30 May 2007. Antipsychotic drugs are highly effective treatments for the positive symptoms of schizophrenia, but the serious and sometimes permanent side effects of these medications make successful long-term maintenance treatment challenging for both patient and clinician. Although newer “atypical” medications such as risperidone appear to present less risk of tardive dyskinesia and other extrapyramidal symptoms than first-generation drugs, second-generation agents have troublesome side effect profiles of their own, including disturbances in glucose metabolism, weight gain, and a heightened risk of diabetes (see American Diabetes Association et al., 2004; Haddad, 2004).
These side effects have led to the development of low-dose maintenance treatment protocols, but they have also prompted some researchers to ask whether there may be subgroups of people with schizophrenia who can eventually do well without taking any antipsychotic medications—and if so, whether this population has distinctive characteristics that would make these individuals easier to identify. The ethics of placebo-controlled studies of schizophrenia treatment remain highly controversial (see SRF related news story), but three recent prospective studies used other research designs to address these questions.
Who Succeeds Without Antipsychotics?
It is well-known that many people with schizophrenia stop taking antipsychotic medications after acute hospital treatment (see Fenton and McGlashan, 1987; Lieberman et al., 2005; also see SRF related news story). Martin Harrow and Thomas H. Jobe of the University of Illinois College of Medicine undertook a prospective 15-year follow-up study of 145 psychosis patients, including 64 who eventually received a diagnosis of schizophrenia, to see what types of schizophrenia patients discontinued medications—whether on their own initiative or with the guidance of a physician—and how they fared over the long term.
In particular, Harrow and Jobe were interested in whether patients’ past developmental achievements and their prognostic potential, as assessed during the index hospitalization, were predictive of their success off medication. In addition, the researchers used locus-of-control (LOC) and self-esteem scales at 4.5-year follow-ups to determine whether these personality measures correlated with patients’ medication status and well-being in later years.
As reported in the May 2007 issue of the Journal of Nervous and Mental Disease, Harrow and Jobe found in follow-up assessments at 2, 4.5, 7.5, 10, and 15 years that up to 41 percent of the patients with schizophrenia in the study sample had stopped taking antipsychotic medications, and as many as 25 percent were receiving no mental health treatment whatsoever. However, from the 4.5-year mark to the conclusion of the study, the patients with schizophrenia not taking antipsychotic drugs scored significantly better than those still taking medications on measures of global functioning and adjustment (p <.001). At 15 years, 64 percent of those on antipsychotic medications had psychotic activity, versus 28 percent of the group off medications. Moreover, 83 percent of the subjects with schizophrenia (19 of 23 patients) with a uniformly poor outcome at the 15-year follow-ups were on antipsychotic medications.
Harrow and Jobe found a strong correlation between the 4.5-year LOC and self-esteem scores and the likelihood that a patient would be using antipsychotic medications at each subsequent follow-up. Those patients whose results indicated an “internal” LOC—reflecting a belief that the course of their life is mostly influenced by their own skills and efforts rather than by chance, fate, or other powerful individuals—and those who scored higher in self-esteem were far less likely to be taking antipsychotic drugs at 15 years. Patients who had more significant developmental achievements prior to hospitalization and those deemed during hospitalization to have good prognostic potential were also far less likely to use antipsychotic drugs.
The researchers stress that, overall, schizophrenia has a poor outcome: compared to the control group of patients who had been treated for psychosis but did not have schizophrenia, those with schizophrenia functioned less well at all stages of the study. However, Harrow and Jobe say that their data provide evidence that specific subgroups of patients with schizophrenia with measurable personality traits and prognostic factors may not immediately relapse and may function quite well for a considerable period of time without antipsychotic drugs.
Harrow and Jobe point out that a trend toward better functioning without medications only began to emerge 4.5 to 7.5 years after their patients were discharged from the hospital, and that their long-term, “naturalistic” study design may avoid the inevitable observer bias of clinically based studies. “The controlled trials data on clinic populations of patients suggest that among the patients with schizophrenia who stay in clinic treatment settings for years after the acute phase there is increased risk of relapse when going off antipsychotics,” the authors write. “However, the current data suggest that for the select subgroup of patients with schizophrenia who are not in clinic settings, who have gone off antipsychotics and did not immediately relapse, and stayed off them for a period of time, a surprising number experienced periods of recovery and continued to function well for a considerable period without antipsychotics. Clearly, the present longitudinal data suggest that not all patients with schizophrenia need to use antipsychotic medications continuously throughout their lives.”
If at First You Don’t Succeed . . . .
