3 adrenergic medullary neurons project to the paraventricular thalamic nucleus in the rat. Neurosci.Lett. 1994;176:67-70.

Poltorak M, Wright R, Hemperly JJ, Torrey EF, Issa F, Wyatt RJ, Freed WJ. Monozygotic twins discordant for schizophrenia are discordant for N-CAM and L1 in CSF. Brain Res. 1997;751:152-154.

Portas CM, Goldstein JM, Shenton ME, Hokama HH, Wible CG, Fischer I, Kikinis R, Donnino R, Jolesz FA, McCurley RW. Volumetric evaluation of the thalamus in schizophrenic male patients using magnetic resonance imaging. Biol.Psychist. 1998;43:649-659.

Rapopart JL, Giedd J, Kumra S, Jacobsen L, Smith A, Lee P, Nelson J, Hamburger S. Childhood-onset schizophrenia: progressive ventricular change during adolescence. Arch.Gen.Psychiat. 1997; 54:897-903.

Redday RD, Yao JK. Free radical pathology in schizophrenia: a review. Prost.Leuk.Essent.Fatty Acids 1996;55:33-43.

Reddy R, Sahebarao MP, Mukherjee S, Murthy JN. Enzymes of the antioxidant defense system in chronic schizophrenic patients. Biol.Psychiat. 1991;30:409-412.

Reynolds GP Neurotransmitter systems in schizophrenia. Intern.Rev.Neurobiol. 1995;38:305-339.

Reynolds GP, Mason SL. Are striatal dopamine D4 receptors increased in schizophrenia? J.Neurochem. 1994;63:1576-1577.

Rico B, Cavcada C. Adrenergic innervation of the monkey thalamus: an immunohistochemical study. Neuroscience 1998;84:839-86.

Roberts RC, Conley R, Kung E, Peretti FJ, Chute DJ. Reduced striatal spine size in schizophrenia: a postmortem ultrastructural study. NeuroReport 1996;7:1214-1218.

Roberts RC, Gauther LA, Peretti F, Conley R, Lapidus B. Structural pathology in schizophrenia: a postmortem ultrastructural study. Abst.Soc.Neurosci. 1995;21:237.

Ross BM, Hudson C, Erlich J, Warsh JJ, Kish SJ. Increased phospholipid breakdown in schizophrenia: evidence for the involvement of a calcium-independent phosopholipase A2. Arch.Gen.Psychiat. 1997;54:487-494.

Sampath D, Perez-Polo R. Regulation of antioxidant enzyme expression by NGF. Neurochem.Res. 1997;22:351-363.

Saper CB. Petito CK. Correspondence of melanin-pigmented neurons in human brain with A1-A14 catecholamine cell groups. Brain 1882;105:87-101.

Sawada H, Ibi M, Kihara T, Urushitani M, Akaike A, Kimura J, Shimohama S. Dopamine D2-type agonists protect mesencephalic neurons from glutamate neurotoxicity: mechanisms of neuroprotective treatment against oxidative stress. Ann.Neurol, 1998;44:110-119.

Schulz JB, Bremen D, Reed JC, Lommatzsch J, Takayama S, Wüllner U, Löschmann P-A, Klockgether T, Weller M. Cooperative interception of neuronal apoptosis by BCL-2 and BAG-1 expression: prevention of caspase activation and reduced production of reactive oxygen species. J.Comp.Neurol. 1997;69:2075-2086.

Schwartz BE, Sem-Jacobsen C, Petersen MC. Effests of mescaline, LSD-25 and adrenochrome on depths electrograms in man. Arch.Neurol.Psychiat. 1956;75:579-587.

Seeman P, Guan H-C, Van Tol HHM. Dopamine D4 receptors elevated in schizophrenia. Nature 1993;365:441-445.

Seidman LJ, Faraone SV, Goldstein JM, Goodman JM, Kremen WS, Matsuda G, Hoge EA, Kennedy D, Makris N, Caviness VS, Tsuang MT. Reduced subcortical brain volumes in nonpsychotic siblings of schizophrenic patients; a pilot magnetic resonance imaging study. Amer.J.Med.Genet. 1997;74:507-514.

Selemon LD, Rajkowska G, Goldman-Rakic PS. Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Arch.Gen.Psychiat. 1995;52:805-818.

Selemon LD, Rajkowska G. Goldman-Rakic PS. Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a three-dimensional stereologic counting method. J.Comp>Neurol. 1998;392:402-412.

Sharp JW Phencyclidine (PCP) acts at sigma sites to induce c-fos gene expression. Brain Res. 1997;758:51-58.

Shimizu E, Shirasawa H, Kodama K, Kuroyanagi H, Shirasawa T, Sato T, Simizu B. Glutamate dehydrogenase mRNA is immediately induced after phencyclidine treatment in the rat brain. Schiz.Res. 1997;25:251-258.

