Superior Index Go to the next: Chapter 3
Print Files: A4 Size.
In 2006, the so-called atypical or newer neuroleptics increased their dominance over the $11.5 billion business for antipsychotic drugs. As a group, the antipsychotics placed fourth in sales among all categories of drugs, including anticholesterol, antihypertension, and antidepressant drugs. That such specialized drugs for the treatment of psychosis and mania could garner such a huge market share is a tribute to drug company promotional skills in convincing doctors to use these medications for a wide swath of psychiatric problems, from behavior problems in children to insomnia in adults. Antipsychotic drug sales have nearly doubled since 2002.
Individual antipsychotic drugs earned the following market shares: Seroquel (26%), Risperdal (22%), Zyprexa (21%), Abilify (17%), and Geodon (6%), leaving a mere 8% for others (Vital Signs, 2007). According to IMS Health (2007), Seroquel was ninth among all drugs in sales in the United States in 2006, with total revenues of $3 billion.
In the United States, Seroquel has the growing market advantage of being approved not only to treat mania but also to treat the depression phase of bipolar disorder. It is expected to generate $1.76 billion from "global bipolar disorder sales" in 2008 ("New Hope," 2006). Meanwhile, the rest of the world has not quite caught on to the Seroquel promotional campaign, and Zyprexa and Risperdalled global sales for antipsychotic drugs, with $4.7 billion and $4.6 billion in sales, respectively (IMS Health, 2007 [648]). They were seventh and eighth among all medical drugs.
Despite enormous hype to the contrary, it soon became apparent that these newer medications were no less harmful than the older ones. Studies showing a lower rate of adverse effects simply used comparatively lower doses (Smith, 2001 [1193]). Given that these drugs are neither safer nor more effective than older drugs like perphenazine (Trilafon; see the subsequent sections), and given that they cost a great deal more (Rosenheck et al., 2006 [1106]), this was another triumph of pharmaceutical marketing.
More than a dozen drugs, almost all of them in use for many years, can be classified as neuroleptics. The phenothiazine derivatives were originally the most commonly used class of neuroleptic drugs. Chlorpromazine is the prototype, developed in France and introduced into North America in 1953 by Heinz Lehmann. Its brand name in Canada and England is Largactil, and in the United States, Thorazine. The antidepressant amoxapine (Asendin) is metabolized into a neuroleptic and has similar effects and, more important, adverse effects, such as tardive dyskinesia. All the classic neuroleptics block dopamine, but all of them also affect other neurotransmitter systems.
Most important, all of the newer antipsychotics-aripiprazole (Abilify), ziprasidone (Geodon), paliperidone (Invega), risperidone (Risperdal), quetiapine (Seroquel), olanzapine plus Prozac (Symbyax), and olanzapine (Zyprexa) - also block dopamine. In fact, they are pharmacologically classified as having a high affinity for D2 - meaning that they bind strongly to D2 receptors, causing a strong blockade. The casual reader can find this information in Drug Facts and Comparisons (2007, p. 1280 [379]) and its table "Antipsychotic Receptor Affinity"7 (see also Janssen, 2007 [669], regarding Risperdal).
In addition to textbook summaries, many controlled research studies show that atypicals produce high receptor occupancy. Shortly after olanzapine was introduced, Kapur et al. (1998) [738] used positron emission topography (PET) imaging with 12 patients diagnosed schizophrenic to determine D2 receptor occupancy caused by the new atypical antipsychotic at clinical doses. The patients were medicated until steady state plasma levels were achieved. Patients taking 5-20 mg/day showed 43% to 80% occupancy, while patients taking 30-40 mg/day showed 83% to 88% occupancy. In its usual clinical dose range of 10-20 mg, occupancy varied from 71% to 80%. The authors described this degree of receptor occupancy as similar to that of risperidone.
As a comparison, haloperidol (Haldol) is generally considered to be among the most potent neuroleptics and the most likely to cause extra pyramidal reactions. In a double-blind study of first-episode patients diagnosed with schizophrenia, the subjects were randomly assigned to take 1, 2, 3, or 5 mg/day (Kapur et al., 2000 [736]). If the patients did not respond to the lower doses, they were raised to the limit of 5 mg/day. These are relatively small doses. The recommended initial dose for moderate symptoms or geriatric or debilitated patients is 1-6 mg/day (Drug Facts and Comparisons, 2007 [379]). For severe or chronic patients, it is 6-15 mg/day, with higher doses for prompt control.
All patients were evaluated at 4 weeks. Patients showed a wide range of D2 occupancy (38% to 87%). The likelihood of extrapyramidai reactions increased when occupancy exceeded 78%. Note that all of these occupancy figures are within the same range as those found by the same team (Kapur et al., 1998 [738]) for Zyprexa and Risperdal. This explodes the myth that atypicals have weaker occupancy of D2 receptors.
Remington et al. (2006) [1082] conducted a similar PET study of the long acting injectable form of risperidone at doses of 25, 50, or 75 mg every 2 weeks. After reaching stabilization, nine patients with a diagnosis of schizophrenia or schizoaffective disorder were scanned twice, 3 days postinjection and 5 days before the next injection. According to Remington et al. (2006) [1082], "all three doses of injectable risperidone showed peak D(2) occupancy levels above the 65% threshold associated with optimal clinical response; the 75-mg dose approximated the 80% threshold linked to increased risk of extrapyramidal reactions". Clearly, it is all in the dose; all of the atypicals are potent dopamine blockers.
