I recently wrote a small literature review about this subject, in particular from the viewpoint of how certain recreational drugs compare to natural or schizophrenic psychosis. I have included it below:
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Abstract
Psychosis is a state characterized by symptoms such as hallucinations, delusions, bizarre behavior and thought disorders which generally occur in patients with schizophrenia, a debilitating disease affecting approximately 1% of the population. Additionally, certain psychoactive drugs (amphetamines, NMDA-antagonists and serotonergic hallucinogens) are known for producing a state which is very similar to the psychosis observed in schizophrenia. If these states are caused by similar neurochemical mechanism, these drugs may be valuable as pharmacological models of psychosis in man. Here we investigate the similarities between schizophrenic and drug-induced psychosis in terms of cerebral activation by reviewing studies investigating cerebral metabolism and blood flow during psychosis as well as after administration of certain psychotomimetic drugs. Our results indicate that both schizophrenic and drug-induced psychosis produce a similar pattern of altered activity. Most notably, increased frontal activity as well as altered activity in the thalamus and basal ganglia structures is observed in both cases. These results suggest that psychosis is a result of deficient gating of sensory information from the thalamus to the cortex and this is supported by evidence from animal studies about the effects of psychotomimetic drugs on measures of cortical gating. It is concluded that in terms of psychological effects and safety profile, the serotonergic hallucinogens may be the best human pharmacological model of psychosis.
1. Introduction
1.1 Psychosis and schizophrenia
Psychosis is a state characterized by symptoms such as hallucinations, delusions, bizarre behavior and thought disorders. It is one of the most prominent features of schizophrenia, a lifelong and debilitating disease that occurs in approximately 1% of the population (APA, 2000). The symptoms of schizophrenia are most commonly divided into positive symptoms and negative symptoms. Positive symptoms are hallucinations, delusions, bizarre behavior and thought disorder and thus form the psychotic aspect of the schizophrenic symptom spectrum. Schizophrenia, however, is also characterized by negative symptoms such as affective blunting, poverty of speech, apathy, anhedonia and inattention (Comer, 2005).
The pharmacological treatment of schizophrenia involves a class of drugs referred to as antipsychotics. These drugs are generally effective in reducing the positive, or psychotic, symptoms of schizophrenia but generally do not reduce the negative symptoms. The first drugs proven effective in reducing symptoms of psychosis, chlorpromazine, was discovered more than half a century ago. Since then numerous other antipsychotic drugs have become available. All these drugs have in common that they are antagonists of the D2 class of receptors. In fact, the drugs efficacy in reducing psychotic symptoms is correlated to their affinity for the D2 receptor, and modulation of this receptor remains necessary and even sufficient for antipsychotic action (Kapur & Mamo, 2003).
1.2 Neurotransmitter systems implicated in psychosis
The efficacy and pharmacological profile of antipsychotics lead to the dopamine hypothesis of schizophrenia. This hypothesis states that psychosis occurs due to over-stimulation of D2 receptors in the mesolimbic pathway. It has been suggested that the mesolimbic over-stimulation could lead to stimulus-inappropriate release of dopamine which results in aberrant attributions of salience to environmental stimuli. In this regard, delusions and other aspects of psychosis could be explained as a result of “top-down” cognitive explanations that an individual imposes upon these aberrant salience experiences (Kapur, 2003; Kapur & Mamo, 2003)
Other neurotransmitter systems, primarily the serotonergic and glutamatergic system have also been suggested to be involved in psychosis. A number of abnormalities in the serotonergic system in the brains of schizophrenic patients support the notion that this system is involved in the disease. The abnormalities observed are principally related to the 5HT2 receptor. For instance, brains of schizophrenic patients show a decreased amount of 5HT2 receptors in the frontal cortex (Arora & Meltzer, 1991; Laruelle et al, 1993) while an increase is observed in the nucleus accumbens and ventral putamen (Joyce et al, 1993) compared to controls. Furthermore, the involvement of the 5HT2 receptor in psychosis is supported by the fact that the 5HT2-antagonistic properties of certain antipsychotic drugs such as risperidone and clozapine play a role in their antipsychotic effect.
The glutamate deficiency hypothesis states that dysfunction in glutamate neurotransmission is involved in psychosis. It was suggested by Kim et al (1980) after observing decreased CSF glutamate concentrations in schizophrenic patients. The involvement of the glutamate system is supported by findings of decreased cortical NMDA receptor densities (Ishimaru et al, 1994; Dean et al, 1999) and reduced glutamate release in brain tissue of patient with schizophrenia (Sherman et al, 1991; Dean et al, 1999) compared to controls. Much research has focused on the glutamate hypothesis of schizophrenia. It is currently thought that the abnormal functioning of the glutamatergic system in schizophrenics is primarily associated with abnormalities related to the NMDA receptor. Recently it was suggested that acomprosate, an NMDA-antagonist approved for the treatment of alcohol addiction, might prove beneficial in the early stages of schizophrenia (Paz et al, 2008; Bubenovika-Valesova et al, 2008).
