[SSRI-Research] Robert Whitaker: The case against antipsychotic drugs: a 50-year record of doing more harm than good

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[sSRI-Research] Robert Whitaker: The case against antipsychotic drugs:

a 50-year record of doing more harm than good

 

The case against antipsychotic drugs: a 50-year record of doing more harm than

good

 

Robert Whitaker*

19 Rockingham St., Cambridge, MA 02139, USA

 

Mad in America: Bad Science, Bad Medicine, and the Enduring Mistreatment of the

Mentally Ill (Perseus Publishing, 2002).

* Tel.: +617-499-4354.

 

E-mail address: robert.b.whitaker (R. Whitaker).

0306-9877/$ - see front matter _c 2003 Elsevier Ltd. All rights reserved.

doi:10.1016/S0306-9877(03)00293-7

 

Summary:

 

Although the standard of care in developed countries is to maintain

schizophrenia patients on neuroleptics, this practice is not supported by the

50-year research record for the drugs. A critical review reveals that this

paradigm of care worsens long-term outcomes, at least in the aggregate, and that

40% or more of all schizophrenia patients would fare better if they were not so

medicated. Evidence-based care would require the selective use of

antipsychotics, based on two principles: (a) no immediate neuroleptisation of

first-episode patients; (b) every patient stabilized on neuroleptics should be

given an opportunity to gradually withdraw from them. This model would

dramatically increase recovery rates and decrease the percentage of patients who

become chronically ill.

_c 2003 Elsevier Ltd. All rights reserved.

 

Introduction

The standard of care for schizophrenia calls for patients to be maintained

indefinitely on antipsychotic drugs. The evidence for this practice comes from

research showing the drugs are effective in treating acute psychotic symptoms

and in preventing relapse [1,2]. Historians also argue that the introduction of

neuroleptics in the 1950s made it possible to empty the mental hospitals, and

that this is further proof of the drugs' merits [3]. Yet, long-term outcomes

with schizophrenia remain poor, and may be no better than they were 100 years

ago, when water therapies and fresh air were the treatment of the day [4-7].

 

There is an evident paradox in the research record.The efficacy of neuroleptics

appears to be well established, yet there is a lack of evidence showing that

these drugs have improved patients' lives over the long-term. That paradox

recently stirred an unusual editorial in Eur. Psychiatry, which posed this

question: " After fifty years of neuroleptic drugs, are we able to answer the

following simple question: Are neuroleptics effective in treating

schizophrenia? " [8] A close review of the research literature provides a

surprising answer.

 

The preponderance of evidence shows that the current standard of care -

continual medication therapy for all patients so diagnosed - does more harm than

good.

 

Did neuroleptics enable deinstutionalization?

 

The belief that the introduction of chlorpromazine,marketed in the US as

Thorazine, made it possible to empty state hospitals stems from research by

Brill and Patton. In the early 1960s, they reported that the patient census at

state mental hospitals in the US declined from 558,600 in 1955 to 528,800 in

1961. Although they did not compare discharge rates for drug-treated versus

placebo-treated patients, they nevertheless concluded that neuroleptics must

have played a role in the decline since it coincided with their introduction.

The fact that the two occurred at the same time was seen as the proof [9,10].

 

However, there were obvious confounding factors. In the early 1950s, the

Council of State Governments in the US urged the federal government to share the

fiscal burden of caring for the mentally ill, and proposed that " out-patient

clinics should be extended and other community resources developed to care for

persons in need of help, but not of hospitalization " [11, 12]. As part of this

agenda, states began developing community care initiatives, funneling the

mentally ill into nursing homes and halfway houses. This change in social policy

could easily have been responsible for the slight drop in patient numbers

observed by Brill and Patton.

 

Moreover, there was one state that did compare discharge rates for schizophrenia

patients treated with and without drugs, and its results do not support the

historical claim made for neuroleptics. In a study of 1413 first-episode male

schizophrenics admitted to California hospitals in 1956 and 1957, researchers

found that " drug-treated patients tend to have longer periods of

hospitalization... furthermore, the hospitals wherein a higher percentage of

first admission schizophrenic patients are treated with these drugs tend to have

somewhat higher retention rates for this group as a whole " . In short, the

California investigators determined that neuroleptics, rather than speed

patients' return to the community, apparently hindered recovery [13].

