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Schizophrenia Bulletin Advance Access originally published online on February 3, 2006
Schizophrenia Bulletin 2006 32(2):300-302; doi:10.1093/schbul/sbj045
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© The Author 2006. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org.

Rationale and Parameters for Medication-Free Research in Psychosis

Thomas H McGlashan

Bola (this issue) makes a case for off-medication periods being relatively safe in schizophrenia, at least in some circumstances. What are the implications of this for research and for the clinical care of research participants?

In 1977 Carpenter, Strauss, and I argued that a place should remain in psychosis research for medication-free investigation.1 Our ultimate rationale for this position was that "we know virtually nothing about the etiology of schizophrenia."1p14 Today I maintain that our ignorance remains as profound as it was 29 years ago and that unraveling the mysteries of schizophrenia still requires observing it under natural conditions, ie, without antipsychotic medications. On the other hand, medication has revolutionized the treatment of psychosis, and it is absolutely required under certain circumstances. My comments here will touch upon both elements of this conundrum and will address the conditions under which the dual aims of scientific clarity and patient safety can be realized.


   The Case Against Medication
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 The Case Against Medication
The Case for Medication
 The Case for Periods...
 References
 
Antipsychotics obscure the pathophysiology of psychosis by altering the neurobiology of the brain and the natural history of disorder. Dopamine D2 receptor blockade is the final common path to chemical antipsychotic activity.2 The dopamine system underlies reward prediction and motivational salience.3 When overactive, it aberrantly assigns importance to specific experiences, which results in positive symptoms. When underactive, it attenuates motivational salience for all events, which results in negative symptoms. In the short term, acute D2 blockade detaches salience and the patient's investment in positive symptoms. In the long term, chronic D2 blockade dampens salience for all events in everyday life, inducing a chemical anhedonia that is sometimes labeled postpsychotic depression4,5 or neuroleptic dysphoria.6–11

Maintenance medication with chronic D2 blockade may also induce changes in the natural history of the patient's disorder. We postulated 29 years ago1 that initial exposure to antipsychotics may actually increase the risk of relapse but that, like tardive dyskinesia, this risk could be masked by continuing medication. Without question medication and relapse are related,12 and today that relationship has come to mean medication is required to prevent relapse. What we asked in 1977 was whether the actual risk for relapse would be as high in samples that were never exposed to neuroleptics to begin with.

Clinical trials randomizing first-episode psychotic patients to a no-drug arm are not likely to happen in the foreseeable future, but the question about chemically induced relapse risk and chronic deficit may not be merely academic. The long-term (9- and 10-year) outcome data emerging from 2 well-treated, first-episode samples13–15 suggest that deterioration in schizophrenia does not plateau as seen in older, long-term follow-up patient samples where exposure to medications was absent or intermittent.16–19 Could it be that the drug-related chronic deficits in motivational salience for experience lead to a form of extra-institutional institutionalization? Do we free patients from the asylum with D2 blocking agents only to block incentive, engagement with the world, and the joie de vivre of everyday life? Medication can be lifesaving in a crisis, but it may render the patient more psychosis-prone should it be stopped and more deficit-ridden should it be maintained.


   The Case for Medication
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 The Case Against Medication
 The Case for Medication
The Case for Periods...
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The benefits of medication are profound. Active psychosis is a dangerous, life-threatening state. Behavior is often unpredictable because of misperceptions, misconceptions, and irrational thinking. The gravest dangers are suicide, homicide, and physical injury. Almost as important are paralyses of judgment and empathy resulting in violations of social convention and trust and leading ultimately to social isolation and stigmatization. For persons in this state of mind, antipsychotic medications are unquestionably a powerful therapeutic tool. Furthermore, the efficacy of drugs for active psychosis is inexpensive compared with nondrug alternatives that would require varying degrees of hospital/institutional care. Drugs are also portable, unlike treatment teams, and facilitate rapid emancipation of the remitted patient to the community.

