EDITORIAL
`Treatment of Schizophrenia and Spectrum Disorders:
`Pharmacotherapy, Psychosocial Treatments, and
`Neurotransmitter Interactions
`
`The Primacy of Dopamine and Focus on
`Positive Symptoms
`The modern era in the biological treatment of schizophre-
`nia was initiated with the observation that chlorpromazine,
`originally studied for its sedative effects, had the ability to
`treat delusions and hallucinations. The hypothesis that the
`antipsychotic action of chlorpromazine was caused by its
`ability to block the stimulation of brain dopamine recep-
`tors (Carlsson and Lindqvist 1963), along with the hypoth-
`esis that amphetamine-induced psychosis was caused by
`the increased availability of dopamine (Randrup and
`Munkvard 1972; Snyder 1973), were the pivotal ideas that
`catalyzed the intense effort to link dopamine and schizo-
`phrenia and to understand the role of dopamine in brain
`and behavior. The group of neuroleptic drugs that resulted
`from the dopamine hypothesis of schizophrenia shaped not
`only the treatment of schizophrenia but also the basic
`conception of the disease process itself. The neuroleptic
`drugs facilitated the closing of vast numbers of psychiatric
`beds and the initiation of community treatment for schizo-
`phrenia, two factors that have had enormous consequences
`for patients and their families, for the mental health
`professions and psychiatry in particular, and for society as
`a whole. Unfortunately, the challenge of treating patients
`with schizophrenia in the community using neuroleptic
`drugs as the mainstay of treatment has not been adequately
`met, as evidenced by only modest advances in improving
`outcome in schizophrenia and the large numbers of people
`with schizophrenia in the United States who are homeless
`or incarcerated.
`The usually successful treatment of the positive symp-
`toms of schizophrenia with neuroleptic drugs led directly
`to diagnostic criteria for the disorder (DSM III, IV) that
`emphasized these symptoms and focused both preclinical
`and clinical research more on understanding the etiology
`of positive symptoms and developing better treatments for
`them than on other aspects of schizophrenia (e.g., the
`cognitive deficit) than was warranted in terms of their
`importance for outcome. Many embraced the reductionist
`view that the core aspects of schizophrenia might result
`from one or more abnormalities of the dopaminergic
`system, leading to models that characterized the onset and
`course of schizophrenia—negative symptoms and cogni-
`tive deficits, for example—as the consequence of abnor-
`malities in dopaminergic activity. Interest in the cognitive
`
`© 1999 Society of Biological Psychiatry
`
`deficits of schizophrenia waned as evidence accumulated
`that the neuroleptic drugs were ineffective in their treat-
`ment. The concept that any new treatment of schizophre-
`nia had to be effective in controlling positive symptoms
`rather than, for example,
`the cognitive deficit
`in this
`disorder came to dominate new drug development. Many
`of these views are still widely held.
`
`Beyond Positive Symptoms and Dopamine
`in the Treatment of Schizophrenia: The
`Importance of the Atypical Antipsychotic
`Drugs, Negative Symptoms, and Cognition
`Beginning in the 1980s, interest in the negative symptoms
`of schizophrenia (i.e.,
`lack of spontaneity, anhedonia,
`affective flattening, and avolition) reemerged as a primary
`goal of the treatment of schizophrenia. An early influential
`model of the etiology of negative symptoms ascribed them
`to supposedly irreversible structural changes in the brain
`(Crow 1980). Subsequently,
`the possibility that
`these
`symptoms were the result of decreased cortical dopami-
`nergic activity emerged (Davis et al 1991; Meltzer 1985).
`There is now enough evidence concerning schizophre-
`nia and its treatment to be able to fairly confidently move
`beyond the disease model shaped by the dopamine/posi-
`tive and negative symptom mold, however. It has become
`abundantly clear that
`treating positive symptoms with
`typical neuroleptics, even when successful,
`leaves the
`majority of patients with schizophrenia significantly dis-
`abled from a functional point of view (Hegarty et al 1994;
`Meltzer 1997). The major reason for this, probably the
`most
`important for many patients, appears to be the
`cognitive deficit present in most but not all patients who
`meet contemporary criteria for schizophrenia (Green
`1996; Meltzer and McGurk 1999). For example, Palmer et
`al (1997) reported that 85% of patients with schizophrenia
`are cognitively impaired compared with the general pop-
`ulation, although it is likely that the other 15% are less
`capable cognitively and from a functional perspective than
`they might have been had they not become psychotic.