Smythies JR. On the function of neuromelanin Proc.R.Soc.London B. 1996;263:491-496.

Smythies JR. The biochemical basis of synaptic plasticity and neural computation: a new theory. Proc.R.Soc.London B. 1997a;264:575-579.

Smythies JR Oxidative reactions and schizophrenia: a review -discussion. Schiz.Res. 1997b;24:357-364.

Smythies JR, Galzigna L. The oxidative metabolism of catecholamies in the brain: a review. Biochim.Biopys.Acta 1998;1380:159-162.

Stevens JR. Enough of pooled averages: been there, done that. Biol.Psychiat. 1997;41:633-635.

Sullivan EV, Lim KO, Mathalon D, Marsh L, Beal DM, Harris D, Hoff AL, Faustman WO, Pfefferbaun A> A profile of cortical grey matter volume deficits characteristic of schizophrenia. Cerebral Cortex 1998, 8, 117-124.

Taubman G, Jantz H. Untersuchung über die dem adrenochrom zugeschrieben psychotoxischen wirkungen. Nervenartz 1957;28:485-488.

Tcherepanov AA, Sokolov BP. Age-related abnormalities in expression of mNAs encoding synapsin 1A, synapsin 1B, and synaptophysin in the temporal lobe of schizophrenics. J.Neurosci.Res. 1997;49:639-644.

Thompson PM, Sower AC, Perrone-Bizzozero NI. Altered levels of the synaptosome associated protein SNAP-25 in schizophrenia. Biol.Psychiat. 1998;43:239-243.

Turner EE, Fedtsova N, Jeste DV. Cellular and moelcular neuropathology of schizophrenia: new directions from developmental neurobiology. Schiz.Res. 1997;27:169-180.

Vawter MP, Cannon-Spoor HE, Hemperly JJ, Hyde TM, VanderPutten DM, Kleinman JE, Freed WJ. Abnormal expression of cell recognition molecules in schizophrenia. Exp.Neurol. 1998;149:424-452.

Volz H-P, Rzanny R, May S, Hegewald H, Preussler B, Hajek M, Kaiser WA, Saver H. 31P magnetic resonance spectroscopy in dorsolateral prefrontal cortex of schizophrenics with a volume selective technique -preliminary findings. Biol.Psychiat. 1997;41:644-648.

Weinberger DR. On localizing schizophrenic neuropathology. Schiz.Bull. 1997;23:537-540.

Whatley SA, Curti D, Marchbanks RM. Mitochondrial involvement in schizophrenia and other functional psychoses. Neurochem.Res. 1996;21:995-1004.

Wolf SS, Hyde TM, Saunders RC, Herman MM, Weinberger DR, Kleinman JE. Autoradiographic characterization of neurotensin receptors in the entorhinal cortex of schizophrenic patients and control subjects. J.Neural.Trans.[Gen.Sect]. 1995;102:55-65.

Wright P, Takei N, Rifkin L, Murray RM. Maternal influenza, obstetric complications, and schizophrenia. Amer.J.Psychiat. 1995;152:1714-1720.

Wyatt RJ. Neurodevelopmental abnormalities and schizophrenia. A family affair. Arch.Gen.Psychiat. 1996; 53:11-15.

Yao JK, van Kammen DP. Incorporation of 3H-arachidonic acid into platelet phospholipids of patients with schizophrenia. Prost.Leuk.Essent.Fatty Acids 1996;55:21-26.

Yao JK, Reddy RD, van Kammen DP, McElhinny LG, Korbanic CW. Reduced level of the antioxidant proteins in schizophrenia. Biol.Psychiat. 1998a;43:123S.

Yao JK, Reddy R, van Kammen DP. Reduced level of plasma antioxidant uric acid in schizophrenia Psychiatr. Res. 1998b;80: 29-39.

Yao JK, Reddy R, McElhiney LG, van Kammen DP. (1998c). Reduced status of plasma total antioxidant capacity in schizophrenia. Schiz.Res. 1998c;32: 1-8.

Yurgelun-Todd DA, Renshaw PF, Grubex SA, Ed M, Waternaux C, Cohen BM. Proton magnetic resonance spectroscopy of the temporal lobes in schizophrenics and normal controls. Schiz.Res. 1996;19:55-59.

Zaidel DW, Esiri MM, Harrison PJ. The hippocampus in schizophrenia: lateralized increase in neuronal density and altered cytoarchitectural asymmetry. Psychol.Med. 1997;27:703-713.

Zipursky RB, Seeman MV, Bury A, Langevin R, Wortzman G, Katz R. Deficits in gray matter volume are present in schizophrenia but not bipolar disorder. Schiz.Res. 1997;26:85-92.