 

The true period of deinstitutionalization in the US was from 1963 to the late

1970s, the exodus of patients driven by social and fiscal policies. In 1963,

federal government began picking up some of the costs of care for the mentally

ill not in state institutions, and two years later, Medicare and Medicaid

legislation increased federal funding for care of mental patients provided they

were not housed in state hospitals. Naturally, states responded by discharging

their hospital patients to private nursing homes and shelters. In 1972, an

amendment to the Social Security act authorized disability payments to the

mentally ill, which accelerated the transfer of hospitalized patients into

private facilities. As a result of these changes in fiscal policies, the number

of patients in state mental hospitals dropped from 504,600 to 153,544 over a

15-year period (1963-1978) [14].

 

Establishing efficacy: The pivotal NIMH trial

 

The study that is still cited today as proving the efficacy of neuroleptics for

curbing acute episodes of schizophrenia was a nine-hospital trial of 344

patients conducted by the National Institute of Mental Health in the early

1960s. At the end of six weeks, 75% of the drug-treated patients were " much

improved " or " very much improved " compared to 23% of the placebo patients. The

researchers concluded that neuroleptics should no longer be considered mere

" tranquilizers " but " antischizophrenic " agents. A magic bullet had apparently

been found for this devastating disorder [1].

 

However, three years later, the NIMH researchers reported on one-year outcomes

for the patients. Much to their surprise, they found that " patients who

received placebo treatment were less likely to be rehospitalized than those who

received any of the three active phenothiazines " [15]. This result raised an

unsettling possibility: While the drugs were effective over the short-term,

perhaps they made people more biologically vulnerable to psychosis over the long

run, and thus the higher rehospitalization rates at the end of one year.

 

The NIMH withdrawal studies

 

In the wake of that disturbing report, the NIMH conducted two

medication-withdrawal studies. In each one, relapse rates rose in correlation

with neuroleptic dosage before withdrawal. In the two trials, only 7% of

patients who were on placebo relapsed during the following six months. Twenty

three percent of the patients on less than 300 mg of chlorpromazine daily

relapsed following drug withdrawal; this rate climbed to 54% for those receiving

300-500 mg and to 65% for patients taking more than 500 mg. The researchers

concluded: " Relapse was found to be significantly related to the dose of the

tranquilizing medication the patient was receiving before he was put on placebo

- the higher the dose, the greater the probability of relapse " [16].

 

Once more, the results suggested that neuroleptics increased the patients'

biological vulnerability to psychosis. Other reports soon deepened this

suspicion. Even when patients reliably took their medications, relapse was

common, and researchers reported in 1976 that it appeared that " relapse during

drug administration is greater in severity than when no drugs are given " [17]. A

retrospective study by Bockoven also indicated that the drugs were making

patients chronically ill. He reported that 45% of patients treated at Boston

Psychopathic Hospital in 1947 with a progressive model of care did not relapse

in the five years following discharge, and that 76% were successfully living in

the community at the end of that follow-up period. In contrast, only 31% of

patients treated in 1967 with neuroleptics at a community health center remained

relapse-free over the next five years, and as a group they were much more

" socially dependent " - on welfare and the relapse studies are cited to

support a paradigm of care that emphasizes continual drug therapy for

schizophrenia patients. But upon closer examination, a new picture emerges. The

real world first-year relapse rate for patients maintained on neuroleptics is

understood to be 40%, while the rate for patients gradually withdrawn from the

drugs is 33%. Thus, once bad trial design is eliminated, the evidence for

continual medication disappears. At the same time, evidence appears showing that

a majority of patients - two-thirds in the gradual withdrawal studies - can do

fairly well without the drugs.

 

Doing more harm than good

 

Although this review of neuroleptics may seem surprising, the research record

actually is quite neutral. Instead, the research record shows harm done, and the

record is consistent across nearly 50 years of research. [see " Timeline to

Failure " in Appendix A.]

 

A better model: the selective use of neuroleptics

 

At the very least, this history argues that the best model of care would involve

selective use of neuroleptics. The goal would be to minimize their use. Several

investigators in Europe have developed programs based on that goal, and in every

instance they have reported good results. In Switzerland, Ciompi established a

house modeled on Mosher's Soteria Project, and in 1992 he concluded that

first-episode patients treated with no or very low doses of medication

" demonstrated needing other forms of support - than those in the 1947 cohort

[18].