The benefits of medication are also obvious, almost as obvious today as they perhaps were to the astonished alienists in the 1950s who bore first witness to chlorpromazine's power to unravel the knots of psychosis. The therapeutic power of medication has been scientifically validated countless times since then, and it is now the primary treatment of schizophrenia. In today's climate, treating schizophrenia without medication mobilizes high anxiety among treaters for the safety of their patients from irrationality and for the safety of themselves from litigation.


   The Case for Periods of Medication-Free Research in Psychosis
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 The Case Against Medication
 The Case for Medication
 The Case for Periods...
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Antipsychotics alter the pathophysiology and the natural history of schizophrenia. At the same time, they are the most rapid, effective, and economical treatment for active psychosis. How do we resolve this tension? Two approaches are offered, one focusing on pre-onset detection of high-risk cases and the other on creating safe conditions for the drug-free study of active and remitted states in established psychosis.

Early detection and intervention in the prodromal phase of first psychosis offers the potential for therapeutic advance in the form of preventing onset and/or progression of disorder.20–22 The major scientific promise of early detection, however, is the opportunity to study the pathophysiology of psychosis medication-free. True-positive high-risk cases can now be reliably identified and monitored prospectively to the onset of psychosis.23 This offers 2 advances in scientific design. First, it makes possible the prospective tracking of changes leading to psychosis, as opposed to retrospective reconstructions of those changes, which ultimately remain speculative and nonfalsifiable. Second, this tracking can be done free of medication because clinically there is not yet any dangerous loss of reality testing and/or behavioral control and because medicolegally there is not yet any DSM diagnosis of psychosis.

This approach demands active, frequent, and careful monitoring of "prodromal" cases. If the considerable psychosocial resources required for such monitoring cannot be offered by the clinical research team, then the research should not proceed.

Medication-free research could also be engineered for established schizophrenia, for patients either actively psychotic or in remission, if an equivalent level of safety could be established, as in the case of prodromal schizophrenia. For established psychosis, this requires the availability of even more psychosocial resources than the "prodromal" situation. Medication-free active psychosis, for example, can only be studied in the context of 24-hour hospitalization with constant observation. Medication-free remitted psychosis can only be studied in the context of the patient consenting to a contract to undergo regular monitoring and to comply with a recommendation for the institution or reinstitution of medication by the monitoring team.

Both of these scenarios for the established patient can be created but are problematic scientifically and economically. Scientifically, the samples of patients consenting to such research conditions are likely to be less severely ill and therefore not representative of the larger population of persons with psychosis. Economically, such resources required for safety simply do not exist, at least in the American managed health care system. Such resources would have to be part of the direct costs of research grants. Up to now, National Institutes of Health policy has proscribed any culture of providing clinical treatment infrastructure that supports research addressing questions other than the efficacy of the clinical treatment infrastructure under investigation. Unless and until that policy can be successfully challenged and altered, medication-free research in psychosis will be possible only in the "prodromal" situation. Given this, the time may be near to generate such policy challenges.


  Footnotes
 
To whom correspondence should be addressed; e-mail: thomas.mcglashan{at}yale.edu.


   References
Top
 The Case Against Medication
 The Case for Medication
 The Case for Periods...
 References
 

  1. Carpenter, WT, McGlashan, TH, Strauss, JS. The treatment of acute schizophrenia without drugs: an investigation of some current assumptions. Am J Psychiatry 1977; 134:14–20.[Free Full Text]

  2. Kapur, S and Mamo, D. Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27:1081–1090.[CrossRef][Medline]

  3. Kapur, S, Mizrahi, R, Li, M. From dopamine to salience to psychosis: linking biology, pharmacology, and phenomenology of psychosis. Schizophr Res 2005; 79:59–68.[CrossRef][Web of Science][Medline]

  4. McGlashan, TH and Carpenter, WT. An investigation of the postpsychotic depressive syndrome. Am J Psychiatry 1976; 133:14–19.[Abstract/Free Full Text]

  5. McGlashan, TH and Carpenter, WT. Postpsychotic depression in schizophrenia. Arch Gen Psychiatry 1976; 33:231–239.[Abstract/Free Full Text]