Indeed, some of the older neuroleptics have less affinity or impact on D2 than the newer ones. Molindone (Moban), for example, has a decidedly weak affinity for D2 (Drug Facts and Comparisons, 2007 [379]), but it is rarely used.
Atypical neuroleptics are commonly given to children. Moran-Gates et al. (2007) [946] from the Massachusetts General Hospital and Harvard Medical School examined the brain tissue of juvenile and adult rats treated with risperidone. They found that risperidone "has high affinity for D2 receptors in both age groups, which is in agreement with other published reports" (p. 451). However, they found that long-term dosing (3 weeks) had a much more profound impact on the D2 receptors of the juvenile animals, causing an increase in the number of these receptors. There was a 90% increase in D2 receptor binding in juvenile rats, compared to 30% in adults, "which further reflects the greater sensitivity of developing animals" (p. 453) to longer-term exposure to risperidone. This up-regulation (increased dopamine receptors in response to dopamine blockade) is considered the likely mechanism of extrapyramidal reaction and tardive dyskinesia. Unfortunately, the prescription of antipsychotic or neuroleptic drugs to children and youth continues to rise.
Much is also made of the observation that the newer atypical neuroleptics impact on a greater variety of neurotransmitter systems than the older ones (e.g., Lieberman et al., 2005b [843]). However, there is no reason to suspect that impacting on multiple neurotransmitter systems would improve either safety or efficacy. To the contrary, it would seem bound to increase the spectrum of adverse effects. But even in regard to their inpact on multiple neurotransmitter systems, the atypicals are not unique. All of the older neuroleptics affect at least three neurotransmitter systems, such as serotonin and histamine, and several affect four or five of them. For example, old-fashioned thioridazine (Mellaril) impacts at least five neurotransmitter systems.
Despite these facts, establishment psychiatry - including Lieberman et al. (2005a) [842], the most cited neuroleptic study in years (see subsequent paragraphs) - continues to describe the atypicals as possessing a significantly and clinically important lower affinity for D2 receptors. Why would so many experts buy into drug company propaganda that the atypicals have a relatively low affinity for D2 and that their greater impact on numerous receptors is somehow an advantage? Because the experts are closely allied professionally and economically with the drug companies and their interests. As in the giant National Institute of Mental Health (NIMH) - sponsored Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study by Lieberman et al. (2005a) [842], virtually all the experts have a high affinity for drug company "receptors," finding way of making considerable money as consultants, researchers, and speakers' bureau members. Jeffrey Lieberman, first author in the CATIE study, reports having received research funding from AstraZeneca Pharmaceuticals, Bristol-Myers Squib, GlaxoSmithKline, Janssen Pharmaceutica, and Pfizer and consulting and educational fees from AstraZeneca, Bristol Myers Squid, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Novartis, Pfizer, and Solvay. The first seven CATIE authors report extensive ties to drug companies, and the eighth, Soni Davis, is an employee of Quintiles, a giant support firm for the drug industry, specializing in helping speed drugs to the market. The ninth author also has ties to drug companies, and the last three worked for the government. It is astonishing that NIMH would conduct its most important study of antipsychotic drugs by relying entirely and exclusively on experts with drug company ties.
Although this fact seems to have been lost on most medication prescrition writers, the dopamine-blocking capacity of all the newer antipsychotic drugs means that their adverse effects will include the worst effects of the older neuroleptics, including the production of tardive dyskinesia and neuroleptic malignant syndrome (chapter 4; see the individual drug labels in the Physicians' Desk Reference, 1973, 1978, 1995-2007). It also helps to account for their primary effect of deactivation. In addition, the newer antipsychotic drugs pose even greater risks of causing potentially life-threatening disorders, including marked obesity, elevated cholesterol, and potentially lethal diabetes, cardiovascular disease, and pancreatitis.
Overall, the concept of atypical is a marketing ploy with little clinical reality. These drugs combine the risks associated with the older neurolepties with very serious new risks. Nonetheless, health care providers, including sophisticated physicians, seem taken in by the claims. Adamou and Hale (2004) [12], for example, expressed surprise when three of their patients developed extrapyramidal reactions, including one severe case with "oculo-gyric crisis, dysarthria, torticollis, dysphagia, tremor, and rigidity". (One wonders if he had an elevated temperature and a missed case of neuroleptic malignant syndrome.) Different neuroleptics require different doses for similar effects and may exaggerate one or another toxic effect. They also vary in the length of time they remain active in the body. Nonetheless, with some exceptions, most of these drugs can be described as a single group sharing the same characteristics and side effects. There is no evidence that any of these drugs has a substantially different impact on mental functioning, other than the tendency for some to produce more sedation. In my clinical experience, Zyprexa, Seroquel, Abilify, and Risperdal, for example, are at least as potent in suppressing the will and motivation as any of the older antipsychotic drugs.
Various neuroleptics are also used for nonpsychiatric purposes, usually in smaller doses for shorter durations. However, severe effects can sometimes develop from these limited uses. Reserpine (Serpasil) is a neuroleptic that is more often used to suppress the symptoms of tardive dyskinesia (chapter 4). Prochlorperazine (Compazine) is used as an antiemetic and rarely as a neuroleptic. If given in sufficient doses to manifest psychoactive effects, these drugs produce the same emotional indifference as the other antipsychotic drugs.
