The ability of PCP or ketamine to induce a schizophrenia-like psychosis has by now become well established [64
]. Although PCP psychosis is sometimes suggested as a model for negative-symptom schizophrenia, and amphetamine- or LSD-psychosis, as a model for positive symptoms [46
], such a clear distinction does not hold up upon closer inspection. In PCP- or ketamine-induced psychosis, the relative proportions of positive and negative symptoms are highly similar to those observed in both acute and chronic schizophrenia, whereas in amphetamine- or LSD-induced psychosis the level of positive vs. negative symptoms is far in excess of the pattern observed even in acute schizophrenia stages [46
]. Thus, most parsimoniously, NMDAR antagonist-induced psychosis produces a psychosis that closely models both the positive and negative symptoms of schizophrenia, whereas amphetamine or LSD produce psychoses possibly resembling the pattern observed in mania, but unlike the pattern observed in typical schizophrenia.
PCP psychosis also uniquely incorporates cognitive symptoms similar to those observed in schizophrenia, including deficits in conceptual disorganization, abstract thinking, mannerisms and poor attention [97
]. Although amphetamine has some effect on conceptual disorganization, no effect on cognitive symptoms have been observed. Furthermore, although some additivity between amphetamine and ketamine effects has been observed, the degree of interaction did not reach statistical significance [97
], suggesting that dopaminergic hyperactivity is neither necessary or sufficient to produce the types of cognitive symptoms observed in schizophrenia.
A distinction between ketamine-induced symptoms and those of schizophrenia is in the production of hallucinations. During ketamine-induced psychosis, visual perceptual distortions are common but organized auditory hallucinations are rare. This is unlike established schizophrenia, in which auditory hallucinations are far more common. However, the pattern of sensory disturbances seen during ketamine administration does resemble the pattern observed early in the course in schizophrenia [21
] where both auditory and visual perceptual disturbances are common, and acute ketamine challenge may be viewed best as a model of prodromal or acute incipient schizophrenia, rather than later, more chronic, phases. Nonetheless, in patients with established schizophrenia, increases in hallucinatory activity are observed during ketamine challenge [100
]. Further, in primates, apparent hallucinatory behavior (i.e. threatening non-existent objects) is not observed during acute PCP treatment, but does emerge during chronic administration [111
]. There is evidence for an additive effect of amphetamine and ketamine in the production of auditory hallucinations [97
], suggesting dual DA and NMDA contributions to positive, as opposed to negative, symptoms.
Of all the symptom clusters associated with schizophrenia, positive symptoms are best understood. Positive symptoms are induced not only by NMDAR antagonists, but also reliably by dopaminergic agents, suggesting that the DA system plays a key role. Furthermore, D2 receptor antagonists have a reliable effect on positive symptoms at doses that occupy approximately 60% of striatal D2 receptors, supporting the concept that dopaminergic hyperactivity is sufficient to produce a psychosis-like state [80
]. NMDAR antagonists induce increased striatal DA release [144
], along with increased positive symptoms [22
], consistent with the concept that these agents operate in part through stimulation of frontostriatal dopaminergic systems
Dopaminergic hyperactivity in schizophrenia has also been confirmed by challenge studies showing increased amphetamine-induced DA release in acutely decompensated patients [83
] (). Similar effects are induced in normal volunteers by pretreatment with ketamine [84
] (), suggesting that underlying disturbances in NMDAR function might underlie the dopaminergic hyperactivity seen in schizophrenia. Similar effects are induced by PCP treatment in rodents and are reversed by concurrent treatment with glycine [68
] (), suggesting that NMDAR-based interventions may be effective in reversing positive as well as negative symptoms of schizophrenia ().
Figure 2 A. Scatter plots showing increased amphetamine-induced dopamine (DA) release in schizophrenia, as measured by displacement of [123I]IBZM. Inset: Image of [123I]IBZM binding in striatum prior to and following amphetamine administration. From . B. Scatter (more ...)
Figure 3 A. Effects of PCP and glycine on amphetamine-induced DA release in frontal cortex and striatum. From . B. Schematic diagram of effects on interactions between NMDA, GABA and DA in striatum.