`There are now numerous studies indicating that clozapine,
`the prototype of the group of atypical antipsychotic drugs,
`produces much less blockade of striatal dopamine recep-
`tors than typical neuroleptics or even the atypical antipsy-
`chotics that are most closely related to it such as olanza-
`pine, quetiapine, and risperidone (Farde et al 1992; Kapur
`
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`PII S0006-3223(99)00245-5
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`1
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`

`1322
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`BIOL PSYCHIATRY
`1999;46:1321–1327
`
`Editorial
`
`and Remington 1999). Indeed, some of the key benefits of
`clozapine, such as the ability to improve cognition and the
`negative symptoms of schizophrenia, may be due, in part,
`to the ability to increase dopaminergic activity in the
`prefrontal cortex, a brain region that, together with tem-
`poral lobe regions such as the hippocampus, is essential
`for cognition. We have now found, however, that olanza-
`pine is able to block extrastriatal dopamine receptors at
`doses that spare many striatal dopamine receptors. This
`may be the case for other atypical antipsychotic drugs with
`similar pharmacology as well. Thus, dopamine receptor
`blockade may be more important to the action of the
`atypical antipsychotic drugs than previously thought and
`may contribute to the limited efficacy of selective 5-HT2a
`receptor antagonists, such as M100907, that do not block
`D2 dopamine receptors.
`The three articles in this issue of Biological Psychiatry
`concerning the treatment of schizophrenia and the related
`condition, borderline personality disorder, as well as the
`article by Carlsson and colleagues summarizing some of
`their current thinking about the neurotransmitters involved
`in the etiology of schizophrenia and the implications for
`developing superior treatments, reflect in varying degrees
`that breakdown of the old dopamine-based paradigm. In its
`stead is a new model that has, in my opinion, tremendous
`heuristic value to shape how we conceptualize, study, and
`treat what is now called schizophrenia. The limitations
`and, perhaps, approaching end of the neuroleptic era in the
`treatment of schizophrenia is documented in John Kane’s
`treatment overview article, which cites the influential
`review of Hegarty et al (1994) that showed only about a
`20% increment in moderate-good outcome in schizophre-
`nia after the addition of the neuroleptic drugs, reaching an
`overall rate maximum of 55% over a decade ago, followed
`by a significant decrease in the proportion of good
`responders. The evidence for the greater benefits of the
`atypical antipsychotic drugs, such as clozapine, risperi-
`done, olanzapine, and quetiapine, is quite strong in many
`outcome domains, even though effect sizes are relatively
`modest (Fleischhacker 1999; Leucht et al 1998). The mean
`changes obscure the fact that these agents have been of
`incredible value to many patients who did not respond to,
`or could not tolerate, the typical antipsychotic drugs. Near
`miraculous improvement occurs in a limited number of
`fortunate individuals. The majority of patients, however,
`remain moderately to severely disabled, despite full or
`partial control of positive symptoms. The most exciting
`findings with these drugs are that 1) clozapine can signif-
`icantly diminish positive symptoms in more than 50% of
`the patients who fail to respond to the typical neuroleptics;
`2) it does not produce tardive dyskinesia; and 3) it can
`improve some domains of cognition, especially verbal
`fluency, secondary memory, and some measures of atten-
`
`tion (Fleischhacker 1999; Kane et al 1998; Meltzer 1997;
`Meltzer and McGurk 1999). Risperidone, olanzapine,
`quetiapine, and ziprasidone share these characteristics to
`various extents (Leucht et al 1999; Purdon 1999; Tandon
`et al 1997). Much further research is needed to understand
`how best to use these agents and to gain a fuller appreci-
`ation of
`their efficacy in schizophrenia and other
`conditions.
`My view that these agents can improve some types of
`both primary and secondary negative symptoms, albeit to
`a modest extent in most patients and usually only in those
`patients with high initial levels of negative symptoms at
`the start of treatment (Meltzer 1991, 1995) is still contro-
`versial (Carpenter et al 1995; Remington and Kapur 1999).