Other nonpsychiatric preparations with neuroleptic effects include some antihistamines, such as methdilazine (Tacaryl) and trimeprazine (Temaril); some antinausea drugs, such as thiethylperazine (Torecan); and adjuncts to anesthesia, such as propiomazine (Largon) and promethazine (Phenergan), which is also used as an antinausea, anti-motion-sickness agent. These drugs are less potent than neuroleptics used in psychiatry, but in sufficient doses, they have similar adverse effects.
Metoclopramide (Reglan) is used in gastroesophageal reflux, diabetic gastric stasis, and as an antiemetic. Reglan is identical to older neuroleptics in its effects. It is well established that Reglan can cause irreversible neurological effects identical to the routinely used neuroleptics. Some researchers estimate the prevalence of Reglan-induced tardive dyskinesia to be 100 times more than the 0.2% reported in the Physicians' Desk Reference.
I have evaluated numerous cases of infants and children who have been treated with Reglan for gastric problems, resulting in severe and varied neurological disorders, apathy, retarded growth, and developmental delay. In cases familiar to me, the doctors recognized that the condition of the children was declining but failed to identify Reglan as the offending agent. While continuing the Reglan, they submitted the children to costly, dangerous, and intrusive medical tests in search of the elusive cause. In some of my forensic cases, doctors ended up blaming the mothers for "poisoning" their children when, in reality, the doctors themselves were dispensing the poison.
Although in many ways they can be treated as a single group of drugs, especially in regard to producing lobotomy-like activation, there are significant differences among the antipsychotic or neuroleptic drugs. Risperidone and clozapine provide examples.
The only atypical antipsychotic drug that lacks a high affinity for D2 i clozapine. It has a relatively weak tendency to block D2, and therefore: is the only one that is less likely to produce common adverse neurological effects like tardive dyskinesia. However, clozapine so often produce a dangerous and potentially lethal drop in the white blood cell count (agranulocytosis) that it requires continuous monitoring with blood test and is infrequently prescribed. Ironically, while classified as an atypical neuroleptic, clozapine is a very old drug that was originally taken off the market in some European countries because of its toxicity, before it was later reintroduced into the U.S. market in 1989 with much fanfare, as if were a brand new drug with great promise.
Clozapine causes a particularly high rate of grand mal seizures, estimated at 4% to 5% in the first year. This is a very serious hazard. The drug frequently produces severe low blood pressure and increased heart rate, potentially resulting in cardiovascular collapse. It can also cause hypertension. It can cause fever and a flulike syndrome. Respiratory arrest has been reported (Westlin, 1991 [1337]). It can be particularly hazardous for the elderly, who may risk falls, cardiovascular problems, or delirium (Pitner et al., 1995).
Although not a potent D2 blocker, clozapine seems to be more potent in this regard in the limbic (emotion-regulating) system than in the striatal region (which controls both emotion and voluntary movement; Chiodo et al., 1983 [277]). Because of the drug's greater impact on the frontal lobes and limbic system, it was thought that it would produce more "therapeutic" effect with fewer extrapyramidal side effects. The drug probably does produce a more profound deactivation or lobotomy-like syndrome in some patients, accounting for its reputation for sometimes working better than other neuroleptics. As a result, it probably has a greater risk of producing permanent frontal lobe damage and tardive dementia or tardive psychosis.
Concern about clozapine's especially damaging effect on higher brain function was voiced as early as 1977 by Ungerstedt and Ljungberg [1275], based on the European experience. Chouinard and Jones (1982) [282] pointed to observations on reactive psychoses following withdrawal from clozapine and commented, "This convincing evidence of clozapine's ability to induce supersensitivity psychosis might be related to both the short halflife of the drug and its greater affinity for mesolimbic dopamine receptors". Observations have also indicated that withdrawal psychoses may be more frequent and severe than with the older neuroleptics (see chapter 5). There is a report of a clozapine withdrawal syndrome that includes new symptoms of agitation, restlessness, shakiness, dyskinesia, confusion, sweating, aggression, and suicidal behavior ("Clozapine Withdrawal Syndrome," 1994; Richardson et al., 1993 [1084]). Supersensitive or withdrawal psychoses occur when the antipsychotic drug dose is reduced or stopped. It can be viewed as the mental equivalent of tardive dyskinesia, since both probably result from a reactive hyperactivity of the previously blocked dopamine functions (chapter 5).
Clozapine's anticholinergic effects can cause confusion and delirium as well as sedation and lethargy. The severity of withdrawal psychosis may be due to cholinergic rebound. Clozapine can aggravate or cause hypersalivation, glaucoma, constipation and ileus, and urinary retention (Baldessarini et al., 1991 [92]). Weight gain is also a potentially very serious problem.
While reportedly producing fewer extrapyramidal reactions, clozapine can produce every one of the neurological reactions associated with neuroleptic use, including neuroleptic malignant syndrome (Anderson et al., 1991 [46]; Dasgupta et al., 1991 [331]) and tardive dyskinesia (Weller et al., 1993) [1332].
Clozapine's efficacy has been highly touted to the public but in reality is questionable, even by conventional standards (see comments of psychiatrist Herbert Meltzer in Winslow, 1990 [1347]). Furthermore, in the arena of neuroleptics, consistent with the brain-disabling principles, a better or stronger drug is in reality a more suppressive and potentially more destructive drug.