Despite the strong association of dopaminergic hyperactivity and positive symptoms of schizophrenia, however, there are several nuances to positive symptoms that have yet to be fully incorporated into most operative models of schizophrenia. First, many patients with schizophrenia show persistent positive symptoms even following almost total block of D2 receptors. Second, in detailed in vivo imaging studies, hyperactivity of DA systems has been found only during acute stages of the illness, when correlations with positive symptoms are observed. In contrast, limited dopaminergic hyperactivity is seen during remitted states, despite the persistence of positive symptoms [47
The persistence of positive symptoms in many patients even after D2 blockade is most consistent with the concept that dopaminergic hyperactivity, of itself, is not the final step leading to psychosis, but rather acts via downstream elements. One critical element appears to be GABAergic outflow neurons from striatum, which, in general, produce behavioral inhibition. These neurons receive both inhibitory innervations via D2 receptors and excitatory innervations via NMDAR receptors. Thus, dopaminergic hyperactivity and NMDAR underactivity would produce similar net effects on output [64
In terms of treatment, this model would imply that D2 blockade could compensate for underactivity of these neurons even if such underactivity were caused primarily by loss of normal NMDAR-mediated excitatory drive. In such case, however, reduction of activity via D2 blockade would be limited by the degree of basal dopaminergic tone. Thus, as seen in schizophrenia, even total blockade of D2 receptors might be insufficient to compensate for loss of excitatory drive to these neurons. Similarly, in rodent models, antipsychotics show only partial effectiveness in reversal of NMDAR-induced hyperactivity [13
A second point of convergence of DA and NMDA models is at the level of local regulation of presynaptic DA release. Within striatum and frontal cortex, presynaptic DA release is under control of intrinsic inhibitory GABAergic neurons which, in turn, are activated by NMDAR. Even in studies where no immediate effects of NMDAR antagonists were observed on striatal DA release, significant potentiation of amphetamine-induced DA release has been observed, similar to that observed in schizophrenia [83
In striatum, regulation of DA release appears to be modulated by GABAB
receptors localized to presynaptic DA terminals. GABA release, in turn, is modulated by NMDAR located on GABA interneurons, with stimulation leading to increased GABA release [71
]. Furthermore, NMDAR antagonist-induced DA dysregulation can be reversed by NMDAR potentiators, such as glycine or glycine transport inhibitors, suggesting that these may be effective in treatment of positive, as well as negative, symptoms of schizophrenia [65
Although NMDAR antagonists reliably produce negative symptoms in normal volunteers, as well as a “dissociative state” in primates, the mechanisms underlying these effects are poorly understood. In dopaminergic models of schizophrenia, attempts were often made to attribute negative symptoms to Parkinsonian-like dopaminergic hypofunction, either longitudinally or cross-sectionally with hypoactivity in some regions coinciding with hyperactivity in others [37
]. However, approaches that were effective in treatment of Parkinsons disease have not proven highly efficacious in treatment of negative symptoms, suggesting distinct neurochemical substrates.
Negative symptoms are typically divided into broad domains including blunted affect, anhedonia-asociality, avolition-apathy and alogia/inattention [10
]. However, strong intercorrelation is seen between domains, leaving unresolved whether these are separate syndromes or simply different manifestations of the same underlying pathophysiological processes. Furthermore, these concepts continue to evolve clinically, prompting need to develop new neural conceptualizations.
In keeping with DA models, the key conceptualization of negative symptoms in schizophrenia until recently focused on anhedonia, defined primarily as decreased ability to experience pleasure from external events. These deficits were postulated to reflect impairments primarily within mesolimbic dopaminergic systems, and thus were well embedded within standard dopaminergic models. Over recent years, however, detailed studies of anhedonia have failed to confirm decreased hedonic capacity in individuals with schizophrenia. Thus, when asked how much they enjoy a given situation, patients generally report a similar degree of enjoyment as controls [91
Similarly, patients show similar understanding of internal emotional states as controls [90
]. Although subjects often show impaired sensitivity to emotional valence, this deficit has recently been related to impaired ability to process the acoustic [104
] or visual [24
] properties necessary to extract valence, rather than impaired comprehension of emotion itself.