 

Drug treatment versus experimental forms of care

 

With debate over the merits of neuroleptics rising, the NIMH revisited the

question of whether newly admitted schizophrenia patients could be successfully

treated without drugs. There were three NIMH-funded studies conducted during the

1970s that examined this possibility, and in each instance, the newly admitted

patients treated without drugs did better than those treated in a conventional

manner.1

 

In 1977, Carpenter reported that only 35% of the nonmedicated patients in his

study relapsed within a year after discharge, compared to 45% of those treated

with neuroleptics. The non-medicated patients also suffered less from

depression, blunted emotions, and retarded movements [20]. A year later,

Rappaport et al. [21] reported that in a trial of 80 young male schizophrenics

admitted to a state hospital, only 27% of patients treated without neuroleptics

relapsed in the three years following discharge, compared to 62% of the

medicated group. The final study came from Mosher, head of schizophrenia

research at the NIMH. In 1979, he reported that patients who were treated

without neuroleptics in an experimental home staffed by nonprofessionals had

lower relapse rates over a two-year period than a control group treated with

drugs in a hospital. As in the other studies, Mosher reported that the patients

treated without drugs were the better functioning group as well [22, 23].

 

The three studies all pointed to the same conclusion: Exposure to neuroleptics

increased the long-term incidence of relapse. Carpenter's group defined the

conundrum - There is no question that, once patients are placed on medication,

they are less vulnerable to relapse if maintained on neuroleptics. But what if

these patients had never been treated with drugs to begin with? We raise the

possibility that antipsychotic medication may make some schizophrenic patients

more vulnerable to future relapse than would be the case in the natural course

of the illness [20]. In the late 1970s, two physicians at McGill University in

Montreal, Guy Chouinard and Barry Jones, offered a biological explanation for

why this was so. The brain responds to neuroleptics - which block 70-90% of all

D2 dopamine receptors in the brain - as though they are a pathological insult.

To compensate, dopaminergic brain cells increase the density of their D2

receptors by 30% or more. The brain is now " supersensitive "

to dopamine, and this neurotransmitter is thought to be a mediator of

psychosis. The person has become more biologically vulnerable to psychosis and

is at particularly high risk of severe relapse should he or she abruptly quit

taking the drugs. The two Canadian researchers concluded: Neuroleptics can

produce a dopamine supersensitivity that leads to both dyskinetic and psychotic

symptoms. An implication is that the tendency toward psychotic relapse in a

patient who has developed such a supersensitivity is determined by more than

just the normal course of the illness. . . the need for continued neuroleptic

treatment may itself be drug induced [24,25]. Together, the various studies

painted a compelling picture of how neuroleptics shifted outcomes away from

recovery. Bockoven's retrospective and the other experiments all suggested that

with minimal or no exposure to neuroleptics, at least 40% of people who suffered

a psychotic break and were diagnosed with schizophrenia would not

relapse after leaving the hospital, and perhaps as many as 65% would function

fairly well over the long-term. However, once first-episode patients were

treated with neuroleptics, a different fate awaited them. Their brains would

undergo drug-induced changes that would increase their biological vulnerability

to psychosis, and this would increase the likelihood that they would become

chronically ill.

 

The world health organization studies

 

In 1969, the World Health Organization initiated a study to compare outcomes for

schizophrenia in " developed " countries with outcomes in " undeveloped " countries.

Once again, the results were surprising. Patients in the three poor countries -

India, Nigeria and Colombia - were doing dramatically

______________________________

 

1 In the early 1960s, May conducted a study that compared five forms of

treatment: drug, ECT, psychotherapy, psychotherapy plus drug, and mileu therapy.

Over the short-term, the drug-treated patients did best. As a result, it came to

be cited as proof that schizophrenia patients could not be treated with

psychotherapy. However, the long-term results told a more nuanced story.

Fifty-nine percent of patients initially treated with mileu therapy but no drugs

were successfully discharged in the initial study period, and this group

" functioned over the follow-up (period) at least as well, if not better, than

the successes from the other treatments " . Thus, the May study suggested that a

majority of first-episode patients would fare best over the long-term if

initially treated with " mileu therapy " rather than drugs [19].