1.3 Psychotomimetic drugs as models of schizophrenia and psychosis
Not only schizophrenia can result in a state of psychosis. For centuries, various psychoactive substances in the form of mushrooms (psilocybin), cacti (mescaline) or root bark (N,N-dimethyltryptamine) have been used in religious and mystic rituals because of their ability to produce visionary and ecstatic states. These effects are generally considered as positive by the user, and increased recreational use has lead to most of these substances being banned in the western world, as seen recently by the Dutch governments ban on the sale of “magic” psilocybin-containing mushrooms. However, although ingestion of these drugs is generally considered pleasant and rewarding, many users also report feelings of fear and find the experience threatening. In fact, the symptoms of intoxication by these substances include hallucinations, delusions thought disorder, depersonalization and derealization (Vollenweider, 2001), which, when considered objectively are very similar to those seen in the acutely psychotic schizophrenic patient. In fact, due to the ability of these drugs to reliably mimic symptoms of psychosis the term “psychotomimetic” has been coined to refer to these substances. The symptomatic similarity between schizophrenic and drug induced psychosis raises the question whether these substances, although generally considered drugs of abuse, could prove scientifically useful as pharmacological models of schizophrenic psychosis.
There are indications that some of these substances may indeed prove to be valuable as models of natural psychosis. Currently, three classes of drugs of abuse are known to produce a mental state very similar to psychosis. More specifically, intoxication with NMDA-antagonists such as ketamine or PCP, as well as serotonergic hallucinogens such as psilocybin and LSD is known to result in acute psychosis-like symptoms (Vollenweider, 2001). The indirect dopamine agonists amphetamine and methamphetamine, although generally not causing an acute psychotic state, are known to result in a severe and persistent psychotic episodes after long-term, heavy use (Iyo et al, 2004). Interestingly, these three classes of psychotomimetic drugs act on the three main neurotransmitter systems which have been hypothesized to be involved in schizophrenia. This suggests that, besides the obvious similarities in overt psychological symptoms between natural psychosis and the drug-induced form, there may also be similarities in the underlying neurochemical mechanisms between natural and drug-induced psychosis.
If natural and drug induced psychosis do rely on similar mechanisms, these drugs may indeed prove valuable as pharmacological models of psychosis in healthy humans. The drugs could be used to induce a transient, reversible psychotic state in human volunteers to test certain hypothesis of psychosis under controlled laboratory conditions. A good human model of psychosis would fill an important gap in schizophrenia research as no other good models are currently available. Although these drugs are already known to influence prepulse inhibition, a measure of cortical gating associated with schizophrenia, in animal models (Suemaru et al, 2008), it is clear that these models do not capture the emotional, cognitive and underlying pathogenic complexity of human psychosis. A valid human pharmacological model of schizophrenia may prove useful in gaining a better understanding of the pathogenic mechanisms involved in psychosis on a systems level; directing attention towards novel pharmacological targets and the initial testing of novel antipsychotic medication in humans.
1.4 Investigating schizophrenia in humans: neuroimaging
In order to determine if psychotomimetic drugs could function as valid models for psychosis, similarities in underlying pathogenic mechanisms must be established. One major approach to investigating the mechanisms involved in schizophrenia in humans is the measuring of functional brain alterations, such as changes in cerebral metabolism and blood flow, using Positron Emission Tomography (PET) or Single-Photon Emission Computed Tomography (SPECT) neuroimaging (Ebmeier et al, 1995; Desco et al, 2003). A large number of early studies reported decreased frontal activity (“hypofrontality”) at rest to be associated with schizophrenia, and resting hypofrontality in schizophrenia consequently achieved the status of a paradigm in neuropsychiatry (Ebmeier et al, 1995). However, it soon became clear that the situation was more complex. Early studies often used heterogeneous patient samples, including both medicated and unmedicated or chronic and recent-onset schizophrenics in the same sample. When differentiating between these groups of patients it seems that hypofrontality is mainly observed in chronic patients with a history of antipsychotic treatment, while drug-naïve patients with acute psychotic symptoms in fact display just the opposite pattern, namely increased frontal activation (“hyperfrontality”) (Ebmeier et al, 1995). Moreover, the hyperfrontality seems to be correlated with the intensity of psychotic symptoms (Vollenweider & Geyer, 2001).