A basic tenet of the brain-disabling principles is that all psychiatric drugs affect human beings and animals in a like fashion, without specificity for any disorder. Sorge et al. (2004) [1204] found that clozapine affects human and rat physiology in similar ways, including disrupting the sleep-wake cycle and producing abnormal brain temperatures.
Chapter 1 examined three risperidone studies that confirm the brain disabling principles of psychiatric treatment by demonstrating that the drug causes a metabolic suppression in the frontal and temporal lobes (deactivation) that occurs in both normal persons and patients diagnosed with schizophrenia, and that this disabling effect correlates with a reduction in the expression of symptoms, such as hallucinations and delusions, that require a fully functioning brain. As previously noted, if measured, the effect would also correlate with an overall reduction in spontaneous mental activity and verbal expressions, which are common clinical phenomena in patients who experience psychomotor retardation in response to neuroleptics.
Risperdal was first marketed in 1994 as an atypical neuroleptic. The clinical trials, most of which lasted a few weeks, were too short to determine the rate of tardive dyskinesia and many other adverse effects. Indeed, the brief controlled clinical trials used for the approval of both clozapine and risperidone do not provide sufficient information to determine either efficacy or safety since the drugs would be used for months and years in individual patients, rather than for a few week (see chapter 13). Patients taking the medications over the coming years will provide the experimental data. However, since Risperdal is a potent dopamine blocker, it should have been anticipated that it would cause similar adverse reactions as the older neuroleptics. In my own experience I have evaluated many cases of tardive dyskinesia caused by Risperdal, Zyprexa, and Geodon. Meanwhile, the Food and Drug Administration (FDA) has required the same tardive dyskinesia and neuroleptic malignant syndrome warnings on the labels of clozapine and risperidone as on the labels of the older neuroleptics.
Risperdal has a particular tendency to produce adverse stimulant effects, including insomnia, agitation, and anxiety. Probably because of these stimulant effects, it may have an increased risk of causing mania (Dwight et al., 1994 [388]). Stimulation may also account for risperidone-induced rage attacks and the urge to resume substance abuse, although the author of the report believes that these reactions are due to despair from increased psychological insight (Post, 1994 [1047]). In addition to stimulation, the drug frequently causes fatigue, sleepiness, or insomnia.
Risperdal causes all the extrapyramidal reactions found with other neuroleptics, including tardive dyskinesia (Addington et al., 1995 [15]) and neuroleptic malignant syndrome (Mahendra, 1995 [865]; Singer et al., 1995 [1184]; see chapter 4). It is too early to tell if the rate of tardive dyskinesia will differ from that of other neuroleptics.
A report found that even small doses of Risperdal (average dose of 1.7 mg/day) produced or worsened acute extrapyramidal reactions in one-third of an elderly population suffering from dementia (Baker, 1996 [88]). Among 41 patients, 6 developed new parkinsonism, 5 had a worsening of previous parkinsonism, one developed cervical dystonia, and one developed neuroleptic malignant syndrome while also taking Tegretol and Mellaril.
Like most neuroleptics, Risperdal can cause mammary cancer in rats and mice, but this finding has not been taken seriously enough by the FDA, the profession, or the drug companies.
In 2005, an NIMH multisite study called CATIE compared the older neuroleptic perphenazine (Trilafon) and atypical neuroleptics olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), and ziprasidone (Geodon; Lieberman et al., 2005a [842]; see also Nasrallah, 2007 [969]; Rosenheck et al., 2006 [1106]; Weiden, 2007a [1319]). Phase I involved 1,460 patients diagnosed with schizophrenia initially randomly assigned in a doubleblind study to one of the five neuroleptics. The study lasted 18 months, with safety and tolerability outcomes evaluated at 1, 3, 6, 9, 12, 15, and 18 months.
In a shock to clinicians and the pharmaceutical industry alike, there was little difference among the various medications, including old-fashioned, inexpensive perphenazine, in regard to the primary criterion for efficacy, the length of period that the patients remained on their randomly assigned initial medication. Overall, a whopping 74% discontinued the study medication before 18 months: 64% for olanzapine, 74% for risperidone, 75% for perphenazine, 79% for ziprasidone, and 82% for quetiapine. According to Lieberman (2005a) [842], "the majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or other reasons".
Note that perphenazine (Trilafon) is in the middle of the pack; there was no statistical difference between it and the leader, olanzapine (Zprexa). But Zyprexa had the worst adverse effect profile (see subsequent sections).
In addition, over the length of the study, treatment effects equalize among all the medications as measured on the Positive and Negative Syndrome Scale and the Clinical Global Impressions Scale. Again, there was no advantage to the newer antipsychotic drugs. These two scales are among the most commonly used to rate treatment effectiveness of these medications.
The most poorly tolerated drug, quetiapine (Seroquel), is the most commonly used in the United States and brings in the greatest revenue. Its success is a marketing triumph, not a clinical one.
Clozapine (Clozaril) was also studied, but because of the requirements for blood testing for agranulocytosis, it was not double blind. Once again demonstrating the power of clinical bias, as the only drug that was not blinded, clozapine demonstrated some greater efficacy than the others.