______________________________

 

better at two-year and five-year follow-ups than patients in the US and four

other developed countries. They were more likely to be fully recovered and

faring well in society - " an exceptionally good social outcome characterized

these patients " , the WHO researchers wrote - and only a small minority had

become chronically sick. At five years, about 64% of the patients in the poor

countries were asymptomatic and functioning well. In contrast only 18% of

patients in the rich countries were in this best-outcomes category. The

difference in outcomes was such that the WHO researchers concluded living in a

developed nation was a " strong predictor " that a schizophrenic patient would

never fully recover [26]. These findings naturally stung psychiatrists in the US

and other rich countries. Faced with such dismal results, many argued the WHO

study was flawed and that a number of the patients in the poor countries must

not have been schizophrenic but ill with a milder form of psychosis. With

that criticism in mind, the WHO conducted a study that compared two-year

outcomes in 10 countries, and it focused on first-episode schizophrenics all

diagnosed by Western criteria. The results were the same. " The findings of a

better outcome of patients in developing countries was confirmed " , the WHO

investigators wrote. In the poor countries, 63% of schizophrenics had good

outcomes. Only slightly more than one-third became chronically ill. In the rich

countries, the ratio of good-to-bad outcomes was almost precisely the reverse.

Only 37% had good outcomes, and the remaining patients did not fare so well

[27]. The WHO investigators did not identify a cause for the stark disparity in

outcomes. However, they did note there was a difference in the medical care that

was provided. Doctors in the poor countries generally did not keep their

patients on neuroleptics, while doctors in the rich countries did. In the poor

countries, only 16% of the patients were maintained on neuroleptics. In

the developed countries, 61% of the patients were kept on such drugs. Once

again, the research record told the same story. In the WHO studies, there was a

correlation between use of the medications on a continual basis and poor

long-term outcomes.

 

MRI studies

 

While most researchers have used MRIs to investigate possible causes of

schizophrenia, a small number have employed this technology to study the effects

of neuroleptics on the brain. These investigators have found that the drugs

cause atrophy of the cerebral cortex and an enlargement of the basal ganglia

[28-30]. Moreover, researchers at the University of Pennsylvania reported in

1998 that the drug-induced enlargement of the basal ganglia is " associated with

greater severity of both negative and positive symptoms " [31]. In other words,

they found that the drugs cause changes in the brain associated with a worsening

of the very symptoms the drugs are supposed to alleviate.

 

Relapse studies

 

As discussed earlier, evidence for the efficacy of neuroleptics is stated to be

two-fold. First, the NIMH trial in the 1960s found that neuroleptics are more

effective than placebo in curbing acute episodes of psychosis. Second, the drugs

have been shown to prevent relapse. In 1995, Gilbert reviewed 66 relapse

studies, involving 4365 patients, and summed up the collective evidence: Fifty

three percent of patients withdrawn from neuroleptics relapsed within 10 months,

versus 16% of those maintained on the drugs. " The efficacy of these medications

in reducing the risk of psychotic relapse has been well documented, " she wrote

[2]. At first glance, this conclusion seems to contradict the research showing

that the drugs made patients chronically ill. There is an answer to this puzzle

however, and it is a revealing one. The studies by Rappaport, Mosher and

Carpenter involved patients who, at the start of the experiment, were not on

neuroleptics but were then treated either with placebo or

a neuroleptic. And in those studies, relapse rates were lower for the placebo

group. In contrast, the 66 studies reviewed by Gilbert were drug-withdrawal

studies. In the studies she analyzed, patients who had been stabilized on

neuroleptics were divided into two cohorts: One would keep on taking the drugs

and the other would not, and the studies reliably found

that people withdrawn from their neuroleptics were more likely to become sick

again.

 

Thus, the literature suggests that relapse rates fall into three groups: lowest

for those not placed on neuroleptics in the first place, higher for those who

take the drugs continuously, and highest of all for those withdrawn from the

drugs. Yet even that picture is misleading. First, for the most part, the

drug-withdrawal studies were conducted in a select group of " good responders " to

neuroleptics, rather than in the general patient population. In the real world,

up to 30% of hospitalized patients do not respond to neuroleptics. Among those

who do and are discharged, more than one-third relapse within the next 12 months

and need to be rehospitalized, even though they reliably take their medications.

Thus, fewer than 50% of people who suffer a schizophrenic break respond to

standard neuroleptics and remain relapse-free for as long as a year, but the

relapse studies, to a large degree, were conducted in this group of good

responders.