`There should be no dispute, however,
`that
`they can
`markedly improve negative symptoms per se in some
`patients. To varying extents, the additional advantages
`these agents have with regard to compliance, superior
`effects on mood and suicidality, decreased hospitalization,
`and improved functional outcomes, which are based in
`part on improved cognitive function, leads to both reduced
`overall direct costs of treatment and indirect costs, making
`them a dominant treatment. As such, they should be the
`sole drugs prescribed for schizophrenia, especially when
`long-acting formulations become available within the next
`few years. Further research to optimize the use of these
`agents for their numerous indications are necessary. For
`example, the concept that they owe some of their advan-
`tages to low D2 dopamine receptor blockade relative to
`5-HT2a receptor blockade in the mesolimbic and meso-
`striatal systems, if true, dictates that concomitant treatment
`with neuroleptics should be avoided. The duration of trials
`with the atypical agents in treatment-resistant patients and
`the use of concomitant medication or ECT to augment
`response has not been adequately investigated. The possi-
`ble use of these agents in the prodromal period of
`schizophrenia, before
`the
`emergence of psychosis
`(McGorry 1998), is perhaps the most important issue to
`clarify in the next decade because it is clear that for many
`patents, the newer drugs, although superior to the neuro-
`leptics, are unable to fully reverse already-established
`impairment in cognition, negative symptoms, and social
`disability. A recent study of Tsuang et al (1999) has shown
`that risperidone has some benefit to improve cognition and
`mild functional disability in first-degree relatives of peo-
`ple with schizophrenia who meet no diagnostic criteria for
`psychiatric illness. This is consistent with the possibility of
`preventing the poor outcome of schizophrenia by identi-
`fying individuals with prodromal schizophrenia and utiliz-
`ing the antipsychotic agent with the best risk-to-benefit
`ratio available, recognizing that long-term treatment over
`a course of many years, at least through the peak years of
`risk, may be needed.
`
`2
`
`

`

`Editorial
`
`BIOL PSYCHIATRY
`1999;46:1321–1327
`
`1323
`
`Integrating Psychosocial Treatment and the
`Atypical Antipsychotic Drugs
`The role of psychosocial treatment in the treatment of
`schizophrenia is well reviewed by Lauriello et al, who
`rightfully emphasize the importance of the larger domains
`of outcome, such as social adjustment and employment,
`and correctly conclude, in my judgement, that psychoso-
`cial treatments may be the means of achieving these goals.
`At the same time, they note how little data there are
`supporting the conclusion that the current modalities of
`psychosocial treatment are effective in this regard, having
`shown mainly a time-limited effect on relapse prevention.
`It should be noted, however, that all of the studies they
`review date from the neuroleptic era. The efficacy of these
`modalities in patients treated with the atypical antipsy-
`chotics could be significantly superior because of the
`greater ability of these agents to improve cognition and
`negative symptoms and because of better compliance and
`the ability to delay or even prevent recurrence of positive
`symptoms. Future research with psychosocial treatment
`should examine the differential benefit of intensive appli-
`cation during the first years of the illness, including the
`prodromal period if possible, if they are to have their
`maximal impact. This is not to diminish their potential
`value in conjunction with the atypical agents in more
`chronic patients. Controlled research in this area is most
`difficult but deserves to be supported because of the
`importance of satisfactorily demonstrating an additive or
`synergistic effect of psychosocial treatment and pharma-
`cotherapy. The resources to provide psychosocial treat-
`ment to patients with schizophrenia and their families have
`diminished in the absence of convincing evidence for their
`efficacy and the increased expenditures for the atypical
`antipsychotic drugs. Studies to demonstrate the benefit of
`the various forms of psychosocial
`treatment used in
`conjunction with the novel antipsychotic drugs are ur-
`gently needed. Positive results in such studies are the only
`way that society will provide funding for this form of
`therapy for the vast majority of patients who cannot
`support it with their own resources.
`
`Novel Uses of the Atypical Antipsychotic
`Drugs: Personality Disorders
`Further testing of the atypical antipsychotic drugs in
`conditions other than schizophrenia in which neuroleptic
`drugs previously have been shown to be effective but
`poorly tolerated should also be a high priority. Clozapine
`and quetiapine have been found to be highly effective and
`very well tolerated in treating dopaminomimetic psycho-
`ses in Parkinson’s disease (Scholz and Dichgans 1985).
