Progress in Neuro-Psychopharmacology & Biological Psychiatry 48 (2014) 155–160

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Is schizophrenia a supersensitivity psychotic reaction?☆

Mary V. Seeman a, Philip Seeman b,⁎ a Departments of Psychiatry, University of Toronto, 260 Heath St. West, Suite 605, Toronto, Ontario M5P 3L6, Canada b Departments of Pharmacology, University of Toronto, 260 Heath St. West, Suite 605, Toronto, Ontario M5P 3L6, Canada article info abstract

Article history: Adolf Meyer (1866–1950) did not see schizophrenia as a discrete disorder with a specific etiology but, rather, as a Received 30 August 2013 reaction to a wide variety of biopsychosocial factors. He may have been right. Today, we have evidence that gene Received in revised form 3 October 2013 mutations, brain injury, drug use (cocaine, amphetamine, marijuana, , and steroids), prenatal Accepted 3 October 2013 infection and malnutrition, social isolation and marginalization, can all result in the signs and symptoms of Available online 12 October 2013 schizophrenia. This clinical picture is generally associated with supersensitivity to dopamine, and activates dopamine neurotransmission that is usually alleviated or blocked by drugs that block dopamine D2 receptors. Keywords: fi D1D2 receptor dimer While the dopamine neural pathway may be a nal common route to many of the clinical symptoms, the D2 receptor components of this pathway, such as dopamine release and number of D2 receptors, are approximately normal D2D2 receptor dimer in schizophrenia patients who are in remission. Postmortem findings, however, reveal more dimers of D1D2 Dopamine release and D2D2 receptors in both human schizophrenia brains and in animal models of schizophrenia. Another finding Mutation in animal models is an elevation of high-affinity state D2High receptors, but no radioactive ligand is yet available to Psychosis selectively label D2High receptors in humans. Psychotogens It is suggested that synaptic dopamine supersensitivity in schizophrenia is an attempt at compensation for the original damage by heightening dopamine neurotransmission pathways (preparing the organism for fight or flight). The dopamine overactivity is experienced subjectively as overstimulation, which accounts for some of the clinical symptoms, with attempts at dampening down the stimulation leading to still other symptoms. Reaction and counter-reaction may explain the symptoms of schizophrenia. © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Contents

1. Introduction...... 156 2. Thehistoricalviewofschizophreniaasareaction...... 156 3. Thedopaminesupersensitivereaction...... 156 4. Theschizophreniasupersensitivereactionandpresynapticneuronpruning...... 157 5. Theschizophreniasupersensitivereactionviadopaminerelease...... 157 6. TheschizophreniasupersensitivereactionviadopamineD2receptors...... 157 7. Theschizophreniasupersensitivereaction,dopamineD2Highreceptors,anddimers...... 157 8. Idiopathicsupersensitivityinschizophrenia,andantipsychotic-inducedsupersensitivity...... 157 9. Theschizophreniaexperiential/behavioralreactiontothesupersensitivesynapse...... 157 9.1. Misattributionsordelusions...... 158 9.2. Hallucinations...... 158 9.3. Cognitive deficits...... 158 9.4. Thoughtdisorder...... 158 9.5. Negativesignsandsymptoms...... 158 9.6. Moodchanges...... 158 9.7. Movementdisorder...... 158 10. Psychotogens...... 158 11. Clinicaltreatmentimplications...... 158 Funding...... 159 References...... 159

☆ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited. ⁎ Corresponding author. Tel.: +1 416 486 3456. E-mail address: [email protected] (P. Seeman).

0278-5846/$ – see front matter © 2013 The Authors. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pnpbp.2013.10.003 156 M.V. Seeman, P. Seeman / Progress in Neuro-Psychopharmacology & Biological Psychiatry 48 (2014) 155–160