Another naturalistic follow-up study by Tadashi Nishikawa and colleagues at Seiwakai Nishikawa Hospital in Hamada, Japan, and at the National Institutes of Health in Baltimore, Maryland, also provides evidence that discontinuation of antipsychotic medications is a viable option for some patients with schizophrenia.
In an analysis accompanied by eight case reports in the spring 2007 issue of Psychiatry, Nishikawa and colleagues report that eight out of 30 remitted patients (26.7 percent; selected from a total population of 300 +/- 20) followed for an average of 10.7 years in a five-step drug withdrawal program were able to forego antipsychotic drugs for more than 2 years, even after multiple psychotic episodes. In one case, a patient did not take antipsychotic drugs for 15 years, until a relapse required a brief course of drug therapy.
Remission was defined as follows: "(a) total scores in each of nine clinical dimensions of Positive and Negative Syndrome Scale, including the positive and negative syndrome and depression, were either 1 or 2, (b) patients kept up normal social and occupational functioning, and (c) the same condition lasted at least 3 months under neuroleptic medication."
The team emphasizes that in half of these eight cases patients needed two or more attempts at antipsychotic withdrawal to reach a drug-free state, an outcome that could be obscured by more standard study designs. “These cases would be counted as ‘relapse’ or ‘dropouts’ in short-term randomized control studies,” the Nishikawa team writes. The researchers argue that with intensive follow-up care, minor relapses and repeated withdrawal programs may help patients to achieve a drug-free state in the long term, especially if withdrawal is accompanied by social-skills training.
The Nishikawa group’s data show that younger patients with acute onset of symptoms, as well as those who receive antipsychotics at lower doses or for a shorter period of time, are most likely to successfully withdraw from the drugs for extended periods. The authors argue that high-dose maintenance regimens may induce neuronal adaptations that make withdrawal more difficult (see Lieberman et al., 1994). “Even though this is an open study with a limited number of patients,” the Nishikawa team writes, “our results suggest that approximately one fourth of remitted schizophrenics could discontinue maintenance neuroleptic medication even after multiple episodes.”
Relapse: Too High a Risk?
A more cautious conclusion emerged from a shorter-term clinical study published in the May issue of the Journal of Clinical Psychiatry by Lex Wundering and colleagues at the University Medical Center in Groningen, The Netherlands. In this work, researchers compared antipsychotic maintenance treatment to “guided discontinuation” of the drugs in 131 schizophrenia patients in remission after a first episode of psychosis. For the purposes of the study, the researchers defined remission as a sustained improvement in positive symptoms for 6 months; negative and disorganizational symptoms were not considered in admission criteria.
The patients, who were randomly assigned to receive maintenance treatment or guided discontinuation, were followed for 2 years following their first response to drug treatment, and were assessed using the Positive and Negative Syndrome Scale (PANSS) after the required 6-month remission, at 15 months, and at 24 months. Measures of drug side effects, social functioning, and quality of life were also taken at some of these same intervals.
The 63 patients in the maintenance group received treatment according to American Psychiatric Association guidelines, with preference given to low doses of second-generation antipsychotics, while in 65 patients the dosage was gradually tapered off and discontinued if possible. If signs of relapse or positive symptoms occurred, clinicians were instructed to restore the dosage to its previous effective level.
The Groningen team found that relapse rates were twice as high in the discontinuation group (43 percent vs. 21 percent, p = .011), and only about 20 percent of the group was successful in discontinuing the drugs. The PANSS scores, hospitalization time, and side effects were virtually identical in both groups, leading the researchers to conclude that the risk of relapse outweighs any other benefit that might come from universally tapering off medication in first-episode patients: “Given the relatively small number of patients who were successfully discontinued (21.5 percent), the twice-higher relapse rates with the discontinuation strategy, the selected patient sample of stably remitted and cooperative patients included in the trial, and the lack of substantial advantages of the discontinuation strategy over maintenance treatment, the discontinuation strategy does not seem to offer sufficient benefits over maintenance treatment to implement the strategy in regular practice for all remitted first-episode patients,” Wunderink and colleagues write.—Peter Farley.
Harrow M, Jobe TH. Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications: a 15-year multifollow-up study. J Nerv Ment Dis. 2007;195(5):406-414. Abstract
Nishikawa T, Hayashi T, Koga I, Uchida Y. Neuroleptic withdrawal with remitted schizophrenics: a naturalistic follow-up study. Psychiatry. 2007;70(1):68-79. Abstract
Wunderink L, Nienhuis FJ, Sytema S, Slooff CJ, Knegtering R, Wiersma D. Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. J Clin Psychiatry. 2007;68(5):654-661. Abstract