  6. Van Putten, T, May, PRA, Marder, SR, Wittman, LA. Subjective response to antipsychotic drugs. Arch Gen Psychiatry 1981; 38:187–190.[Abstract/Free Full Text]

  7. Hogan, TP, Awad, AG, Eastwood, MR. Early subjective response and prediction of outcome to neuroleptic drug therapy in schizophrenia. Can J Psychiatry 1985; 30:246–248.[Web of Science][Medline]

  8. Awad, AG. Subjective response to neuroleptics in schizophrenia. Schizophr Bull 1993; 19:609–616.[Abstract/Free Full Text]

  9. Naber, D. A self-rating to measure subjective effects of neuroleptic drugs, relationships to objective psychopathology, quality of life, compliance, and other clinical variables. Int Clin Psychopharmacol 1995; 10:suppl133–138.

  10. Voruganti, LNP and Awad, AG. Personal evaluation of transitions in treatment (PETiT): a scale to measure subjective aspects of antipsychotic drug therapy in schizophrenia. Schizophr Res 2002; 56:37–46.[Medline]

  11. Naber, D, Karow, A, Lambert, M. Subjective well-being under neuroleptic treatment and its relevance for compliance. Acta Psychiatr Scand 2005; 111:suppl42729–34.[Medline]

  12. Gitlin, M, Nuechterlein, K, Subotnik, KL, et al. Clinical outcome following neuroleptic discontinuation in patients with remitted recent-onset schizophrenia. Am J Psychiatry 2001; 158:1835–1842.[Abstract/Free Full Text]

  13. Milev, P, Ho, BC, Arndt, S, Andreasen, NC. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. Am J Psychiatry 2005; 162:495–506.[Abstract/Free Full Text]

  14. Andreasen, NC, Moser, DJ, O'Leary, DS, Ho, BC. Longitudinal changes in neurocognition during the first decade of schizophrenia illness. Schizophr Bull 2005; 31:348.

  15. Hoff, A, DeLisi, LE, Maurizio, A. Longitudinal neuropsychological findings of first-episode schizophrenia after ten years of illness. Schizophr Bull 2005; 31:326.

  16. McGlashan, TH. A selective review of recent North American long-term follow-up studies of schizophrenia. Schizophr Bull 1988; 14:515–542.[Abstract/Free Full Text]

  17. McGlashan, TH and Fenton, WS. Subtype progression and pathophysiologic deterioration in early schizophrenia. Schizophr Bull 1993; 19:71–84.[Abstract/Free Full Text]

  18. Harding, CM, Brooks, GW, Ashikaga, T, Strauss, JS, Breier, A. The Vermont longitudinal study of persons with severe mental illness: I. methodology, study sample, and overall status 32 years later. Am J Psychiatry 1987; 144:718–726.[Abstract/Free Full Text]

  19. Harding, CM, Brooks, GW, Ashikaga, T, Strauss, JS, Breier, A. The Vermont longitudinal study of persons with severe mental illness: II. long-term outcome of subjects who retrospectively met DSM-III criteria for schizophrenia. Am J Psychiatry 1987; 144:727–735.[Abstract/Free Full Text]

  20. McGlashan, TH and Johannessen, JO. Early detection and intervention with schizophrenia: rationale. Schizophr Bull 1996; 22:201–222.[Abstract/Free Full Text]

  21. McGorry, PD, Yung, AR, Phillips, LJ, et al. Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms. Arch Gen Psychiatry 2002; 59:921–928.[Abstract/Free Full Text]

  22. McGlashan, TH, Zipursky, RB, Perkins, D. The PRIME North America randomized double-blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis: I. study rationale and design. Schizophr Res 2003; 61:7–18.[CrossRef][Web of Science][Medline]

  23. Miller, TJ, McGlashan, TH, Rosen, JL, et al. Prospective diagnosis of the initial prodrome for schizophrenia based on the structured interview for prodromal syndromes: preliminary evidence of interrater reliability and predictive validity. Am J Psychiatry 2002; 159:863–865.[Abstract/Free Full Text]


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