A. Pharmacological Evidence
The psychotogenic effect of amphetamine and other DA-enhancing drugs, such as methylphenidate and l-dopa, is a cornerstone of the classical DA hypothesis of schizophrenia. Two sets of observations are relevant to this issue. First, repeated exposure to high doses of psychostimulants in nonschizophrenic subjects might gradually induce paranoid psychosis. This well-documented observation shows that sustained increase in DA activity is psychotogenic. Second, low doses of psychostimulants that are not psychotogenic in healthy subjects might induce or worsen psychotic symptoms in patients with schizophrenia. This observation indicates that patients with schizophrenia have an increased vulnerability to the psychotogenic effects of DA-enhancing drugs.
a. Amphetamine-Induced Psychosis in Nonschizophrenic Subjects. Although mentioned in 1938 (Young and Scoville, 1938), amphetamine-induced psychosis was not clearly recognized as a possible consequence of chronic amphetamine use until 1958 on the publication of a 42-case monograph by Connell (1958). In this chapter, Connell provided the ''classical'' definition of amphetamine psychosis, as ''a paranoid psychosis with ideas of references, delusions of persecution, auditory and visual hallucinations in the setting of a clear sensorium'' and concluded that ''the mental picture may be indistinguishable from acute or chronic paranoid schizophrenia'' (Connell, 1958).
In the early 1970s, several studies experimentally induced amphetamine psychosis in nonschizophrenic amphetamine-abusers in order to better document the clinical pattern of this syndrome (Angrist and Gershon, 1970; Bell, 1973; Griffith et al., 1968). These experiments formally established that sustained psychostimulant exposure can produce paranoid psychosis in nonschizophrenic individuals. This reaction does not occur in the context of a delirium since subjects maintain a clear sensorium during the episode and are able to recollect the episode after its resolution. Since these studies were performed before the conceptualization of the symptoms of schizophrenia into positive and negative (Crow, 1980), they did not formally assess negative symptoms. These papers only include anecdotal reports of emotional blunting, withdrawal, or alogia, thereby, suggesting that sustained and excessive stimulation of DA systems does not consistently induce what is now defined as the ''negative'' symptoms of schizophrenia.
Ellinwood (Ellinwood 1967; Ellinwood et al., 1973) provided one of the most insightful descriptions of amphetamine-induced psychosis by conceptualizing the condition as a continuum that evolves from the gradual onset of paranoid tendencies to delusional paranoia. The first step is characterized by stimulation of interpretative mental activities (great attention to details, intense feeling of curiosity, repetitive searching, and sorting behavior). Ellinwood sees in Sherlock Holmes, a regular cocaine user, a prototypical example of the endless search for meanings (my mind rebels at stagnation). With increased exposure, these paranoid tendencies and interests for the minutiae develop into an intermediate stage, which is characterized by marked enhancement of perceptual acuity, sustained ''pleasurable'' suspiciousness, and compulsive probing behavior. Finally, this inquisitive behavior is reversed and projected to others (persecution), leading to paranoia and ideas of references. The ''enhancement of sensitive acuity'' develops into hallucinations, initially auditory, then visual and tactile. The sensorium remains clear until toxic delirium is reached. Thought disorders might manifest toward the end of the continuum near the toxic stage. Kapur (2003) recently reformulated and modernized the Ellinwood ''Sherlock Holmes'' theory by defining schizophrenia psychosis as a state of aberrant salience.
Another important property of psychostimulants is their ability to induce reverse tolerance or ''sensitization'' (Kalivas et al., 1993; Robinson and Becker, 1986). Long-term sensitization to psychostimulants is a process whereby repeated exposure to these drugs results in an enhanced response on subsequent exposures. The relevance of this process for the pathophysiology of schizophrenia has been reviewed (Laruelle, 2000b; Lieberman et al., 1997). Subjects who abused psychostimulants and experienced stimulant-induced psychotic episodes are reported to remain vulnerable to low doses of psychostimulants (Connell, 1958; Ellinwood et al., 1973; Sato et al., 1983). In these subjects, exposure to psychostimulants at doses that do not normally produce psychotic symptoms can trigger a recurrence of these symptoms. The similarity between these patients and the patients with schizophrenia in terms of vulnerability to the psychotogenic effects of psychostimulants has led to the theorization that schizophrenia might be associated with an ''endogenous'' sensitization process (Glenthoj and Hemmingsen, 1997; Laruelle, 2000b; Lieberman et al, 1990).