CATIE once again confirmed that patients do not like to take these drugs, largely due to their adverse effects, but also because of their lack of helpfulness. As noted, at the completion of the 18-month study, 74% of patients discontinued their original drug. Nasrallah (2007) [969] viewed this as confirmation that "both patients and clinicians are often dissatisfied with the outcome achieved". There were many alternative methods for evaluating this study (e.g., Weiden, 2007a [1319]), but none gave a particular favorable picture of any of the drugs, and none gave a significant advantage to any of the several atypicals over the older drug, perphenazine.
There has been much hype about the newer antipsychotics posing less risk of causing extrapyramidal side effects and tardive dyskinesia. However as already discussed, with the exception of clozapine, they are all potent dopamine blockers (subtype D2), and all D2 blockers cause extrapyramidal effects and tardive dyskinesia. Nasrallah (2007) [969] summed up, "There were no statistically significant differences between the rates of extrapyramidal side effects, movement disorders, or akathisia" (p. 9). However, more patients treated with perphenazine discontinued treatment because of extrapyramidal effects (Lieberman et al., 2005a [842]), suggesting that they were more distressing. Lieberman et al. (2005a) stated in their discussion that "the proportion of patients with extrapyramidal symptoms did not differ significantly among those who received first-generation and second generation drugs in our study. Despite this finding, more patients discontinued perphenazine than other medications owing to extrapyramidal effects". Compared to the other drugs, 8% of perphenazine patients discontinued because of extrapyramidal effects, versus 2% to 4% for the newer drugs.
Anticholinergic drugs are typically given to patients with extrapyramidal symptoms in order to provide relief. According to Lieberman et al. (2005a) [842], "fewer patients receiving quetiapine were prescribed anticholinergic drugs (3% vs. 8 to 10%)". The real news is that patients taking the older drug, perphenazine, received roughly the same amount of anticholinergic drugs as patients taking all the newer drugs (except for quetiapine), indicating again that there was little or no difference between the older drug and the newer one in regard to causing extrapyramidal symptoms.
A point that seems to missed is that since the older drug, perphenazine, was in the middle of the pack in terms of how long patients remained on it, the extrapyramidal effects did not make perphenazine overall less tolerable than the newer antipsychotics. According to Lieberman et al. (2005a) [842], "there were no significant differences between groups in time until discontinuation due to intolerable side effects". CATIE confirmed the high risk of developing metabolic syndrome, an array of adverse effects related to weight gain, elevated blood sugar, and elevated cholesterol, while exposed to atypical neuroleptics such as Zyprexa, Risperdal, and Seroquel. CATIE measured weight change, proportion of patients gaining weight, average weight change per month, blood glucose increased, hemoglobin A1c change (a diabetes test), cholesterol change, and triglyceride change. They did not measure another variable, blood pressure. The metabolic syndrome puts patients at risk for diabetes and cardiovascular disease. In a subtest of 689 patients, where the best data were available, the prevalence of metabolic syndrome was a shocking 40.9% to 42.7%, depending on the criteria, for the atypical antipsychotic drugs. Shockingly, more than 50% of the females developed metabolic syndrome.
Consistent with the huge numbers of lawsuits being settled by Eli Lilly for Zyprexa - induced diabetes (chapter 14), Zyprexa was the worst offender in regard to causing the metabolic syndrome. Zyprexa patients gained an average of 2 pounds/month. That would add up to 36 pounds in 18 months. Zyprexa patients also had greater problems with elevated glycosylated hemoglobin, total cholesterol, and triglycerides. As a medical expert in product liability cases against Eli Lilly, I have evaluated cases in which Zyprexa caused the sudden onset of lethal diabetes in relatively young adult patients who were previously free of the disorder.
If these drugs were not being prescribed to so-called mental patients, and especially to those labeled as schizophrenic, the findings on metabolic syndrome would probably lead the FDA to withdraw them from the market.
We will examine recent studies, some involving atypical neuroleptics, confirming that antipsychotic drugs shorten the life span. The production of a metabolic syndrome undoubtedly contributes to this increased risk of dying. However, this risk was also detected in regard to the older neuroleptics. It is due, at least in part, to the indifference to oneself, including lack of self-care, caused by all lobotomizing agents, including the neuroleptics.
One of the great myths within psychiatry is the specificity of neuroleptics such as Thorazine, Haldol, Prolixin, Zyprexa, Risperdal, Seroquel, or Geodon for the treatment of patients diagnosed with schizophrenia8. Despite a lack of confirmatory studies (reviewed in Breggin, 1983b [181], 1991c [190]; Jackson, 2005 [657]), many clinicians and researchers postulate a specific antipsychotic, and even an antischizophrenic, effect for these drugs. The concept is used to justify neuroleptic treatment as a legitimate medical approach. Instead, the neuroleptics produce what can be called a deactivation syndrome or effect, a central aspect of the lobotomy syndrome.
To help organize the clinical material that follows, it may be helpful to begin with a closer look at the concept of deactivation (Breggin, 1993 [194]):
"The term deactivation will be used to designate a continuum of phenomena variously described as disinterest, indifference, diminished concern, blunting, lack of spontaneity, reduced emotional reactivity, reduced motivation or will, apathy, and, in the extreme, a rousable stupor."
The deactivation effect is the essence of what is euphemistically called the antipsychotic effect. Consistent with the brain-disabling principles of psychiatric treatment, this lobotomy-like impact is the sought after, primary, and supposedly therapeutic effect. Any specific antipsychotic effect is very speculative compared to the obvious and almost unvarying lobotomy-like deactivation effect.