An alternative explanation for apparent anhedonia and asociality may come from reward theory, in which subjects balance effort, reward and delay. Individuals will, in general, work harder now for greater reward later, but only to a point. Whether or not individuals choose immediate or delayed reward depends in part upon how much extra work is needed (“effort discounting”) and how long the delay is between action and reward (“delay discounting”). In schizophrenia, severity of negative symptoms has been correlated with increased delay discounting, with no difference in processing of reward magnitude [52
]. Similarly, using different methodology, patients show normal “in the moment” experience, but reduced correlation between enjoyment and motivation to repeat an action, also suggesting either reduced ability to learn enjoyment/reward associations, or reduced ability to translate pleasure to action [151
Processes such as delay discounting can be explicitly modeled in rodents. In rats, ketamine specifically increased delay discounting, similar to the pattern observed in schizophrenia, whereas low dose amphetamine had an effect opposite that observed in both schizophrenia and following ketamine administration. By contrast, low doses of amphetamine reduced delay discounting while higher doses increased effort discounting [42
], neither of which effects are reported in schizophrenia. Finally, the antipsychotic flupenthixol also increased effort discounting, possibly contributing to avolition observed in schizophrenia. Thus, “weakening of the wellsprings of volition” in schizophrenia may reflect primarily a reduced ability to forego small immediate reward in exchange for greater reward later.
A second key component of negative symptoms is ambivalence, which may underlie the construct of avolition-apathy. In this construct, patients are less able to ignore the negative aspects of enjoyable situations, or positive aspects of aversive situations. Furthermore, increased ambivalence correlated significantly with severity of SANS-rated negative symptoms [152
], supporting the importance of the ambivalence concept. As with other aspects of cognitive impairment in schizophrenia, this implies dysfunction of “winner take all” mutually inhibitory circuits, which allows commitment to one of two alternative action patterns.
Overall brain substrates for negative symptoms remain to be determined. In one recent study, however, NMDAR binding in middle inferior frontal cortex showed a significant correlation with the BPRS negative subscale, suggesting that ketamine may induce negative symptoms through interaction with the NMDAR within this brain region [147
Cognitive or “disorganized” symptoms
A final classic feature complex of schizophrenia is a disorganization of thought and behavior, evaluated using items such as poor attention, conceptual disorganization, difficulties in abstract thinking and disorientation. Similar deficits are seen following NMDAR antagonist administration, supporting a role of NMDAR in normal attentional and thought organizational processes. The fact that these symptoms cluster together and involve language makes it tempting to localize these types of dysfunctions to brain language regions.
Two ketamine studies have utilized a fine grain approach to analyze thought disorder in patients with schizophrenia relative to normal volunteers. The first used the Thought, Language and Communication scale, which characterizes thought disorder across a range of potential patterns [4
]. Both normal volunteers receiving ketamine and schizophrenia patients showed high scores on poverty of speech and content, circumstantiality, loss of goal, perseveration, and tangentiality, all items theoretically linked to ability to maintain short duration memory traces within brain language regions. In contrast, both groups showed low rates on items such as echolalia, semantic or phonetic paraphasias, or neologisms, features that are classically observed following structural damage to posterior language regions.
A second study also noted increased perseveration following both ketamine administration and in schizophrenia [36
]. In contrast, patients showed no change in idea density, a deficit that is characteristic of Alzheimer’s disease, again showing relative specificity of the symptoms in schizophrenia relative to other neurocognitive disorders. Thus, as with other features of schizophrenia, cognitive symptoms appear to reflect dysfunction of specific processes within language regions, rather than structural lesions to the regions themselves.
Difficulties in abstract thinking manifests as preferring literal meanings of expressions relative to symbolic meanings. Impaired abstract thinking is one of the best replicated findings following NMDAR antagonist administration [e.g. 96
]. As with conceptual disorganization, difficulty in abstract thinking may be seen as difficulty in “switching off” the more common, literal meaning of a word in order to permit associations to be made with the less common, more conceptual meaning. The fact that NMDAR antagonists produce such deficits implicates NMDAR in the selection process. The location of the relevant NMDAR, as well as the local circuitry involved, remains to be determined.