1. Introduction reframed mental illness in terms of biopsychosocial “reaction types” rather than biologically-specific disease entities. As early as 1906, Most investigators acknowledge that there are many risk factors that Meyer considered dementia praecox to be a “reaction type,” acluster contribute to schizophrenia. These include various gene mutations of maladaptations that, together, constituted an attempt to cope with (both new and inherited), prenatal malnutrition or infection, birth biopsychosocial stressors. anoxia/injury, brain trauma, drug abuse (cocaine, amphetamine, The present suggestion that schizophrenia may be a hyperactive marijuana, phencyclidine, and steroids), social isolation and dopamine supersensitive reaction to a variety of possible causes fits marginalization. Nevertheless, despite the impact of many different Meyer's general framework of schizophrenia as a reactive disorder. factors, the brain can react to them all similarly to produce the signs and symptoms of schizophrenia, the specific experiential and 3. The dopamine supersensitive reaction behavioral expression of which can, and does, vary from patient to patient. The present work develops the idea that synaptic dopamine This common general reaction is associated with supersensitivity supersensitivity compensates for an original early injury (or mutation) to dopamine (Lieberman et al., 1987; Seeman, 2011), and overactivity by heightening dopamine neurotransmission pathways. Subjectively, of dopamine neurotransmission, which is usually alleviated or blocked the patient experiences this as overstimulation, a generally unpleasant by drugs that block dopamine D2 receptors (Madras, 2013). sensation that leads to symptoms and to attempts at adaptation. At present, there is no diagnostic test or unique biological marker Out of such attempts at compensation arise the variety of signs and for schizophrenia, either associated with or extraneous to the dopamine symptoms that have been identified with schizophrenia. Patients with system. For example, while all target the dopamine schizophrenia, whether treated or untreated, are known to be D2 receptor, the number of these receptors has been found to be supersensitive to dopamine-like compounds (Lieberman et al., 1987), approximately normal in the cerebral cortex of patients, as long as with intensification of symptoms or the development of new symptoms they have not been medicated with antipsychotics (Seeman, 2013a, in following the administration of dopamine-like agonists. The present press). Numbers may differ, however, in specificpartsofthebrain, mini-review outlines “the schizophrenia reaction” in terms of the such as an apparent reduction in presynaptic D2 receptors in the molecular components of synaptic sensitivity and thalamus (reviewed by Seeman, in press). the patient's automatic compensation. The psychopathology and molecular mechanisms that trigger While there are many molecular components underlying the overactivity at the D2 receptor, either by presynaptic or postsynaptic biological basis of the schizophrenia reaction, it is not known, of course, events, offer a potential pathway that might unravel the vulnerable in what sequence such components become active. Nevertheless, for elements that underlie schizophrenia. For over half a century, a door the present purpose of this mini-review, the order of these components into the psychotic brain has been opened via the strategy of searching is organized as follows (see also Fig. 1): for the mechanism of drug action and working backwards a. Neuron cell pruning. to identify the brain networks involved in psychosis. The first effective b. Activation of dopamine release. drugs were (Delay et al., 1952) and the related c. Activation of dopamine D2 receptors. , followed by the -type antipsychotics and d. Induction of dopamine D2High receptors. the more recent second generation antipsychotics, with their diverse structures and receptor binding profiles. Despite the different chemical At present, the evidence indicates that the signs and symptoms of structures and the multi-receptor affinity of many of the effective psychosis, originating from whatever cause, are associated with an drugs, a common target for all the antipsychotics is now recognized to overactive dopamine system. This may result from a combination of be the so-called antipsychotic receptor, more commonly known as the increased presynaptic neural pruning, a high release of dopamine dopamine D2 receptor (Seeman et al., 1975). (Howes et al., 2012), altered numbers of dopamine D2 receptors While D2-blocking drugs usually alleviate delusions and (Seeman, 2013a, in press), and/or an increased sensitivity of the D2 hallucinations within a matter of a few days (Delay et al., 1952; Kapur receptor to dopamine (Seeman, 2011). This view is supported by the et al., 2005), the dissipation of negative symptoms, such as apathy, and the cognitive difficulties associated with schizophrenia, may 1. Lesion (mutation, injury, drugs) require antipsychotics that act on targets other than the D2 receptor. At present, however, potentially new antipsychotic drugs acting on other targets such as receptors for dopamine D1, D3, D4, D5, 2. Increased release of dopamine cannabinoid-1, neurokinin-3, serotonin, neurotensin, ampakines, and sigma sites have not been shown to be clinically effective. High While there is renewed interest in the hypoglutamate theory of 3. Receptor sensitization via more D2 receptors psychosis based on the fact that glutamate antagonists such as phencyclidine and trigger psychosis, it is known clinically High High that haloperidol (which has high affinity for D2, but low affinity for 4. More D2D2 or D2 D2 dimers glutamate receptors) effectively alleviates the psychosis secondary to phencyclidine or ketamine (Giannini et al., 1984–1985, 2000). High Moreover, it is uncertain whether glutamate receptor agonists such 5. More D1D2 or D1D2 dimers as pomaglumetad methionil or LY404,039 have any antipsychotic fi fi ef cacy. A four-week trial had little or no ef cacy against positive 6. Supersensitive behavior symptoms or negative signs when compared to (Kinon et al., 2011; Seeman, 2012a). 7. Subjective awareness of internal over-stimulation 2. The historical view of schizophrenia as a reaction