We will find that nearly all psychiatric drugs can produce some degree of deactivation. Even stimulants, such as Ritalin, can cause sufficient apathy or indifference in a child to enable adults to more easily control or direct the child (see chapter 11). The SSRIs, such as Prozac and Paxil, can also produce an apathy syndrome (chapter 7). However, deactivation appears in its purest form in neuroleptic treatment.
Deactivation is closely related to the frontal lobe syndrome; it describes the affective or emotional component. Adams and Victor (1989) divide the manifestations of frontal lobe syndrome into (a) cognitive and intellectual changes such as loss of abstract reasoning and planning, (b) personality deterioration, and (c) "impairment or lack of initiative and spontaneity" [14] (p. 333). Deactivation refers to the impairment of initiative and spontaneity, which Adams and Victor call the most common effect of frontal lobe disease.
Similarly, Stuss and Benson (1987) ascribed two basic functions to the anterior portion of the frontal lobes: "sequence, set, and integration" and "drive, motivation, and will" [1225] (p. 241). The "most common alteration is apathy" [1225] (p. 242). Neuroleptic-induced impairment of the frontal lobes acts primarily by causing apathy, along with a profound degree of spellbinding.
Much of what we know about the frontal lobe syndrome comes from studying the effects of psychosurgery, whose primary clinical effect is the production of deactivation, or what Kalinowsky (1973) called "diminished concern" [724] (p. 20). My clinical experience and reviews of the literature (Breggin, 1975 [174], 1980 [176], 1981b [178]) as well as neuropsychological research (Hansen et al., 1982) [595] indicate that the newer stereotactic procedures, such as cingulotomy, amydalotomy, and thalamotomy, continue to produce a frontal lobe syndrome, especially deactivation. Hansen et al. (1982) described the impact of modern psychosurgery in a way that is indistinguishable from neuroleptic deactivation effects:
"The patient's options for action are reduced by a weakening of initiative and ability to structure his situation; emotionality fades, is organized more shallowly and is more dependent upon the immediate situation. Contact with other people becomes more flattened and the immediate bearing more mechanical." ([595] p. 115)
Lobotomy patients literally do not know what hit them. They are so profoundly spellbound by the injury that they often have no awareness that anything has been done to them. Some live on a euphoric (superficially silly) level, most lapse into deep apathy; none are left with the ability to understand what has happened to them.
As we shall see, pioneers in the use of antipsychotic drugs almost uniformly cited deactivation as the main clinical effect of neuroleptics. Because of this, clinicians often referred to the neuroleptic effect as a chemical lobotomy (Haase, 1959) [588]. Bleuler (1978) observed that longterm neuroleptic use "also often dampens the vitality and the initiative of the person" [148] (p. 301). He concluded, "So we see that long-term maintenance with neuroleptics is fraught with some of the same disadvantages that are ascribed to lobotomies" (p. 301). Chapter 5 will discuss permanent cognitive impairment and dementia from these drugs.
Since the hallmark of medication spellbinding is a lack of appreciation or concern about adverse mental effects, any substance that produces indifference or apathy is highly spellbinding. Patients taking neuroleptics can become so spellbound that they appear robotic or zombielike, with litle awareness of or interest in themselves or their environment. They commonly think that they are doing somewhat better on the drugs, despite the fact that they are grossly impaired by a parkinsonian emotional flatness and psychomotor retardation (chapter 4).
Deactivation can result from dysfunction in either the frontal lobes and limbic system (as an aspect of frontal lobe syndrome) or the basal ganglia (as an aspect of subcortical dementia). It can also occur through dampening down the reticular activating system, a network in the lower portion of the brain that energizes all of its processes. All neuroleptics, including the newer atypicals, impair the dopaminergic pathways to all of these regions.
Dopamine is one of the most studied neurotransmitter systems in the brain. It has numerous receptor subtypes, including D2, which provides, nerve trunks from the region of their origin in the basal ganglia to the limbic system, frontal lobes, and reticular activating system. Blockade of D2 is key to neuroleptic effects, including deactivation and some of the more serious adverse effects, including tardive dyskinesia and neuroleptic malignant syndrome. All drugs that block D2 can cause these potentially disastrous effects.
The neuroleptic deactivation effect so closely resembles psychosurgery in its clinical impact because it disrupts the same regions of the brain. Classical lobotomy, for example, cuts the descending fibers from the frontal lobes to deeper brain structures, while the neuroleptics tend to impair the ascending dopaminergic fibers.
Any drug that blocks D2, including every newer antipsychotic medication, will, in sufficient doses, produce a lobotomy-like effect.
The very first report on the psychiatric use of chlorpromazine was published in France by Delay and Deniker (1952 [343]; translated in Jarvik, 1970 [671]). Their article described the actual state of the patient for a medical world that as yet had no familiarity with the drug:
"Sitting or lying, the patient is motionless in his bed, often pale and with eyelids lowered. He remains silent most of the time. If he is questioned, he answers slowly and deliberately in a monotonous, indifferent voice; he expresses himself in a few words and becomes silent." (Jarvik, 1970 [671])
They also described the patient as "fairly appropriate and adaptable. ... But he rarely initiates a question and he does not express his anxieties, desires or preferences" (Jarvik, 1970 [671]).