`Borderline personality disorder would seem to be a con-
`
`dition in which the atypical antipsychotic drugs would be
`of major benefit because the elements of this disorder
`(e.g., psychosis, mood instability, depression, impulsivity
`and anger) have been found to be responsive to atypical
`antipsychotic drugs in patients with schizophrenia and
`major mood disorders. Further, there is evidence, reviewed
`in the article by Schulz et al
`in this issue,
`that
`the
`neuroleptic drugs are effective in some patients with this
`syndrome but poorly tolerated. It is disappointing that
`there are no published controlled studies to validate the
`efficacy of the atypical antipsychotic drugs in borderline
`personality disorder because there is equivocal anecdotal
`evidence to support this indication. The study reported
`here is another open, small trial. Because the authors
`found a high placebo response rate in this condition in a
`previous double-blind study with risperidone, it is surpris-
`ing that they did not go directly to a placebo-controlled
`study with olanzapine. What one can glean from this
`report is that the weight gain with olanzapine (8.9 ⫾ 6.0 lb
`during the eight week trial) led to its discontinuation in
`four of nine patients (44%), suggesting that tolerability for
`this agent may not be high in individuals with borderline
`personality disorder, regardless of efficacy. It should be
`noted, however, that the majority of patients with schizo-
`phrenia treated with olanzapine, as well as the patients in
`the Schulz et al study, have only slight weight gain, so this
`side effect does not preclude its use in many patients.
`Pharmacologic and other means of controlling weight gain
`with drugs such as clozapine, olanzapine, and quetiapine
`are a high priority. An atypical antipsychotic drug with
`lesser weight gain propensity than olanzapine (e.g., zi-
`prasidone and low-dose risperidone) should be tested in a
`placebo-controlled trial, with a neuroleptic as an active
`comparator and a maintenance phase, in patients with
`borderline personality disorder, as well as schizotypal and
`schizoid personality disorders.
`
`The Role of Serotonin, Glutamate, GABA,
`and Acetylcholine in Schizophrenia and the
`Pharmacotherapeutics of Schizophrenia and
`Related Conditions
`The widespread adoption of the atypical antipsychotic
`drugs and their undeniable clinical advantages for many
`patients with schizophrenia and other indications has
`provided encouragement for the development of additional
`novel strategies to obtain new antipsychotic agents with
`superior efficacy and fewer side effects, such as weight
`gain, sedation, hypotension, and so forth, that are shared
`by many, if not all, the available agents. Much attention
`has been given to the importance of 5-HT2a receptor
`antagonism, together with weak D2 receptor antagonism,
`in their action (Altar et al 1986; Meltzer 1999; Meltzer et
`al 1989). There have been at least six additional series of
`
`3
`
`

`

`1324
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`BIOL PSYCHIATRY
`1999;46:1321–1327
`
`Editorial
`
`compounds of different chemical classes with this profile
`that have been shown preclinically to have atypical anti-
`psychotic properties. Other 5-HT receptors, however, such
`as the 5-HT1a, 5-HT2c, 5-HT6, and 5-HT7 receptors
`(Meltzer 1999), as well as the D3 and D4 dopamine
`receptors, and, as pointed out by Carlsson et al in this
`issue, drugs targeting NMDA- and AMPA-type glutamate
`receptors also appear promising. The circuitry underlying
`these strategies is discussed by Carlsson et al here and by
`others (Jakab and Goldman-Rakic 1998; Wang and Ar-
`vanov 1998). The ability of the novel antipsychotics to
`enhance cholinergic function in the prefrontal cortex
`(Ichikawa et al 1999; Meltzer et al 1999), as well as other
`data (Bymaster et al 1998), points to the importance of
`acetylcholine as well. In my view, drugs that improve
`cognitive function and negative symptoms, in addition to
`positive symptoms, are what is needed for the treatment of
`schizophrenia and related conditions. If they lack the
`ability to treat positive symptoms, however, they might be
`effectively combined with low doses of the current gen-
`eration of agents effective to treat such symptoms unless
`these effects are incompatible because of pharmacody-
`namic interactions.
