Cut Off: Here an example best serves the purpose for understanding. 

LETS say that 50% of the drug Treatment group responded positively,

But 40% of the placebo also responded positively.

Reporting the difference as an arbitrarily cut-off score can make small difference seem quite large. 

If 45% is the cut-off score chosen by the researcher as “improvement” then you have 100% success for drug group and 100% failure by placebo. Get it.  However,

Relative Difference: Reporting the Relative Difference between 40% and 50% is performed like this….50% minus 40% is 10%, but researchers are likely to state 50% is 25% higher than 40% (10 out of 40.), and this will make it seem like 25% of the people responded to the drug rather than the 10%.  Tricky.

11) Failure to Consider Social Functioning as an Outcome Measure

Schizophrenia refers to a persistent mental disorder with serious cognitive, interpersonal, vocational, and social impairments. Of 2000 controlled schizophrenia trials, however, a mere 6% evaluated social functioning while 81% evaluated psychiatric symptoms or behavior (Thornley & Adams, 1998). Given that over 90% of participants in these trials, even during the last decade, were hospitalized patients (and mostly American or British), findings cannot be generalized to the vast majority of individuals diagnosed with schizophrenia. Until measures of social and vocational functioning are carefully integrated into clinical trials, such trials cannot provide meaningful information about the real-life “effectiveness” of neuroleptics on domains besides acute symptom exacerbation.

This point has long been recognized (e.g., Barnes, Milavic, Curson, & Platt, 1983; Diamond, 1985) but has not sufficiently influenced the design of contemporary drug trials, even of atypicals, which are sometimes touted as fitting well with the era of community treatment. For example, in a meta-analysis of all 30 available RCTs comparing clozapine with conventional neuroleptics, Wahlbeck, Cheine, Essali, and Adams (1999) observed a clinical advantage for clozapine, and even that patients were more satisfied with their treatment, but noted, “there was no evidence that the superior clinical effect of clozapine is reflected in levels of functioning; on the other hand, global functioning and pragmatic outcomes were frequently not reported” (p. 990).

12) Failure to Consider the Impact of Abrupt Drug Withdrawal

13) Failure To Distinguish Between “Relapse” and “Withdrawal-Induced Psychosis

Closely related to the previous point, this issue has been raised explicitly by Cohen (2001). Withdrawal or discontinuation syndromes should normally be expected whenever drugs that significantly alter brain function—and trigger changes in neurochemistry as the brain adapts to this alteration—are abruptly withdrawn. Besides obvious motor disorders, discontinuation syndromes have been outlined since the 1960s in studies of neuroleptic treatment of psychotic, non-psychotic, and non-psychiatric conditions. Nevertheless, systematic investigation of withdrawal syndromes has been thoroughly neglected (Breggin & Cohen, 2000; Tranter & Healy, 1998). Syndromes following lithium, antidepressant, and benzodiazepine withdrawal have been recognized as true withdrawal effects that often frankly mimic the symptoms for which the drug was originally prescribed (Goodwin, 1994; Schatzberg et al., 1997). Do observed reactions following drug withdrawal constitute a reemergence of psychiatric symptoms indicating the need for continued treatment, or “discontinuation-associated iatrogenic risk” (Suppes, Baldessarini, Faedda, Tondo, & Tohen, 1993, p. 131) indicating the need for less abrupt withdrawal?

Since Ekblom, Eriksson, and Lindstrom's (1984) early description of two cases of rapid-onset (24-48 hours), very pronounced psychosis following abrupt clozapine withdrawal, several virtually identical reports of rapid-onset, “supersensitivity” withdrawal psychosis with serious deterioration have been published—especially involving atypical neuroleptics and quick disappearance of symptoms upon reinstituting the drug (e.g., Berecz et al., 2000; Durst, Teitelbaum, Katz, & Knobler, 1999; Llorca, Vaiva, & Lancon, 2001). In one RCT, Tollefson and colleagues (1999) observed 25% of patients abruptly withdrawn from clozapine and switched to placebo for only three to five days develop the following “core symptoms”: “delusions, hallucinations, hostility, and paranoid reactions” (p. 435).