 

In 1998, Hogarty pointed out how this study design led to a mistaken

understanding of true relapse rates with antipsychotics: " A reappraisal of the

literature suggests a one-year, post-hospital, relapse rate of 40% on

medication, and a substantially higher rate among patients who live in stressful

environments, rather than earlier estimates of 16% " [32]. At the same time, the

relapse studies were designed in ways that exaggerated the risk of relapse in

the drug-withdrawn groups. In response to Gilbert, Baldessarini analyzed the

same 66 studies, only he divided the drug-withdrawn cohort into

" abrupt-withdrawal " and " gradual-withdrawal " groups. He determined that the

relapse rate in the abruptly withdrawn group was three times higher than in the

gradual group [33]. In other words, it was the abrupt cessation that caused much

of the excess relapse risk. Indeed, in a further review of the relapse

literature, Baldessarini found that only one-third of schizophrenia patients

gradually

withdrawn from their drugs relapsed within six months and that those who

reached this six-month point without become sick again had a good chance of

remaining well indefinitely. " The later risk of relapsing was remarkably

limited, " he concluded [34].

 

The relapse studies are cited to support a paradigm of care that emphasizes

continual drug therapy for schizophrenia patients. But upon closer examination,

a new picture emerges. The real world first-year relapse rate for patients

maintained on neuroleptics is understood to be 40%, while the rate for patients

gradually withdrawn from the drugs is 33%. Thus, once bad trial design is

eliminated, the evidence for continual medication disappears. At the same time,

evidence appears showing that a majority of patients - two-thirds in the gradual

withdrawal studies - can do fairly well without the drugs.

 

Doing more harm than good

 

Although this review of neuroleptics may seem surprising, the research record

actually is quite consistent. The pivotal NIMH study in the early 1960s found

that the drugs had a short-term benefit, but that over the long-term the

drug-treated patients had higher relapse rates. Similarly, in his retrospective

study, Bockoven found that patients treated with neuroleptics were more likely

to become chronically ill. The experiments by Carpenter, Mosher, and Rappaport

all showed higher relapse rates for drug-treated patients, and in 1979, Canadian

investigators put together a biological explanation for why this would be so.

 

The World Health Organization reported higher recovery rates in poor countries

where patients were not regularly maintained on the drugs. Finally, the MRI

studies by investigators at the University of Pennsylvania confirmed the problem

of drug-induced chronicity in a compelling way. The drug treatment caused a

pathological change in the brain associated with a worsening of symptoms - that

is a convincing example of cause and effect.

 

Thus, there is a preponderance of evidence showing that standard neuroleptics,

over the long-term, increase the likelihood that a person will become

chronically ill. This outcome is particularly problematic when one considers

that the drugs also cause a wide range of troubling side effects, including

neuroleptic malignant syndrome, Parkinsonian symptoms, and tardive dyskinesia.

Patients maintained on standard neuroleptics also have to worry about blindness,

fatal blood clots, heat stroke, swollen breasts, leaking breasts, impotence,

obesity, sexual dysfunction, blood disorders, painful skin rashes, seizures,

diabetes, and early death[35-40]. Once all these factors are considered, it is

hard to conclude that standard neuroleptics are therapeutically neutral.

Instead, the research record shows harm done, and the record is consistent

across nearly 50 years of research. [see " Timeline to Failure " in Appendix A.]

 

A better model, the selective use of neuroleptics

 

At the very least, this history argues that the best model of care would involve

selective use of neuroleptics. The goal would be to minimize their use. Several

investigators in Europe have developed programs based on that goal, and in every

instance they have reported good results. In Switzerland, Ciompi established a

house modeled on Mosher's Soteria Project, and in 1992 he concluded that

first-episode patients treated with no or very low doses of medication

" demonstrated significantly better results " than patients treated conventionally

[41]. In Sweden, Cullberg reported that 55% of first-episode patients treated in

an experimental program were successfully off neuroleptics at the end of three

years, and the others were being maintained on extremely low doses of

chlorpromazine. Moreover, patients treated in this manner spent fewer days in

the hospital than conventionally treated patients during the follow-up period

[42,43]. Lehtinen and his colleagues in Finland now have five-year

results from a study that involved treating first-episode patients without

neuroleptics for the initial three weeks and then initiating drug treatment only

when " absolutely necessary " . At the end of five years, 37% of the experimental

group had never been exposed to neuroleptics, and 88% had never been

rehospitalized during the two-to-five-year follow-up period [44,45].