Notice the nonspecific nature of these effects. Not only symptoms such as anxiety, but also desires and preferences, are aborted or buried beneath indifference or apathy. As Delay and Deniker put it, there is an "apparent indifference or the slowing of responses to external stimuli" and "the diminution of initiative and anxiety" (Jarvik, 1970) [671]. Once again, this is iatrogenic helplessness and denial with spellbinding effects.
Heinz Lehmann introduced chlorpromazine into North America via Montreal in May 1953. Lehmann and Hanrahan (1954) [826] published the first article in English promoting its psychiatric use. They stated,
"The aim is to produce a state of motor retardation, emotional indifference, and somnolence, and the dose must be increased accordingly as tolerance develops."
The doses required for achieving "retardation," "emotional indifference," and "lethargy" rarely exceeded 800 mg/day, and sometimes did not exceed 100 mg/day. Much larger doses-sometimes thousands of milligrams - were often used in the past and are sometimes used in contemporary treatment by psychiatrists.
Writing with that burst of honesty so characteristic of pioneers, Lehmann and Hanrahan (1954) [826] go on to say,
"The patients under treatment display a lack of spontaneous interest in the environment ... they tend to remain silent and immobile when left alone and to reply to questions in a slow monotone. ... Some patients dislike the treatment and complain of their drowsiness and weakness. Some state they feel `washed out,' as after an exhausting illness, a complaint which is indeed in keeping with their appearance."
Lehmann and Hanrahan (1954) [826] recognized that they were suppressing their patients without specifically affecting or improving symptoms such as hallucinations and delusions: "We have not observed a direct influence of the drug on delusional symptoms or hallucinatory phenomena".
The following year, Lehmann (1955) [823] published his second article on chlorpromazine. With relatively small doses, he found the primary brain-disabling effect: "Many patients dislike the `empty feeling' resulting from the reduction of drive and spontaneity which is apparently one of the most characteristic effects of this substance". He also spoke of "lassitude" and compared the effects to lobotomy: "In the management of pain in terminal cancer cases, chlorpromazine may prove to be a pharmacological substitute for lobotomy".
The first British report concerning chlorpromazine as a psychiatric treatment (Anton-Stephens, 1954 [56]) confirmed the impact of the drug using small doses (200 mg/day). Anton-Stephens called it psychic indifference and again compared it to lobotomy.
Throughout the 1950s, some psychiatric texts continued to accurately describe the impact of the neuroleptics on the mind. Here, for example, is the lobotomy-like clinical picture of maximum benefit described by Noyes and Kolb [996] in the 1958 edition of Modern Clinical Psychiatry:
"If the patient responds well to the drug, he develops an attitude of indifference both to his surroundings and to his symptoms. He shows decreased interest in response to his hallucinatory experiences and a less assertive expression of his delusional ideas." ([996] p. 654, italics added)
It has become fashionable in contemporary psychiatry to deny the primary lobotomizing effects of the neuroleptics, but occasionally, recognition can be found in the literature. In a 1991 editorial in Biological Psychiatry titled "Neuroleptic Dysphoria," [406] Emerich and Sanberg described various adverse emotional reactions to Haldol and other neuroleptics, including "cognitive blunting". The editorial describes the self-administration of Haldol by Belmaker and Wald (1977) [123], in which each of these "normal experimental subjects" "complained of a paralysis of volition, lack of physical and psychic energy. The subjects felt unable to read, telephone or perform household tasks of their will, but could perform these tasks if demanded to do so". The editorial also mentioned reports of other mind-subduing effects, including "chemical straightjacketing," "lack of motivation," and a feeling "like a shade coming down". The editorial failed to make the obvious comparison to lobotomy, but its observations are entirely consistent with and confirm the brain-disabling principles of psychiatric treatment described in chapter 1.
Given so many acknowledgments by researchers that neuroleptics work by subduing the brain and mind, and sometimes the body itself, it is remarkable that psychiatric drug advocates continue to promote these drugs as if they have a specifically ameliorating effect on psychosis, mania, or schizophrenia.
In clinical discussions, the lobotomy effect is now sometimes subsumed under neuroleptic-induced deficit syndrome (NIDS). Malcolm Lader (1993) [800], chairperson of an international symposium on the subject, wrote,
"The benefits of treatment with classical neuroleptics are, however, obtained at the expense of a number of side effects, and many patients frequently complain of feeling `drugged' or drowsy and of being unable to concentrate; they lack motivation and are emotionally unresponsive: they also appear slow-moving and physically rigid. Some patiems have complained of `feeling like a zombie.' " ([800] p. 493)
The zombie effect is the ultimate manifestation of medication spellbinding as a central aspect of the brain-disabling effects of psychiatric drugs.
At the symposium, Wolfgang Straus (as cited in Lader, 1993 [800]) described a related neuroleptic-induced dyscognitive syndrome characterized by "aphasia, thought disturbances, emotional withdrawal, difficulties in directing thought by will, ambivalence, thought deprivation, and reduced creativity" ([800] pp. 495-496). Noting that early studies tried to demonstrate improved cognitive functioning on neuroleptics, Straus observed that more rigorous studies confirmed a detrimental effect.
Chapter 1 provided examples of research studies confirming the braindisabling principles in regard to risperidone, one of the most commonly used atypical antipsychotics.