The view of schizophrenia as a reaction to a variety of potential 8. Psychotic signs and symptoms causes was promoted by the Swiss American psychiatrist, Adolf Meyer (1866–1950), in the early 1900s (Noll, 2011; Yuhas, 2013). Meyer Fig. 1. Biochemical progression from lesion to psychosis. M.V. Seeman, P. Seeman / Progress in Neuro-Psychopharmacology & Biological Psychiatry 48 (2014) 155–160 157 fact that the positive symptoms of delusions and hallucinations are amphetamine, methamphetamine, phencyclidine, cocaine, caffeine, alleviated in the majority of patients by D2-blocking medications. marijuana congeners, and . Such an elevation of D2High receptors in more than twenty 4. The schizophrenia supersensitive reaction and presynaptic animal models of psychosis (Seeman, 2011)isconsistentwiththe neuron pruning long-standing observation that schizophrenia patients are more sensitive than control subjects to dopamine-like stimulants such The automatic reduction of central nervous system neurons, as methylphenidate (Lieberman et al., 1987). known as pruning, is a well-known phenomenon (see Maor-Nof However, at present, the functional state of the D2 receptor cannot and Yaron, 2013, for refs.). In humans, pruning of dopamine neurons be measured in humans. The agonists (such as [11C]PHNO) that have occurs between 2 and 20years of age and then slowly continues at been used to study this issue (Graff-Guerrero et al., 2009)donot between 2% and 3% per decade (Seeman et al., 1987a,b). selectively label D2High receptors. Radioactive agonists such as [11C] However, in the schizophrenia thalamus, several reports show PHNO label both D2High and D2Low receptors, which may explain the evidence that suggest that there may be fewer than normal presynaptic inability to selectively measure D2High receptor numbers in human D2 receptors and fewer presynaptic terminals, as monitored by brain scans (Seeman, 2012b). However, the new long-lived [18F]- benzamide ligands (Buchsbaum et al., 2006; Kegeles et al., 2010; Talvik agonist ligand may be able to label D2High sites successfully in the et al., 2003, 2006; Tuppurainen et al., 2006; Yasuno et al., 2004), future (Sromek et al., 2011). especially in association with a genetic variant in the dopamine D2 In addition to an increase in the proportion of D2High receptors, receptor (with a T in rs 1076560 in intron 6) (reviewed by Seeman, there is an increase in the proportion of D2D2 dimers (Wang et al., in press). Such reductions may be a result of neural pruning in the 2010) and D1D2 dimers (Perreault et al., 2010) in postmortem thalamus. schizophrenia brain striatal tissue (compared to non-affected brains), Neural presynaptic pruning would be expected to lead to denervation findings that are associated with an elevation in D2High receptors. supersensitivity in a given specific brain region, analogous to that which While it is well established that long-term administration of occurs in early stages of Parkinson's disease. antipsychotic medication can increase the number of dopamine D2 and D2High receptors and their sensitivity to dopamine (Samaha, 5. The schizophrenia supersensitive reaction via dopamine release 2013; Silvestri et al., 2000), the antipsychotics at the same time effectively reduce the number of D2High receptors that have previously It has been established that patients with schizophrenia release more been induced by a psychotogen such as amphetamine (Seeman, 2009). endogenous dopamine than do individuals without schizophrenia, as measured by a challenge with a low dose of amphetamine (Laruelle et al., 1999). This effect of amphetamine occurs during the acute stages 8. Idiopathic supersensitivity in schizophrenia, and antipsychotic- of schizophrenia but not when the patients are in clinical remission. induced supersensitivity