 

Those results are much better than any achieved in the US following the standard

model of continual medication. Indeed, in his meta-analysis of such experimental

studies, John Bola at the University of Southern California concluded that most

" show better long-term outcomes for the un-medicated subjects " [23].

 

The atypicals: dawn of a new era?

 

Admittedly, the record of poor long-term results reviewed here was produced by

standard neuroleptics. The poor outcomes may also reflect prescribing practices

in the US that, until the late 1980s, involved putting patients on high dosages.

The long-term research record for clozapine and other atypicals like risperidone

and olanzapine has yet to be written. One hopes that these newer drugs will

lead to better outcomes, but there are reasons to be skeptical. As is now

widely acknowledged, the clinical trials of the atypicals were biased by design

against the old ones, and thus there is no compelling evidence that the new ones

are truly better [46]. While the risk of tardive dyskinesia may be reduced with

the atypicals, they bring their own set of new problems, such as an increased

risk of obesity, hyperglycemia, diabetes, and pancreatitis [47-49].

 

Together, these side effects raise the concern that the atypicals regularly

induce metabolic dysfunction of some kind, and thus their long-term use will

lead to early death. The atypicals also have been shown to cause an increase in

D2 receptors, just like the old ones do, and that is believed to be the

mechanism that makes medicated patients more biologically vulnerable to

psychosis [50].

 

Summary

 

The history of medicine is replete with examples of therapies that were eagerly

embraced for a period and then later discarded as harmful. A scientific

examination of the evidence is supposed to save us from such folly today. And

science has in fact provided research data to guide prescribing practices. The

evidence consistently reveals that maintaining all schizophrenia patients on

antipsychotics produces poor long-term outcomes, and that there is a large group

of patients - at least 40% of all people so diagnosed - who would do better if

they were never exposed to neuroleptics, or, in the alternative, were encouraged

to gradually withdraw from the drugs. (The percentage of patients diagnosed with

schizoaffective disorder, or some milder form of psychosis, that could do well

without the drugs is undoubtedly much higher.) This conclusion is not a new one,

either. Nearly 25 years ago, Jonathan Cole, one of the pioneering figures in

psychopharmacology, published a paper provocatively

titled " Maintenance Antipsychotic Therapy: Is the Cure Worse than the Disease? "

After reviewing the research data, he concluded that " an attempt should be made

to determine the feasibility of drug discontinuance in every patient " [17].

 

The evidence supported a standard of care that involved gradual withdrawal. The

research record of neuroleptics since that time - most notably the WHO studies

and the MRI study by investigators at the University of Pennsylvania - confirms

the wisdom of his advice.

 

Indeed, Harding's long-term study shows that gradual withdrawal is an essential

step on the path to full recovery. She found that one-third of the schizophrenia

patients on the back wards of a Vermont state hospital in the 1950s were

completely recovered thirty years later, and that this group shared one

characteristic: all had long since stopped taking neuroleptics [51]. She

concluded that it was a " myth " that patients must be on medication all their

lives, and that in " reality it may be a small percentage who need medication

indefinitely " [52].

 

Yet, in spite of all this evidence, today there is almost no discussion within

psychiatry of adopting practices that would involve using neuroleptics in a

selective manner, and that would integrate gradual withdrawal into the standard

of care. Instead, psychiatry is moving in the opposite direction and prescribing

antipsychotics to an ever larger patient population, including those said simply

to be " at risk " of developing schizophrenia. While this expansion of the use of

antipsychotics serves obvious financial interests, it is treatment that is

certain to harm many.

 

Appendix A

 

A timeline for neuroleptics.

 

Preclinical

 

1883 Phenothiazines developed as synthetic dyes.

1934 USDA develops phenothiazines as insecticide.

1949 Phenothiazines shown to hinder rope-climbing abilities in rats.

1950 Rhone Poulenc synthesizes chlorpromazine, a phenothiazine, for use as an

anesthetic.

 

Clinical history/standard neuroleptics

 

1954 Chlorpromazine, marketed in the US as Thorazine, found to induce symptoms

of Parkinson's disease.

1955 Chlorpromazine said to induce symptoms similar to encephalitis lethargica.

1959 First reports of permanent motor dysfunction linked to neuroleptics, later

named tardive dyskinesia.

1960 French physicians describe a potentially fatal toxic reaction to

neuroleptics, later named neuroleptic malignant syndrome.