1.5 Evaluating pharmacological models with neuroimaging
The acute psychoses observed in patients with schizophrenia seem to be clearly related to a pattern of increased frontal metabolism. This raises the question of whether drug-induced psychosis, considering the strong similarity in symptoms, is also associated with a similar functional alteration. If this is the case, it supports the notion that similar mechanisms are involved and that psychotomimetic drugs may indeed be valid models of psychosis. Here we will investigate whether similar functional alterations can be observed in both schizophrenic and drug-induced psychosis. We do this by reviewing studies investigating cerebral metabolism and blood flow in schizophrenic patients and compare these to studies investigating changes in metabolism and blood flow after administration of either three classes of psychotomimetics. This will allow us to determine whether certain drugs more closely resemble schizophrenic psychosis than others and thus may be considered a better, more valid model than others. Furthermore, knowledge about changes in functional activation and the pharmacology of psychotomimetics may allow us to gain an understanding about the neural correlates of psychosis on a systems level.
The focus of this investigation is on the psychosis associated with schizophrenia. For this reason we will not review studies involving patients who are receiving antipsychotic mediation. In fact, since even a single dose of antipsychotic medication has been shown to produce significant alterations in cerebral metabolism (Liddle et al, 2000; Ngan et al, 2002) we will focus our review exclusively on studies investigating cerebral activation in patients who have never previously received antipsychotic medication. In order to most specifically measure abnormalities associated with psychosis, we further restrict our analysis to studies measuring resting activation, as opposed to activation during performance of various cognitive or other tasks which are more likely to reflect differences in cognitive processing, intelligence or other factors which may differ between schizophrenic and healthy individuals. We compare these studies to those investigating activation following administration of psychotomimetics. We consider each class of psychotomimetic drug as a separate model. In the amphetamine model we include studies involving the indirect dopamine agonists amphetamine and methamphetamine. Our NMDA-antagonist model includes all studies involving ketamine and phencyclidine. Finally, in our serotonin-hallucinogen model we included the indoleamine hallucinogens psilocybin, lysergic acid diethylamide (LSD), dimethyltryptamine (DMT) and the phenethylamine mescaline, all of which are thought to produce their psychotomimetic action primarily through activity at the 5HT2A receptor (Marek & Aghajanian, 1998).
In accord with previous literature, our results also indicate resting hyperfrontality in psychotic schizophrenic patients. Additionally, our review reveals similarities in brain activation, including hyperfrontality, between psychotic schizophrenics and all three pharmacological models of psychosis. These results suggest a similar underlying mechanism and seem to support the cortical gating theory of schizophrenia (Carlsson & Carlsson, 1990), which states that psychosis can be understood as cortical over-activation following deficient gating of sensory information due to defects in cortico-striato-thalamo-cortical (CSTC) feedback loops. We discuss the similarities between our results and those from animal models of thalamo-cortical gating deficiencies such as pre-pulse inhibition (PPI) and discuss the future value of the pharmacological models of psychosis in schizophrenia research.
2. Method
We compared patterns of cerebral activation and their relationship with psychotic symptoms in neuroleptic-naïve schizophrenics with those seen after administration of three classes of psychotomimetic drugs to healthy volunteers. We used the Pubmed database to search for relevant articles. For schizophrenia, our inclusion criteria were studies measuring metabolism (with PET) or regional cerebral blood flow (rCBF with SPECT) in neuroleptic-naïve patients diagnosed with schizophrenia. For the pharmacological models our inclusion criteria were that studies measured metabolism (PET), rCBF (SPECT) or BOLD (fMRI) in healthy volunteers receiving either amphetamine or methamphetamine (amphetamine model); ketamine or phencyclidine (NMDA-antagonist model) or psilocybin, LSD, DMT or mescaline (serotonin-hallucinogen model). Relevant articles were selected based on titles and abstracts. Furthermore, we reviewed the references of relevant articles in order to find additional studies not found in the Pubmed database. All articles were gathered in January of 2009. The search terms used for finding relevant articles are listed below.
Schizophrenia
For the articles in this section we used the search terms “schizophrenia” and “schizophrenic” combined with “PET” or “SPECT”. Selection of articles based on titles and abstracts for PET metabolism and SPECT rCBF in neuroleptic naïve schizophrenic patients yielded a total of nine papers. An additional two papers were found from references, resulting in a total of 11 relevant papers.
Amphetamine model
For this section, the search terms “amphetamine” and “methamphetamine” were combined with “PET”, “SPECT” or “fMRI”. Selection of papers based on titles and abstracts for PET metabolism/SPECT rCBF and fMRI BOLD yielded a total of four papers.
NMDA-antagonist model
Articles in this section were found using the terms “ketamine” and “phencyclidine” combined with “PET”, “SPECT” or “fMRI”. Selection of papers based on titles and abstracts for PET metabolism/SPECT rCBF and fMRI BOLD yielded a total of 5 papers. Two more papers were found in the references, yielding a total of seven papers for this section.
Serotonin-hallucinogen model
Here, the search terms “psilocybin”, “dimethyltryptamine”, “LSD” and “mescaline” were combined with “PET”, “SPECT” or “fMRI”. Selection of papers based on titles and abstracts for PET metabolism/SPECT rCBF and fMRI BOLD resulting in a total of six papers.