Considerable research efforts have been devoted to the identification of neuronal substrates involved in sensitization. Several studies have shown that sensitization is associated with increased stimulant-induced DA release in the axonal terminal fields (for references see Laruelle, 2000b). A brain imaging study confirmed that, in humans, sensitization to the effects of amphetamine involves increased amphetamine-induced DA release (Boileau et al., 2003). The imaging studies reviewed below show that patients with schizophrenia display an enhanced amphetamine-induced DA release, supporting the notion of an endogenous sensitization process of subcortical DA system in schizophrenia.
b. Psychotogenic Effects of Amphetamine in Schizophrenic Patients. A number of studies reviewed by Lieberman et al. (1987b) provided evidence that patients with schizophrenia, as a group, display increased sensitivity to the psychotogenic effects of acute psychostimulant administration. In other terms, some, but not all patients with schizophrenia present emergence or worsening of psychotic symptoms after acute exposure to psychostimulants at doses that do not induced psychosis in healthy subjects. The psychotic response appears to be state dependent. First, patients who responded with a psychotic reaction to a psychostimulant challenge during an acute episode failed to show such a response when they were in remission. Second, the propensity to present a psychotic reaction to a psychostimulant challenge is predictive of relapse on antipsychotic discontinuation. Thus, the clinical response to stimulants might ''reveal'' an active phase of the illness that is not readily identifiable by the clinical symptomatology in the absence of a psychostimulant administration.
Since the recognition in 1952 of the antipsychotic properties of chlorproma-zine (Delay et al., 1952), antipsychotic medications have fundamentally altered the course and the prognosis of schizophrenia. They have proven effective at reducing the severity of symptoms and preventing episodes of illness exacerbation. To date, D2 receptor antagonism is the only pharmacological property shared by all antipsychotic drugs. The clinical dose of these drugs is related to their affinity for D2 receptors. D2 receptor antagonism appears both necessary and sufficient for antipsychotic action (as demonstrated by the selective D2 receptor antagonist amisulpride). The fact that patients with schizophrenia improve following administration of D2 receptor antagonists is one of the few irrefutable pieces of evidence in schizophrenia (Weinberger, 1987).
D2 receptor blockade by antipsychotic drugs has been confirmed by a large number of imaging studies (reviewed in Talbot and Laruelle, 2002). In general, these studies failed to observe a relationship between the degree of D2 receptor occupancy and the quality of the clinical response. However, most studies reported doses achieving more than 50% occupancy. The minimum occupancy required for a therapeutic response remains somewhat uncertain. Two studies performed with low doses of relatively selective D2 receptor antagonists (haloper-idol and raclopride) suggest that a minimum of 50% occupancy is required to observe a rapid clinical response (Kapur et al., 2000; Nordstrom et al., 1993). Imaging studies have repeatedly confirmed the existence of a striatal D2 receptor occupancy threshold (about 80%) above which extrapyramidal symptoms (EPS) are likely to occur (Farde et al., 1992). Thus, these data suggest the existence of a therapeutic window between 50% and 80% striatal D2 receptor occupancy. Within this window, the relationship between occupancy and response is unclear, presumably because the variability in endogenous DA (Frankle et al., 2004). Furthermore, the occupancy threshold required for therapeutic effects might differ among drugs.
The introduction of a second generation of antipsychotic (SGA) drugs since the early 1990s has not fundamentally altered the prominence of D2 receptor antagonism in the current treatment of schizophrenia. Most SGAs also potently interact with other receptors, such as the serotonin 5-HT2A receptors, but the possibility to achieve an ''atypical'' profile with a pure D2 receptor antagonist, such as amisulpride, indicates that serotonin pharmacological effects are not absolutely required to produce this effect.
On the other hand, imaging studies have generally reported lower occupancies of striatal D2 receptors at therapeutic doses of SGAs compared to first generation antipsychotic drugs (FGAs). This seems to be especially true for amisulpride, clozapine, and quetiapine, which provide 50—60% D2 receptor occupancy range at clinically effective doses (for review and references see Abi-Dargham and Laruelle, 2005). In contrast, studies with FGAs often reported occupancies exceeding 75%. Thus, a parsimonious hypothesis to account for the SGA superiority is that, in general, clinical results obtained after moderate occupancies (50—75%) are better than after high occupancies (75—100%), and that, for a variety of reasons, SGAs tend to maintain lower occupancies than FGAs. The alternate hypothesis is that the D2 receptor occupancy required for therapeutic effects is lower in SGAs than FGAs. Should the alternate hypothesis be true, the mechanisms responsible for the gain in the occupancy—efficacy relationship of SGAs remain to be fully elucidated.