In the case of animal studies, it is not known whether dopamine release is increased in all of the many animal models of psychotic Moreover, while the schizophrenia reaction may be based on activity. dopamine supersensitivity, prolonged antipsychotic treatment can also add to such supersensitivity. This view is supported by the general 6. The schizophrenia supersensitive reaction via dopamine clinical observation that sudden withdrawal of antipsychotics can D2 receptors precipitate an acute episode of psychosis (Chouinard and Chouinard, 2008). As for the number of dopamine D2 receptors in the human brain Because the dopamine supersensitive reaction in schizophrenia is striatum, these have finally been determined to be approximately somewhat similar to the dopamine supersensitivity that is induced normal (reviewed by Seeman, 2013a, in press), following an extensive by antipsychotic drugs, clarifications have been made by Chouinard number of earlier reports (e.g., Corripio et al., 2011; Farde et al., 1990). and colleagues. For example, these authors earlier hypothesized that However, as mentioned above, there is consistent suggestive schizophrenia was an idiopathic dopamine deficiency disease associated evidence of reduced presynaptic terminals and reduced presynaptic with dopamine supersensitivity (Chouinard and Jones, 1978; Reith et al., numbers of dopamine D2 receptors in the schizophrenia thalamus 1994). They later suggested that some severe and persistent psychotic (Seeman, in press). Such reductions would inevitably lead to denervation symptoms could emerge in association with antipsychotic-induced supersensitivity in this region. dopamine supersensitivity (Chouinard, 1990;seealsoIyo et al., 2013; Kimura et al., 2013; Tadokoro et al., 2012). 7. The schizophrenia supersensitive reaction, dopamine D2High In addition, antipsychotic-induced dopamine supersensitivity can receptors, and dimers occur together with tardive dyskinesia, which appears to be associated with a loss of cholinergic neurons as well as dopamine neurons Although the total number of D2 receptors in the human striatum (Miller and Chouinard, 1993; Seeman and Tinazzi, 2013). may be normal, animal models of psychotic behavior (brain lesions, gene mutations, or harm from psychotogens) all lead to an increase in D2High receptors, which is the high-affinity state or the functional 9. The schizophrenia experiential/behavioral reaction to the state of the D2 receptor (Seeman, 2011). Such factors include brain supersensitive synapse lesions in the hippocampus, frontal cortex, or substantia nigra, and various gene knock-out mutations in mice, including those for Supersensitivity at the level of the synapse can lead to clinical the metabotropic glutamate receptors 2 and 3, the GABA B1 receptor, symptoms either directly or via compensation to dopamine the trace amine 1 receptor, the dopamine D4 receptor, the beta- overactivity. This is seen in the core symptoms of schizophrenia adrenoceptor, and genes for dopamine-beta-hydroxylase, G-protein such as a) misattributions or delusions, b) altered perceptions or receptor kinase, the postsynaptic density 95, catecholamine-O-methyl- hallucinations, c) cognitive deficits, d) disorganization (thought transferase, the dopamine transporter, and RGS-9 (Regulator of disorder), e) isolation and amotivation (negative signs), and also G-protein signaling 9). in symptoms that frequently accompany schizophrenia, such as In addition, the proportion of D2High receptors increased in rat f)alteredmood(depression,ecstasy,andterror)andg)altered striata after administration of the following drugs: corticosterone, movement (agitation, dyskinesia, and catatonia). 158 M.V. Seeman, P. Seeman / Progress in Neuro-Psychopharmacology & Biological Psychiatry 48 (2014) 155–160