Given the above lines of evidence, it is legitimate to wonder how rapid-onset psychoses following neuroleptic withdrawal or cessation might be defined in numerous research projects, not to mention ordinary clinical settings. This author believes that these psychoses are called “relapses,” are attributed to patients' psychiatric conditions, and are seen as confirmation that neuroleptics are “effective” and that their use must continue indefinitely. Do these psychoses point to neuroleptics' effectiveness or neuroleptics' toxicity? We will not know until researchers decide to test the sound hypothesis that they are true withdrawal syndromes which would abate with gradual taper (Cohen, 2001).

14) Failure to Conduct Systematic Studies of Gradual, Patient-Centered and Patient-Directed Drug Withdrawal

Although theoretical, clinical, practical, and ethical justifications for discontinuing or withdrawing neuroleptic drug treatment abound, and although the issue of withdrawal has enormous importance for consumers, rational drug withdrawal may be the least studied topic in clinical psychopharmacology and the one about which clinicians are most ignorant (Breggin & Cohen, 2000). In a 9-line algorithm for “treatment-refractory schizophrenia,” trying a drug-free period is relegated to lines 8 and 9, after augmentation strategies (adding drugs such as lithium), “very high doses” of neuroleptics, electroconvulsive therapy, and the use of “investigational compounds” (Koshino, 1999).

There are many ways to conduct a study to investigate the potential advantages of neuroleptic withdrawal and substitution with non-drug supports. For example, one might select patients (and families) who strongly desire it, educate them about effects to anticipate, help them set up peer and professional support networks, proceed with a very gradual taper (e.g., approximately 10% of the dose reduced every month or two) and adjust its speed based on patients' regular feedback, introduce flexible psychosocial supports (in the form of a personal assistant as proposed by the independent living movement for disabled persons, for example), complement with changes in nutrition and exercise, rehearse cognitive and behavioral strategies for symptom reduction, and avoid major social, vocational, and residential changes during the first few months of the program (as the risk of relapse following drug withdrawal seems non-linearly distributed, with excess risk mostly occurring during the first 12 weeks). (See Breggin & Cohen, 2000.) Despite the hundreds of different interventions that have been tested for schizophrenia, this author is not aware of a single such study in nearly 50 years of neuroleptic therapy. However, a few studies even falling far short of this ideal have yielded positive results (e.g., Liberman et al., 1994). Also, the passage of the Nursing Home Reform Act (part of the Omnibus Bill Reconciliation Act of 1987, or PL 100-203) mandated yearly reviews of the drug regimens of institutionalized dependents in nursing homes and in institutions for the developmentally disabled as a condition of continued federal funding. As a result, systematic neuroleptic dose reductions or withdrawals have been conducted in many establishments. To date, published evaluations of such withdrawal programs have been consistently positive (e.g., Thapa, Meador, Gideon, Fought, & Ray, 1994).

15) Failure to Study and Report Polypharmacy

Treatment of schizophrenic patients with a single drug is the exception rather than the rule. In Western countries, these patients often simultaneously receive more than one neuroleptic as well as various other central nervous system depressants such as benzodiazepines, lithium, anticonvulsants, and antiparkinsonians (Fourrier et al., 2000; Tognoni, 1999). With the advent of managed care in the United States, pressures to decrease length of hospital stay are correlated with increases in the number of patients receiving drugs and in the number of drugs prescribed during an acute hospitalization (Baldessarini, Kando, & Centorinno, 1995). Polypharmacy was previously declared irrational but the arrival of new antipsychotics has provided fresh justifications for the practice (Canales, Olsen, Miller, & Crismon, 1999). Barely understood but clinically significant interactions occur with all agents commonly used in conjunction with neuroleptics (Zumbrunnen & Jann, 1998). Furthermore, most schizophrenic patients smoke heavily, and nicotine is known to decrease blood levels of many neuroleptics (Kelly & McCreadie, 1999). The portrait is further complicated by occasional findings that benzodiazepines are comparable in effectiveness to conventional neuroleptics in the 4-week symptomatic treatment of psychosis (Carpenter, Buchanan, Kirkpatrick, & Breier, 1999).

Despite the preceding points, published systematic evaluations of polydrug regimens are virtually nonexistent. Yet, given the complex chemical cocktails patients routinely ingest, often for years, it may be illusory to attribute any perceived benefits to one particular class of drugs in the cocktail. Furthermore, given that a small proportion of schizophrenic patients—probably less than one fifth—take only a single drug, it is irresponsible to justify the long-term polydrug treatment of schizophrenia by means of studies investigating the relatively short-term administration of a single drug.