A potentially important synergistic effect of 5-HT2A and D2 receptor antagonism is to increase prefrontal DA, an effect not observed with selective D2 or 5-HT2A receptor antagonists administered alone (Gessa et al., 2000; Ichikawa et al., 2001; Melis et al., 1999; Pehek and Yamamoto, 1994; Youngren et al, 1999). This effect might be mediated by the stimulation of 5-HT1A receptors: it is blocked by 5-HT1a antagonists and is also observed following the combination of 5-HT1a receptor agonism and D2 receptor antagonism (Ichikawa et al., 2001; Rollema et al., 2000). Aripiprazole, clozapine, quetiapine, and ziprasidone are also 5-HT1a partial agonists, and this additional property might also contribute to their ability to increase prefrontal DA. As discussed in Section III.B, a decreased prefrontal
DA function might contribute to the cognitive deficits present in patients with schizophrenia, and it is possible that an increase in prefrontal DA induced by SGAs might mediate some of the modest cognitive improvements induced by these drugs (Keefe et al., 1999). Yet, it is unclear whether this increase in prefrontal DA, documented as an acute response in animal studies, is sustained during the course of treatment in patients with schizophrenia.
The discovery of the antipsychotic effect of D2 receptor blockade inspired numerous postmortem studies seeking to determine whether schizophrenia was associated with altered parameters of DA transmission. These postmortem studies have for the most part failed to provide definitive answers, partly because of the confounding effects of antemortem antipsychotic treatment.
Direct measures of tissue content of DA and its metabolites have failed to demonstrate consistent and reproducible abnormalities (for review see Davis et al., 1991; Reynolds, 1989). It should be noted, however, that some studies have reported higher DA tissue levels in samples from patients with schizophrenia in subcortical regions such as caudate (Owen et al., 1978), nucleus accumbens (Mackay et al., 1982), or amygdala (Reynolds, 1983).
Increased density of striatal D2 receptors in patients with schizophrenia has been a consistent finding in a large number of postmortem studies (Cross et al., 1983; Dean et al, 1997; Hess et al, 1987; Joyce et al, 1988; Knable et al, 1994; Lahti et al., 1996; Lee et al., 1978; Mackay et al., 1982; Marzella et al., 1997; Mita et al., 1986; Owen et al., 1978; Reynolds et al., 1987; Ruiz et al., 1992; Seeman et al., 1984, 1987, 1993; Sumiyoshi et al., 1995). Because chronic neuroleptic administration upregulates D2 receptor density (Burt et al., 1977), it is likely that these postmortem findings are related to prior neuroleptic exposure rather than to the disease process per se. In light of these very consistent results with [3H]spiperone, it is interesting to note that the striatal binding of [3H]raclopride has been reported to increase in many studies (Dean et al., 1997; Marzella et al., 1997; Ruiz et al., 1992; Sumiyoshi et al., 1995), but normal in several others (Knable et al., 1994; Lahti et al., 1996; Seeman et al., 1993), even in patients exposed to neuroleptic drugs prior to death. This observation suggests that the increase in [3H]raclo-pride binding is of lower magnitude than the one of [3H]spiperone binding. This discrepancy might simply reflect the observation that, for reasons that are not currently understood, antipsychotic drugs upregulate more [ H]spiperone than [3H]raclopride binding to D2 receptors (Schoots et al., 1995; Tarazi et al., 1997).
A significant increase in D3 receptor number in VST samples from patients with schizophrenia who were off neuroleptics at the time of death has been reported in one study (Gurevich et al., 1997). In contrast, in patients who had been treated with neuroleptics up to the time of death, D3 receptor levels did not differ significantly from those of controls (Gurevich et al., 1997). These data were interpreted as indicating that antipsychotics downregulate the D3 receptor in schizophrenic patients who otherwise have a higher density of this receptor in the VST. The D3 receptor gene expression is under the control of a neutrophin, called BDNF, that is synthesized either in the VTA and the PFC and released in the VST, where it maintains the expression of the D3 receptor (Guillin et al., 2001). One study (Takahashi et al., 2000) has shown increased and two decreased (Hashimoto et al., 2005; Weickert et al., 2003) of BDNF levels in the brain of patients with schizophrenia. D3 receptors are upregulated in the presence of hyper-dopaminergic tone (Bordet et al., 1997; Fauchey et al., 2000; Guillin et al., 2001; Le Foll et al., 2002), under the control of the BDNF, whose synthesis is in turn under the control of the activity of neurons projecting from the PFC or the VTA in the VST.
On the basis of ligand subtraction techniques, several studies have reported increased D4-like receptors in schizophrenia (Marzella et al., 1997; Murray et al., 1995; Seeman et al., 1993; Sumiyoshi et al., 1995). These findings were not confirmed by other studies using the same technique (Lahti et al., 1996; Reynolds and Mason, 1994), nor by a study using [3H]NGD 94-1, a selective D4 ligand (Lahti et al., 1998). Moreover, the hypothesis that clozapine might act by blocking the D4 receptor was not supported by a clinical trial with the D4 selective agent L745,870 (Kramer et al., 1997).