9.1. Misattributions or delusions low-affinity states of the D2 receptor, with the D2High and D2Low receptors rapidly interconverting, depending on the metabolism of The dopamine supersensitive state can lead to excess thoughts and GDP and GTP within the cell (Seeman, 2013b). It should be noted that excess speed of thoughts, which makes them especially vivid. These the two states of D2High and D2Low are constantly interconverting, actions can be replicated by a variety of hallucinogen agonists known and that synaptic and clinical dopamine sensitivity can change in to be active at the dopamine D2 receptor (Seeman et al., 2009). The a matter of minutes, depending on the metabolism of these two vividness of the thoughts lends to them a sense of urgency and an guanine nucleotides. Ups and downs of mood are dealt with differently aura of certainty. Delusions are misattributions that are experienced as by different individuals. Routinization and stereotypy are one way, imperative and believed in with unshakeable conviction. There is accounting for the prevalence of obsessive–compulsive symptoms evidence that overactivity of the dopamine system can kick start the (nearly one third of patients) in schizophrenia (Byerly et al., 2005). procession of events that leads to delusion formation (Howes and Some strategies for dealing with mood oscillation, such as quickly Kapur, 2009). ‘jumping to conclusions’ (which, incidentally, encourages delusion formation) may be an attempt to rapidly establish certainty in order 9.2. Hallucinations to ward off the chaos and ambiguity that results from supersensitive synapses. Hallucinations are most frequently understood as defects of source monitoring (Garrett and Silva, 2003). Memories and inner thoughts 9.7. Movement disorder that flood the brain through supersensitive D2 receptors are experienced as coming from the outside. This has been empirically Adventitious movements such as exaggerated or purposeless arm validated by Brébion et al. (2009). The more rapid the perceptions, the and leg motions, tics, grimacing, repetitive activity, and altered reflexes more errors in context processing and subsequent experience of occur in patients with schizophrenia even when they are not taking attributing inner sensations to external stimuli. Abnormal perceptions antipsychotic drugs. They are probably a direct result of hyper- such as voices heard in one's head, visions, smells, and somatic transmission at dopamine synapses (Van Rossum, 1967) whereas, sensations may all result from dopamine overactivity. after drugs, they reflect dopamine/cholinergic imbalance (Campos et al., 2010; Pappa and Dazzan, 2009; Peluso et al., 2012). Psychomotor 9.3. Cognitive deficits slowing and catatonia are further examples of movement problems associated with schizophrenia and can be viewed as compensations. The probability that dopamine supersensitivity can lead to cognitive difficulties is shown by the fact that D2 receptors, selectively 10. Psychotogens genetically elevated in the striatum, reduce cognitive performance in animals (Kellendonk et al., 2006). Attention and memory problems in Another way of attempting to control chaos is through the use of schizophrenia may directly result from dopamine overstimulation and mind-altering substances. Supersensitivity at the dopamine receptor are worsened by the lowered self-confidence that ensues from them. enhances the reward from nicotine and alcohol, and possibly to marijuana and its congeners (see also Seeman, 2011), further 9.4. Thought disorder reinforcing the abuse of these compounds. A high proportion of patients with schizophrenia also develop substance use disorder Thought disorder may fall into the category of compensation with common street drugs (Volkow, 2009). rather than result directly from overstimulated synapses. Patients A possible biochemical progression from brain injury or gene frequently appear to be playing with words, rearranging them mutation to the psychotic state is summarized in Fig. 1. The original idiosyncratically as poets do. This has been referred to as ‘swerves brain anomaly leads to elevated numbers of D2, D2High, D2D2 dimers, and cryptic references’ (Byerley et al., 2005), a form of juggling and D1D2 dimers. In addition, there is abnormal pruning and the thoughts that come too swiftly, perhaps to make them more heightened release of endogenous dopamine. These factors combine manageable. A problem with communication or ‘unconventional to induce abnormal sensations and behaviors. The patient attempts to discourse’ is a hallmark of schizophrenia (Elvevåg et al., 2010). compensate as best he or she can, and this results in the various Many of the brain regions where dopamine sensitivity occurs are manifestations of schizophrenia. intimately associated with the language. In addition to Broca's area, these regions include Wernicke's area (comprehension), the left 11. Clinical treatment implications temporal gyrus (language storage and retrieval), the insula, the anterior cingulate gyrus, the left inferior frontal cortex, as well as Adolf Meyer did not believe that schizophrenia was something that a portions of the thalamus, and cerebellum (Chouvardas, 1996; person “had” or “was born with” but, rather, that it was a pattern of Nieuwenhuys et al., 2008). All these brain regions contain dopamine symptoms and behaviors that evolved from multiple original causes D2 receptors, but at densities that are between 20% and 50% of the and to which the person tried to adapt, sometimes successfully, densities found in the caudate/putamen region (Charuchinda et al., sometimes not (Meyer, 1922). 1987; Hall et al., 1995). Like Meyer, it is here suggested that patterns of clinical expression in schizophrenia evolve in recurrent cycles of event, reaction and counter- 9.5. Negative signs and symptoms reaction. As such they are relatively unique to every individual and unpredictable in terms of course. There is no finality to a diagnosis of The negative signs and symptoms of schizophrenia, such as social schizophrenia. As Meyer wrote: “… it is also important to lay stress isolation, amotivation, lethargy, can be understood as wholly reactive — upon traits of personality, cultural influences, environmental stressors, compensations designed to ward off dopamine overstimulation (Corin evasive and regressive modes of adaptation” (Double, 2007). and Lauzon, 1992). It is further here suggested that overdrive is a necessary step on the path between initial causation and symptom 9.6. Mood changes expression. 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