3. Results:
In this section we report the results of our literature survey. We will first discuss abnormalities of cerebral metabolism and blood flow and their relationship with psychotic symptoms in schizophrenic patients. Subsequently, we review neuroimaging studies evaluating the various pharmacological models, in order to determine how well they compare to the psychotic state observed in patients with schizophrenia. Unless otherwise specified, all PET studies measure cerebral metabolism using 18Fluorodeoxyglucose-PET; all SPECT studies measure regional cerebral blood flow (rCBF, perfusion) using the 99mTechnetium-hexamethylpropyleneamine oxime radioligand and all fMRI studies index blood flow by means of the Blood Oxygen Level Dependent (BOLD) response.
3.1 Schizophrenia
When looking at alterations of activity schizophrenic patients, a number of cortical as well as subcortical abnormalities have been reported. Cortical abnormalities were first described by Volkow et al. (1986) in an 11C2DG-PET study which demonstrated increased metabolism in the right parietal and temporal lobes in schizophrenic patients compared to healthy control subjects. Cleghorn et al. (1989), on the other hand, described decreased parietal and increased frontal metabolism in schizophrenic patients who were experiencing an acute psychotic episode at the time of the scan. Increased frontal activity was also described by Parellada et al. (1993) in terms of increased rCBF in the prefrontal cortex of acutely schizophrenic patients compared to controls, and by Catafau et al. (1994), who additionally reported increased rCBF in the anterior cingulate and decreased left temporal rCBF in their patient group. Only one study (Vita et al., 1995) reported a decrease in cortical activity associated with schizophrenia. Here, patients showed decreased perfusion in the prefrontal and temporal lobe compared to healthy volunteers.
Patients suffering from schizophrenia seem to exhibit certain subcortical abnormalities as well. Buchsbaum et al. (1996) demonstrated decreased metabolism in the right thalamus and Clark et al. (2001) reported decreased metabolism in both the right and left thalamus in schizophrenic patients, compared to healthy controls. Decreased perfusion in the thalamus of patients relative to healthy controls was also reported by Vita et al. (1995) who additionally found decreased perfusion in the caudate nucleus, putamen and pallidum. Volkow et al. (1986) noted decreased metabolism in the left basal ganglia only, in patients, compared to controls.
A number of papers report specifically on the correlations between altered cerebral activity and psychotic symptoms. Two reports (Sabri et al., 1997a,b) found correlations between rCBF patterns and clinical symptoms measured using the Positive and Negative Symptoms Scale (PANNS, which measures both positive and negative symptoms of schizophrenia). The positive symptoms of formal thought disorder and grandiosity correlated positively with frontal and temporal rCBF. Delusions, hallucinations and distrust correlated negatively with cingulate, left thalamic, left frontal and left temporal rCBF. One of the scales negative symptoms, stereotyped ideas, correlated negatively with left frontal, temporal parietal and cingulate rCBF. A similar pattern was observed by Erkwoh et al. (1997). In accordance with the two previous reports, a correlation was observed between rCBF in the left superior frontal and left superior temporal lobe and the PANNS scale of formal thought disorder. Additionally, decreased rCBF in the anterior cingulate was associated with higher scores on the PANNS delusions scale. Finally, Vita et al. (1995) reported a correlation between positive symptoms and increased perfusion in the subcortical regions of the caudate nucleus, putamen, pallidum and right thalamus while Min et al. (1999) reported an association between decreased left thalamic perfusion and negative symptoms in a group of schizophrenic patients.
3.2 Amphetamine model
Several studies report altered activity in both cortical and subcortical areas following administration of amphetamine. Devous et al. (2001) Used HMPAO/123IIMP SPECT to establish the effect of 0,4mg/kg d-amphetamine on rCBF in healthy volunteers. Amphetamine increased rCBF in mesial and orbital frontal lobe, ventral tegmentum, amygdala and thalamus while decreasing rCBF in the motor and visual cortex, fusiform gyrus and lateral temporal lobe. Völlm et al. (2004) found that 0,15mg/kg methamphetamine increased activation of the medial orbitofrontal cortex, anterior cingulate and ventral striatum.