Striatal D1 receptors have generally been reported to be unaltered in schizophrenia (Joyce et al., 1988; Pimoule et al., 1985; Reynolds and Czudek, 1988; Seeman et al., 1987), although one study reported decreased density (Hess et al., 1987). In the PFC, one study reported no changes (Laruelle et al., 1990) and one reported a nonsignificant increase (Knable et al., 1996).
A large number of studies have reported unaltered DA transporter density (DAT) in the striatum of patients with schizophrenia (Chinaglia et al., 1992;
Czudek and Reynolds, 1989; Hirai et al., 1988; Joyce et al., 1988; Knable et al., 1994; Pearce et al, 1990).
A recent and interesting postmortem finding regarding DA parameters in patients with schizophrenia is the observation of decreased tyrosine hydroxylase (TH)-labeled axons in layers III and VI of the EC and in layer VI of the PFC, a finding suggesting that schizophrenia might be associated with deficit in DA transmission in the EC and PFC (Akil et al., 1999, 2000). This finding was clearly unrelated to premortem neuroleptic exposure. Benes etal. (1997) observed no significant changes in TH-positive varicosities in the DLPFC. In the anterior cingulate region (layer II), these authors observed a significant shift in the distribution of TH varicosities from large neurons to small neurons.
In conclusion, postmortem measurements of indices of DA transmission generated a number of consistent observations in the striatum: (1) The binding of radioligand to D2-like receptors in the striatum of patients with schizophrenia is increased, but the magnitude of this increase varies with the type of radioligands used, and it is difficult to exclude the contribution of premortem antipsychotic exposure in this set of findings. (2) Striatal DAT and D1 receptors density is unaffected in schizophrenia. Several interesting observations such as increase in D3 receptors in the ventral striatum and alteration in TH immunolabeling in several cortical regions do not appear to be consequences of premortem neuroleptic exposure, but these findings have yet to be independently confirmed.
C. Imaging Studies
The development of PET and SPECT imaging techniques in the late 1980s made possible, for the first time, the examination of DA function in vivo in patients with schizophrenia never exposed to antipsychotic drugs (Fig. 3).
a. Striatal D2 and D1 Receptors. Striatal D2 receptor density in schizophrenia has been extensively studied with PET and SPECT imaging. In a meta-analysis (Weinberger and Laruelle, 2001), 17 imaging studies comparing D2 receptor parameters in patients with schizophrenia have been analyzed (included a total of 245 patients and 231 control subjects, Table II) (Abi-Dargham etal., 1998, 2000b; Blin et al., 1989; Breier et al., 1997; Crawley et al., 1986; Hietala et al., 1994b; Knable et al., 1997; Laruelle et al., 1996; Martinot et al., 1990, 1991; Pilowsky et al., 1994; Wong et al., 1986). Updated with a study (Yang et al., 2004), this metaanalysis revealed a small (12%) but significant elevation of striatal D2 receptors in untreated patients with schizophrenia. No clinical correlates of increased D2 receptor-binding parameters could be identified. Studies performed with
butyrophenones (n = 7) show an effect size of 0.96 ± 1.05, significantly larger than the effect size observed with other ligands (benzamides and lisuride, n = 11, 0.19 ± 0.25,p = 0.02). This difference might be due to differences in vulnerability of the binding of these tracers to endogenous DA and elevation of endogenous DA in schizophrenia (Seeman, 1988; Seeman et al., 1989). Interestingly, the fact that D2 receptor levels are increased in healthy monozygotic twin compared to dizygotic twin of patients with schizophrenia has lead to the conclusion that the caudate DA D2 receptor upregulation is related to genetic risk for schizophrenia (Hirvonen et al., 2005). Imaging studies ofD1 receptors have consistently failed to detect abnormalities of D1 receptor availability in the striatum of patients with schizophrenia (Abi-Dargham et al., 2002; Karlsson et al., 2002; Okubo et al, 1997).
b. Striatal Amphetamine-Induced DA Release. The decrease in [11C]raclopride and [123I]IBZM in vivo binding following acute amphetamine challenge has been well validated as a measure of the change in D2 receptor stimulation by DA due to amphetamine-induced DA release (Breier et al., 1997; Laruelle et al., 1997b; Villemagne et al, 1999) (Table III).
Our results (Abi-Dargham et al., 1998; Laruelle et al., 1996), which have been independently replicated (Breier et al., 1997), showed that the amphetamine-induced decrease in [ C]raclopride or [ I]IBZM binding is elevated in untreated patients with schizophrenia compared to well-matched controls (Fig. 4). A significant relationship was observed between the magnitude of this effect and transient induction or worsening of positive symptoms. This exaggerated response of the DA system to amphetamine was observed in both first episode/drug-naive patients and previously treated patients (Laruelle et al., 1999), but was larger in table II
Imaging Studies of Striatal D2 Receptor Parameters in Drug-Naive and Drug-Free Patients with Schizophrenia
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