`The article by Carlsson et al in this issue provides an
`excellent overview of the current ideas concerning schizo-
`phrenia, its pathophysiology, and its treatment, authored in
`part by one of the greatest minds in the history of
`psychopharmacology and biological psychiatry. It is laden
`with new and old concepts based on the type of thoughtful
`integration and synthesis of clinical and preclinical data
`that
`is essential for rapid progress utilizing updated,
`classical concepts, as opposed to “fishing expeditions”
`based on genome scans in patients with schizophrenia or
`identification of genes activated by various models such as
`noncompetitive NMDA-receptor antagonists, such as
`PCP, or by atypical antipsychotic drugs. Carlsson et al
`provide a concise, interesting update on current concepts
`of the role of dopamine, serotonin, acetylcholine, gluta-
`mate, and GABA in schizophrenia, as well as crucial
`directions for future preclinical and clinical research in
`schizophrenia, including biological psychiatry, new drug
`development, and clinical trials. It is an article worth close
`study by anyone with an interest in schizophrenia or one or
`more of its various components, such as delusions, halluci-
`nations, negative symptoms, and cognitive disturbance. Only
`a few points can be highlighted here, and if I appear to focus
`on what I take some exception to, it is only because the
`rest is so cogently argued, one does not need a guide.
`
`Heterogeneity of Schizophrenia
`Among the basic concepts that Carlsson et al discuss in
`this article and other recent publications (Martin et al
`
`1998), now more important than ever in my view, is the
`notion that there is no single biology of schizophrenia.
`Heterogeneity due to subtypes, such as paranoia, pres-
`ence of hallucinations, severity and type of cognitive
`dysfunction, and different phases of the illness (e.g.,
`florid psychosis vs. the quiescent periods characterized
`mainly by negative symptoms), cognitive impairment,
`and functional disability must be taken into account if
`one is to find biological correlates in such clinical
`studies as pharmacologic challenge paradigms, PET
`studies of dopamine and serotonin turnover or receptor
`density, or postmortem neurochemistry, and, I would
`add, genetic association and pharmacogenomic studies.
`The models of schizophrenia that Carlsson et al favor
`emphasize neurocircuitry that involves multiple neuro-
`transmitters interactions, requiring the integrated activ-
`ity of various presynaptic and postsynaptic enzyme and
`receptor-governed processes. It
`is highly likely in a
`heterogeneous syndrome such as schizophrenia that
`there will be a multiplicity of combinations of deficits
`in basal and stimulus-driven responses that produce the
`varied phenotypes. Interactions among neurotransmit-
`ters may make an apparently normal level of activity at
`one receptor subtype pathogenic because of the absence
`of a competing system that normally opposes it. A
`prime example of this would be the 5-HT2a and 5-HT2c
`systems that have a crucial role in mediating responses
`to glutamate and serotonin (Martin et al 1997a). Differ-
`ences in the forms of 5-HT2a and 5-HT2c genes in
`schizophrenia may well underlie some of the heteroge-
`neity in response to clozapinelike antipsychotic drugs
`(Masellis et al 1998) and psychopathology.
`Appreciation of heterogeneity by Carlsson et al leads to
`an interest in the neurochemical differences that underlie
`periods of intensified positive symptoms as opposed to
`those period when such symptoms are absent or minimal.
`It also draws attention to the goal of finding drugs that are
`capable of “stabilizing” rather than merely blocking do-
`paminergic function. It is suggested that partial dopamine
`agonists may be the means to achieve this, a view I do not
`necessarily share. Drugs of this class that have been
`clinically tested in schizophrenia have proven to be inef-
`fective for the most part. Others are still in development
`and testing phases, however, and one hopes that they will
`fulfill the role that Carlsson et al assign to them. The goal
`of “stabilized” dopaminergic function has been achieved
`in many ways, by the atypical antipsychotics that can
`enhance dopaminergic activity in the prefrontal cortex
`(Kuroki et al 1998) and diminish it, via limited dopamine
`receptor blockade, in the mesostriatal and mesolimbic
`systems, and perhaps more extensive blockade of extra-
`striatal dopamine receptors.