Vollenweider et al. (1998) investigated the effects of a rather high dose of d-amphetamine (0,9-1,0mg/kg) on cerebral metabolism. At this dose, amphetamine increased metabolism in the cingulate, caudate nucleus, putamen and thalamus, compared to a baseline scan. Additionally, the drug seemed to produce some abnormal psychological symptoms. Psychological effects of the drug were assessed using the Methodology and Documentation in Psychiatry (AMDP) scale, which includes two main subscales “manic-depression” and “schizophrenia” and the Altered States of Consciousness Questionnaire (APZ), which includes the three subscales Oceanic Boundlessness (OBE, measuring derealization and depersonalisation), Visionary Restructuralization (VUS, measuring illusions, hallucinations and synaesthetic phenomena) and Dread of Ego-dissolution (AIA, measuring thought disorder, anxious ego-integration, loss of control over body and thought and derealization phenomena). Drug effects included an increase in all three subscales of the APZ and the manic-depression subscale of the AMDP, with most subjects reporting euphoria, and a few subjects reporting feelings of dysphoria and depression. Furthermore, the OSE subscale correlated significantly with heightened metabolism in the medial and lateral frontal cortex, cingulate and putamen, and apathy and manic-depression (AMDP) correlated with heightened metabolism in the caudate and putamen.
Only one study (Wolkin et al., 1987) employing 11C2DG PET reported decreased metabolism in the frontal and temporal lobes but also the striatum after d-amphetamine (0,5mg/kg) in healthy volunteers. Psychotomimetic effects were not quantitatively measured although it was noted that “most normal subjects were more socially outgoing and talkative after amphetamine”.
3.3 NMDA-antagonist model
Three recent studies (Jaakko et al., 2003; 2004; 2005) investigated the effects of ketamine on cerebral metabolism and blood flow (15OPET). The subanaesthetic doses of ketamine administered to healthy volunteers produced psychotic-like symptoms such as hallucination, altered body-image and a sense of floating. Increases in rCBF occurred in the frontal cortex, anterior cingulate, thalamus and putamen while increases in glucose metabolism were observed in the frontal and parietal lobes as well as the thalamus.
Breier et al. (1997) found that ketamine (IV at on average 0,01 mg/kg/min) increased metabolism in the prefrontal cortex and caused increases in the psychosis cluster, conceptual disorganisation, unusual thought content and hallucinatory behavior subscales of the Brief Psychiatric Rating Scale (BPRS). Furthermore, there was a significant correlation between the increased prefrontal metabolism conceptual disorganisation.
A particularly comprehensive study on the effects of ketamine (IV at on avarage 0,02-0,03 mg/kg/min) on cerebral metabolism (Vollenweider et al., 1997a) found that ketamine resulted in a global increase of glucose metabolism which was most pronounced in the frontal cortex and anterior cingulate, compared to baseline scans. Additionally, treatment caused a relative increase in frontomedial/occipitomedial and frontomedial/temporomedial ratios. The subjective drug effects were measured using the AMDP, APZ and Ego Pathology Inventory (EPI, measuring aspects of ego pathology) scales. With exception of the AIA subscale of the APZ, ketamine resulted in a significant increase in all rating scales. Subjects experienced depersonalisation, derealisation, hallucinations, thought disorder and apathy. Furthermore, subjects became emotionally withdrawn, showed flattened affects and became concrete in proverb interpretation, suggesting that ketamine mimics not only psychosis but also certain negative symptoms of schizophrenia. Finally, many of the psychotic symptoms correlated with increased metabolism in the frontal cortex, cingulate and putamen as well as increases in the frontal/occipital or frontal/temporal metabolic ratios. The same group (Vollenweider et al., 1997b) demonstrated the importance of NMDA receptors in ketamine action by comparing the effects both the S- and R-ketamine isomers. Since S-ketamine has a 3-4 fold higher affinity for the PCP binding site on the NMDA receptor it was hypothesized to have stronger psychotomimetic properties. Indeed, psychotomimetic doses of S-ketamine markedly increased metabolism in the frontal cortex, anterior cingulate, parietal and left sensorimotor cortex and thalamus and the psychotic-like symptoms correlated with metabolic changes in frontal and left temporal cortex. Equimolar doses of R-ketamine, on the other hand, tended to decrease cerebral metabolism and produce a state of relaxation.
Decreased cortical activity following ketamine (IV at on average 0,009mg/kg/min) was only reported in one other study by Deakin et al. (2008) who found a decreased fMRI BOLD response in the ventromedial frontal cortex and subgenual cingulate but increases in the mid-posterior cingulate, thalamus and temporal cortex which correlated with BPRS psychosis scores
3.4 Serotonin-hallucinogen model
Alterations in cerebral activity are reported following serotonergic hallucinogens as well. Vollenweider et al. (1997c) found that psilocybin (15-20mg) increased global brain metabolism, with most marked increases in the frontal and temporal cortex as well as the anterior cingulate, and basal ganglia. The drug possesses psychotomimetic properties as witnessed by a significant increase in 9 out of the total of 11 subscales of the AMDP, APZ and EPI. Moreover, The AMDP schizophrenia subscale correlated significantly with metabolic increases in the left temperolateral cortex and putamen. Items relating to illusions, hallucinations and derealisation/depersonalization correlated negatively with an observed increase in the frontal-to-temporal metabolic ratio. The AIA subscale correlated with increased anterior cingulate metabolism and left frontal-to-temporal ratio. Ego pathology was generally associated with increased frontal metabolism. Increases in frontal lobe and cingulate metabolism following psilocybin (0,2mg/kg PO) were also found by Gouzoulis-Mayfrank et al. (1999), who reported decreased thalamic activation as well. Here, alterations of cingulate and thalamic metabolism were associated with increases in psychotic symptoms.