1962 California Mental Hygiene Department determines that chlorpromazine and

other neuroleptics prolong hospitalization.

1963 Six-week NIMH collaborative study concludes that neuroleptics are safe and

effective " antischizophrenic " drugs.

1964 Neuroleptics found to impair learning in animals and humans.

1965 One-year followup of NIMH collaborative study finds drug-treated patients

more likely than placebo patients to be rehospitalized.

1968 In a drug withdrawal study, the NIMH finds that relapse rates rise in

direct relation to dosage. The higher the dosage that patients are on before

withdrawal, the higher the relapse rate.

1972 Tardive dyskinesia is said to resemble Huntington's disease, or

" postencephalitic brain damage " .

1974 Boston researchers report that relapse rates were lower in pre-neuroleptic

era, and that drug-treated patients are more likely to be socially dependent.

1977 A NIMH study that randomizes schizophrenia patients into drug and non-drug

arms reports that only 35% of the non-medicated patients relapsed within a year

after discharge, compared to 45% of those treated with medication.

1978 California investigator Maurice Rappaport reports markedly superior

three-year outcomes for patients treated without neuroleptics. Only 27% of the

drug-free patients relapsed in the three years following discharge, compared to

62% of the medicated patients.

1978 Canadian researchers describe drug-induced changes in the brain that make a

patient more vulnerable to relapse, which they dub " neuroleptic induced

supersensitive psychosis " .

1978 Neuroleptics found to cause 10% cellular loss in brains of rats.

1979 Prevalence of tardive dyskinesia in drug-treated patients is reported to

range from 24% to 56%.

1979 Tardive dyskinesia found to be associated with cognitive impairment.

1979 Loren Mosher, chief of schizophrenia studies at the NIMH, reports superior

one-year and two-year outcomes for Soteria patients treated without

neuroleptics.

1980 NIMH researchers find an increase in " blunted effect " and " emotional

withdrawal " in drug-treated patients who don't relapse, and that neuroleptics do

not improve " social and role performance " in non-relapsers.

1982 Anticholinergic medications used to treat Parkinsonian symptoms induced by

neuroleptics reported to cause cognitive impairment.

1985 Drug-induced akathisia is linked to suicide.

1985 Case reports link drug-induced akathisia to violent homicides.

1987 Tardive dyskinesia is linked to worsening of negative symptoms, gait

difficulties, speech impairment, psychosocial deterioration, and memory

deficits. They conclude it may be both a " motor and dementing disorder " .

 

Clinical history/standard neuroleptics

 

1992 World Health Organization reports that schizophrenia outcomes are much

superior in poor countries, where only 16% of patients are kept continuously on

neuroleptics. The WHO concludes that living in a developed nation is a " strong

predictor " that a patient will never fully recover.

 

1992 Researchers acknowledge that neuroleptics cause a recognizable pathology,

which they name neuroleptic induced deficit syndrome. In addition to

Parkinson's, akathisia, blunted emotions and tardive dyskinesia, patients

treated with neuroleptics suffer from an increased incidence of blindness, fatal

blood clots, arrhythmia, heat stroke, swollen breasts, leaking breasts,

impotence, obesity, sexual dysfunction, blood disorders, skin rashes, seizures,

and early death.

 

1994 Neuroleptics found to cause an increase in the volume of the caudate region

in the brain.

 

1994 Harvard investigators report that schizophrenia outcomes in the US appear

to have worsened over past 20 years, and are now no better than in first decades

of 20th century.

 

1995 " Real world " relapse rates for schizophrenia patients treated with

neuroleptics said to be above 80% in the two years following hospital

discharge, which is much higher than in pre-neuroleptic era.

 

1995 " Quality of life " in drug-treated patients reported to be " very poor " .

 

1998 MRI studies show that neuroleptics cause hypertrophy of the caudate,

putamen and thalamus, with the increase " associated with greater severity of

both negative and positive symptoms " .

 

1998 Neuroleptic use is found to be associated with atrophy of cerebral cortex.

 

1998 Harvard researchers conclude that " oxidative stress " may be the process by

which neuroleptics cause neuronal damage in the brain.

 

1998 Treatment with two or more neuroleptics is found to increase risk of early

death.

 

2000 Neuroleptics linked to fatal blood clots.

 

2003 Atypicals linked to an increased risk of obesity, hyperglycemia, diabetes,

and pancreatitis.

 

 

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