`
`4
`
`

`

`Editorial
`
`BIOL PSYCHIATRY
`1999;46:1321–1327
`
`1325
`
`Glutamate-Serotonin Interactions in
`Schizophrenia
`The role of glutamate in schizophrenia is emphasized by
`Carlsson et al, in part, because of the phencyclidine (PCP)
`model of psychosis. The preclinical studies done by this
`group to understand the multiple systems involved in
`controlling the hyperlocomotion produced by NMDA-
`competitive and noncompetitive antagonists versus am-
`phetamine are of tremendous interest. They have con-
`cluded that increased serotonergic tone is the key to the
`hyperlocomotion produced by these agents and that the
`atypical antipsychotic drugs are effective in this model,
`and hence, by virtue of their ability to block 5-HT2a
`receptors while blockade of 5-HT2c receptors should have
`an antagonistic or propsychotic action in schizophrenia
`(Martin et al 1997a, 1998). This is an idea I had previously
`proposed based on a multivariate analysis of the pharma-
`cology of the atypical versus the typical antipsychotic
`drugs (Meltzer et al 1996). Much of this hypothesis by
`Carlsson and colleagues in this issue is based on the
`greater effectiveness of the 5-HT2a antagonist M100907
`to block hyperlocomotion produced by NMDA antago-
`nists compared with spontaneous locomotion, whereas the
`D2 receptor blocker raclopride is equally effective in
`blocking both types of activity (Martin 1997b). Carlsson et
`al (this issue) expected that M100907 alone should have
`antipsychotic activity in some patients but that because of
`heterogeneity, it might not produce such as effect in other
`patients, who might benefit from combination with a D2
`receptor antagonist. The preliminary results of the first
`large-scale trial with M100907 have now been reported. It
`was found to be less effective than haloperidol in treating
`positive symptoms but more effective than placebo in
`patients with schizophrenia in an acute exacerbation (J.
`Shipley, personal communication, August 15, 1999), con-
`sistent with the predictions of Carlsson et al. Based on our
`studies using microdialysis, the combination of M100907
`with low-dose but not high-dose haloperidol, but not
`M100907 alone, can modulate prefrontal cortical and
`mesolimbic dopaminergic activity in a desirable manner.
`A subgroup of patients with schizophrenia with low
`dopaminergic activity on endogenous basis might be
`expected to respond to M100907 alone, whereas others
`would need some D2 receptor blockade. I have suggested
`elsewhere that drugs that have as a component of action
`the ability to stimulate 5-HT2c and 5-HT1a receptors may
`be a promising approach to the development of novel
`antipsychotic agents (Meltzer 1999).
`the most
`In this issue, Carlsson et al propose that
`promising approach to new treatments for schizophrenia
`may involve enhancing glutamatergic function without
`causing neurotoxicity. This is most certainly a reasonable
`
`conclusion. A thorough understanding of the regulation of
`pre- and postsynaptic glutamatergic activity will facilitate
`this probably achievable goal. Drugs that can do this are
`likely to be multireceptor active agents,
`in my view,
`consistent with the complexity of the circuitry that must be
`manipulated and the heterogeneity of schizophrenia. All is
`not lost for receptor specific agents such as 5-HT2a, D2,
`D3, and other antagonists, however. Not only are they
`invaluable as research tools, they may also be able to
`augment the activity of other receptor-specific or multire-
`ceptor agents in specific patients. One size does not fit all
`in schizophrenia, an enduring message provided by the
`neuroleptics vis a vis clozapine and the other atypical
`antipsychotic drugs.
`
`Conclusions
`Although the use of neuroleptic drugs as the sole treatment
`for schizophrenia should no longer be acceptable because
`of their risk of tardive dyskinesia and their limited efficacy
`to treat positive symptoms, negative symptoms, and espe-
`cially the cognitive disturbance of schizophrenia, they will
`continue to be useful in low doses as a means of providing
`D2/D3 receptor blockade when needed to complement
`other agents that are ineffective by themselves to treat
`positive symptoms but effectively treat other components
`of the schizophrenia syndrome. As truly novel drugs for
`schizophrenia and spectrum disorders become available
`for clinical testing, one hopes that the trial designs and the
`clinical investigators who test them, as well as industry
`and regulatory executives who ultimately must decide on
`their availability for clinical use, will remember the
`following: 1) relevant outcome measures encompass more
`than control of positive symptoms; 2) multiple phases of
`the disease process should be explored, not just florid
`psychosis; and 3) these highly sophisticated drugs may be
`active in only some patients. It is likely that this next
`generation of treatments for schizophrenia, whether they
`be based on serotonin, dopamine, glutamate, or other
`strategies, will require psychosocial interventions to make
`them maximally beneficial. In addition, they may be most
`beneficial when given during the prodrome period or even
`before and also will have widespread application for other
`neuropsychiatric disorders if they do not have a heavy
`burden of side effects.
`
`Herbert Y. Meltzer
`
`Department of Psychiatry
`Vanderbilt University School of Medicine
`Psychiatric Hospital
`1601 23rd Avenue, Suite 306
`Nashville, TN 37212
`
`5
`
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`BIOL PSYCHIATRY
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`
`Supported, in part, by grants from the William K. Warren Foundation and
`the Essel Foundation.
`
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