Increased frontal metabolism has been has been reported for serotonergic hallucinogens other than psilocybin as well. Mescaline (500mg PO) resulted in a marked increase in relative frontal perfusion which was most pronounced in the right hemisphere. Additionally, BPRS scores and the “delusions” subscale of the Paranoid Depression Scale (PDS) increased after mescaline administration compared to baseline, confirming the drugs psychotomimetic properties (Hermle et al., 1992; 1998). Oepen et al. (1989) reported increases in left hemisphere rCBF following mescaline (500mg). Increases were observed in the striato-limbic region and they were associated with increased psychotic symptoms measured with the BPRS.
Recently it was demonstrated (Riba et al., 2006) that a third serotonergic hallucinogen, dimethyltryptamine, also produces a similar pattern of cerebral activation. After consumption of ayahuasca (a hallucinogenic drink used by Amazonian Indians, extracted, purified and normalized to 1,0mg/kg dimethyltryptamine in this study) increased rCBF was observed in the frontal cortex (most marked in the right hemisphere) and anterior cingulate as well as the amygdala/parahippocampal gyrus. Furthermore, the drugs psychotomimetic effect was demonstrated by a significant increase in all six subscales of the Hallucinogen Rating Scale (HRS) designed to measure psychosis-like symptoms associated with hallucinogenic drugs such as hallucinations and alterations in cognition and affect.
4. Discussion
4.1 Summary of results
Our results indicate that patients with acute schizophrenia generally show increased activity in the frontal lobe and to a lesser extent the temporal lobe and anterior cingulate compared to healthy control subjects. A number of studies also report decreased activity in subcortical structures of the basal ganglia and thalamus of schizophrenic individuals. These alterations in activity, furthermore, seem to be correlated to the severity of the psychotic symptoms.
When looking at the pharmacological models of psychosis we see that the different models all show certain similarities, albeit to a different extent, in terms of brain activation. In the amphetamine model, some studies report increased activation of the frontal lobe, thalamus and basal ganglia structures. Two out of four studies, however, also showed decreased activation, with one reporting decreased frontal activity as well. The psychological effects of amphetamines, moreover, are not very reminiscent of psychosis and mainly seem to produce a manic state. The results seen in the NMDA-antagonist model are more consistent. The NMDA-antagonist ketamine (no studies with phencyclidine were found) seems to result in increased activation of the frontal lobe, cingulate and thalamus. Ketamine also shows strong psychotomimetic properties, and in terms of psychological effects probably most precisely replicates the schizophrenic symptomatology of all three models, as it not only mimics the psychosis, but additionally seems to produce effects very similar to the negative symptoms associated with schizophrenia such as emotional withdrawal and flattened affect. Finally, the drugs comprising the serotonin-hallucinogen model of psychosis generally also increase activity in the frontal lobe, temporal lobe, cingulate and basal ganglia. One study reports decreased thalamic activation. The psychotomimetic potential of the drugs is very strong as well, although, unlike ketamine, they do not seem to produce any negative symptoms.
4.2 Psychosis as a gating-deficiency: a common pathway
It thus seems that both drug-induced and schizophrenic psychosis share certain similarities in terms of cerebral activation patterns. The increased frontal and temporal activation together with alterations in thalamic and basal ganglia activation and their correlation with psychotic symptoms in schizophrenia seem to support the cortical gating theory of psychosis first proposed by Carlsson and Carlsson (1990). In short, this theory states that psychosis arises from abnormalities in sensory information processing due to deficits in cortico-striato-thalamo-cortical (CSTC) loops. Although several CSTC-loops exist, the limbic loop is thought to be especially important in psychosis. It originates in the temporal lobe, projects to the ventral striatum, including the nucleus accumbens and ventromedial caudate nucleus/putamen. From here, the projection converges on the ventral pallidum and feeds back via the thalamus to the anterior cingulate and frontal cortex. The theory proposes that this loop controls the gating of sensory from the thalamus to the cortex and that disruptions of this loop will result in deficient thalamic gating, causing a “sensory overload” that exceeds the integrative capacity of the cortex and produces symptoms of psychosis such as hallucination, cognitive deficits and ego disorders. The regions implied to be involved in generating psychosis in this theory overlap with regions showing altered metabolism during psychosis: overactivity in the frontal lobe in combination with altered patterns of activation in the thalamus and basal ganglia. Importantly, since these patterns are observed in both schizophrenic and drug-induced psychosis, it suggests that deficient cortical gating may be the cause of psychotic symptoms in both types of psychosis.
An explanation of how psychotomimetic drugs may disrupt cortical gating and thus produce symptoms of psychosis has proposed by Vollenweider and Geyer (2001). Central to this explanation is the part of the CSTC-loop involving the inhibitory projections from the striatum and pallidum to the thalamus. First, amphetamine, by increasing the activity in the inhibitory mesostriatal dopamine pathway, should decrease inhibition to the thalamus. Second, serotonergic projections from the dorsal raphe provide an additional inhibitory input to the striatum. These two inhibitory projections to the striatum are counterbalanced by the excitatory glutamatergic projections arising from the cortex. Thus, amphetamines, NMDA-antagonist and serotonergic hallucinogens all seem to have in common an ability to modulate activity within the projection from the striatum/pallidum to the thalamus, causing deficient thalamic gating resulting in increased frontal activation and psychotic symptoms reported in many studies after drug administration.
Not all studies reviewed, however, seem to support this model. For instance, it is unclear why Vita et al. (1995) found decreased frontal activation in their group of never-medicated, acute psychotic schizophrenics and in fact reported that frontal activation increased after treatment with antipsychotic drugs. They suggest the difference in results may be caused by the use of the cerebellum as a reference region for tracer uptake. This seems unlikely, however, as several others use the cerebellum as a reference as well. Further, in the amphetamine model, Wolkin et al. (1987) reported decreased frontal activity after amphetamine. This could possibly be related to the rather low dose of amphetamine used. Amphetamine, in low doses, is known to reduce symptoms of hyperactivity and impulsivity, most notably in people with high baseline activity levels, and is used clinically in the treatment of ADHD (Riccio et al., 2001; Solanto, 1998). Furthermore, the subjects in this study became more socially outgoing and did not display overt symptoms of psychosis. Since both increased frontal activation and more psychotic-like symptoms were reported at higher amphetamine doses (Vollenweider et al., 1998) it suggests that amphetamine may only be psychotomimetic at particularly high doses. This is supported by the fact that high-dose amphetamine administration over several days as well as heavy methamphetamine abuse does eventually produce psychotic symptoms (Griffith et al, 1972; Iyo et al, 2004).
In the NMDA-antagonist model Deakin et al. (2008) reported decreased as, opposed to increased, frontal activity following administration of ketamine as well. The ketamine dose administered to subjects was the lowest of all the studies reviewed, however. The decreased cortical activity following low-dose ketamine seems to be supported by another study (Vollenweider et al., 1997b) where both S-ketamine and R-ketamine was administered to subjects. The S-ketamine increased cortical activity and caused symptoms of psychosis, conversely, R-ketamine, which has a much lower affinity for the PCP binding site on the NMDA receptor, decreased cortical activity and produced a state of relaxation. This suggests that for ketamine as well as amphetamines, a certain minimum dose is needed to produce psychosis-like symptoms and hyperfrontality, while lower doses seem to produce a paradoxical effect where subjects become more socially outgoing or relaxed. Nonetheless, in general, most studies of either schizophrenia or pharmacological models seem to display a pattern of results compatible with the cortical gating theory.
4.3 Animal models of gating deficiencies
Disruptions in cortical gating following challenges with psychotomimetic drugs are supported by studies in animal models as well. Although there are no animal models of schizophrenia, deficiencies in prepulse inhibition of startle (PPI) seem to provide a valid model of gating deficits in schizophrenia. PPI refers to the phenomena where a weak prepulse attenuates the response to a subsequent startling stimulus. Schizophrenics show deficiencies in PPI, and this deficiency is thought to reflect the gating deficits which according to the sensory gating theory are central to psychotic symptom formation (Braff & Geyer, 1990). Alterations of PPI after drug challenges known to produce disrupted PPI thus offer an operational measure of sensorimotor gating deficits in animals.
Consistent with our findings suggesting cortical gating deficits to be central in psychosis, amphetamines, as well as NMDA-antagonists and serotonergic hallucinogens all produce deficits in PPI in animal models of cortical gating (Suemaru et al, 2008; Braff & Geyer, 1990; Geyer et al, 1999; Geyer et al, 1990). Furthermore, antipsychotic drugs prevent amphetamine from disrupting PPI (Geyer et al, 2001; Suemaru et al, 2008). The ability of serotonergic hallucinogens and NMDA-antagonists to disrupt PPI is also blocked by antipsychotic drugs, but only those with affinity for the 5HT2A receptor (Bakshi et al, 1995, Sipes & Geyer, 1995; Swerdlow et al, 1996; 1998).
It is likely that the impaired PPI seen in animals after administration of psychotomimetics reflect a similar gating deficit causing psychosis and hyperfrontality in humans and thus suggests that psychotomimetics impair cortical gating in animal models, as well as in humans. All psychotomimetic-induced disruptions of PPI additionally seem to be blocked by certain types of antipsychotic drugs, indicating that these models have some predictive validity in terms of the efficiency of antipsychotic drugs. This suggests that in humans, as well, pharmacological-induced psychosis may be reversed by antipsychotic drugs, if this is the case it would increase the utility of the models.
4.4 Validity and utility of human drug models
It is unknown whether the hyperfrontality observed in schizophrenia also occurs due to reduced inhibitory neurotransmission to the thalamus. However, since the resulting hyperfrontality occurs in both types of psychosis, a defect somewhere in the CSTC-loop, eventually leading to decreased gating of sensory information to the cortex seems likely. This lends support the idea that psychotomimetic drugs may have certain validity as models of psychosis in humans, both in terms of psychological symptoms as well as underlying neurochemistry.
There is converging evidence that these human pharmacological models of psychosis may have certain predictive validity in determining the efficiency of antipsychotic drugs as well. First, it was demonstrated that antipsychotic drugs prevent ketamine and serotonin-hallucinogen induced psychotic symptoms as well as ketamine-induced hyperfrontality in humans (Malhotra et al, 1997, Vollenweider et al, 2001). Furthermore, although no official clinical trials have been performed; anecdotal reports confirm the fact that antipsychotic drugs are effective in treating the symptoms of methamphetamine psychosis (Barr et al, 2006). This is in accord with results from animal studies suggesting that drug-induced disruptions of cortical gating can be blocked by antipsychotic drugs as well.
In terms of psychological symptoms, the NMDA-antagonist ketamine and serotonergic hallucinogens seems to most intimately mimic the symptoms of psychosis while amphetamines are mostly associated with symptoms of mania, although psychotic-like symptoms are reported after particularly high doses or long-term use (Vollenweider et al, 1998; Griffith et al, 1972). Because of the ethical and practical concerns with regard to long-term, high-dose amphetamine administration, the future utility of this model in schizophrenia research must be considered limited. Ketamine is the only drug which mimics aspects of schizophrenias negative symptoms as well. Thus ketamine as well as serotonergic hallucinogens are capable of rapidly and reversibly inducing symptoms of psychosis that likely depend on a similar mechanism and seem be blocked by antipsychotic drugs. Hence, they show a good potential as pharmacological models of psychosis in humans.
In terms of possible adverse effects serotonergic hallucinogens seem to have a good safety profile. DMT and psilocybin have minimal abuse potential and psilocybin has the lowest risk of dependence and acute lethality out of 20 commonly abused psychoactive substances (Gable 1993; 2007). On the other hand, NMDA-antagonist drugs, such as ketamine, are known to produce vacuolization, neuronal/axonal degeneration and cell death in several animal species (Low & Roland, 2004; Farber et al, 2002). Although it is unknown whether or to what extent these neurotoxic phenomena occur in humans as well, comparing the safety profile of these two classes of drugs suggests that serotonergic hallucinogens most likely form the best pharmacological model of psychosis in humans; closely mimicking psychosis in terms of psychological effects and underlying cortical gating deficits as well as having a safety profile which does not ethically preclude the substance to be administered to healthy volunteers.
4.5 Conclusion
In summary, similar alterations in functional activation are observed in the human brain following both schizophrenic and drug-induced psychosis. These alterations include increased frontal activation as well as alterations of activity in the thalamus and basal ganglia. This pattern suggests that both types of psychosis may rely on a similar mechanism, where disrupted gating of sensory information from the thalamus to the cortex results in sensory overload. The suggestion is supported by animal models which show that psychotomimetics cause disruptions of cortical gating measured using PPI, a deficit which occurs naturally in psychotic individuals as well. The similarity in effects and likely similarity in underlying mechanisms suggests that drug-induced psychosis may be used as a pharmacological model of schizophrenic psychosis in healthy human volunteers. All three pharmacological models generally produce a similar pattern of altered functional activation, however, in terms of psychological effects, the NMDA-antagonist ketamine as well as the serotonergic hallucinogens seem to mimic the psychotic state most closely and rapidly. The good safety of serotonergic hallucinogens compared to NMDA-antagonists suggests that the former may be considered a particularly good model for use in humans. Future work will have to more closely establish the potential value and intrinsic limitations of this model. For instance, more closely establishing the predictive validity of the model in determining the efficiency of antipsychotic drugs would greatly enhance its utility. Although there are indications it does show some predictive validity, the extent of this must be investigated further. Nonetheless, from the vantage point of schizophrenia research, the pharmacological model offer a way of testing any hypothesis about psychosis in a controlled laboratory condition in healthy volunteers, thus decreasing the reliance on schizophrenic individuals for this type of research and offering a new way of extending our knowledge of psychosis and schizophrenia.
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