Regardless of the mechanism, all neuroleptics produce lobotomylike indifference or deactivation. This is the primary effect of all drugs thus far developed for the control of patients labeled schizophrenic or acutely manic. If the medications failed to produce a deactivation effect, they would not be useful for the control of very difficult or disturbed individuals. We shall find that these drugs are potent dopamine blockers, producing all of the more severe central nervous system impairments caused by other neuroleptics.
If a drug is sufficiently deactivating and spellbinding, it can be used on humans and animals alike under any circumstances where an authority desires to impose control. Thus the antipsychotic drugs are used in every kind of authoritarian or totalitarian institution.
Neuroleptics are routinely used in every institution in which social control and behavioral suppression are a top priority and in which drugs can replace human services (see Breggin, 1983b [181], for details). Although Haldol and Mellaril have been largely displaced by newer drugs such as Zyprexa and Risperdal, the intent remains the same-behavioral control. For decades, the suppression of elderly nursing home inmates with neuroleptics has been a national scandal (Hughes et al., 1979 [639]; Rogers, 1971 [1093]). A study of nursing home residents in Tennessee found that 44% were being given the drugs (studies summarized in Bishop, 1989 [143]). A 1989 Massachusetts study (Avorn et al., 1989 [77]) found that 39% of patients were receiving neuroleptics. According to the report, "in most cases, the prescriptions had been written in the remote past and were refilled automatically".
When public scandal did not substantially improve nursing homes over the years (Kolata, 1991 [775]), Congress passed regulations limiting the use of restraints and medications in nursing homes. These statutes went into effect in 1991, too often with spotty enforcement and therefore in complete success (Spiegel, 1991 [1206]). However, when actually applied, the new regulations have reduced the use of neuroleptics in nursing home settings (Semla et al., 1994 [1155]).
Two decades ago, there was a growing awareness of the inappropriateness and harmfulness of prescribing neuroleptics to elderly patients ("Antipsychotic Drug Therapy," 1988 [55]; Gomez et al., 1990 [543]; Sherman, 1987 [1172]). The use of neuroleptics for the behavioral control of the elderly produces toxicity even more readily than in younger patients, and it cannot substitute for needed human services. Sherman (1987) [1172] called into question the pharmaceutical company practice of placing advertisement for neuroleptics like Haldol and Navane in journals with a geriatric practice orientation.
Unfortunately, the drug companies have now succeeded in convincing health care providers that the newer neuroleptics are safer for the elderly than the older drugs, even though the FDA requires the labels for these drugs to display a black box warning at the top with the bold heading, "Increased Mortality in Elderly Patients with Dementia-Related Psychoses". The atypicals such as Risperdal, Zyprexa, and Geodon cause or increased death rate in elderly patients with dementia as a result of unexplained sudden death, stroke, heart attack, and pneumonia. These drugs also more frequently cause cardiac arrhythmias as well as the metabolic syndrome described earlier in the chapter, all of which especially threater the lives of the elderly.
In 1983, in Psychiatric Drugs: Hazards to the Brain, I devoted consider able time to confirming the brain-disabling principle of neuroleptic treatment by pointing to its effects on a variety of diverse populations. I also discussed other confirmatory sources in the literature. The material in this section that draws on older citations is presented at greater length in my earlier book.
The deactivation syndrome produced by neuroleptics is confirmed by their use in state mental hospitals for the control of patients regardless of their diagnoses and in psychoprisons in the former U.S.S.R. for the control of political dissidents (Block et al., 1977 [149]; "Excerpts From Statement," 1976 [412]; Fireside, 1979 [441]; "`Madhouse' Brainwashing," 1976 [863]; Podrabinek, 1979 [1040]). They have been used in prisons for the suppression of difficult inmates (Booth, 1993 [158]; Coleman, 1974 [302]; Greenhouse, 1979 [564]; Kaufman, 1980 [745]; McDonald, 1979 [904]; Mitford, 1973 [935]; Oregon State Prisoner, 1971 [1012]; Prison Drug Bill, 1977 [1058]). Convicted prisoners have reported that the brain-numbing effects rendered them unable to make a proper defense in court (Espinosa, 1993 [410]; Ogilvie, 1992 [1004]; Pund, 1993 [1063]).
Neuroleptics have been commonly used in institutions for the developmentally disabled to suppress the behavior of children and adults (Kuehnel et al., 1984 [794]; Plotkin et al., 1979 [1039]). Kuehnel and Slama (1984) warned that neuroleptics can further compromise the learning abilities of the developmentally disabled and cause "the sedative 'snowed' effect, which can reduce a client's positive response to learning cues" ([794] p. 94).
Many critical books have decried the use of neuroleptics and other drugs in the suppression of children in hospitals and other settings (Armstrong, 1993 [67]; Hughes et al., 1979 [639]; Sharkey, 1994 [1162]; Wooden, 1976 [1364]). The control of children with neuroleptics will also be discussed in chapter 11 of this book.
The use of neuroleptics in veterinary medicine to control wild and domestic animals provides another illustration of the deactivation effect and its independence from any presumed mental illness in the individual being treated (Booth, 1977 [157]; Hall, 1971 [590]; Rossoff, 1974 [1109]). Hartlage (1965) [603] found that Thorazine dampened the emotional responses of animals, "thereby perhaps providing some clue to the widespread acceptance of the drug as effective in psychiatric settings" (see also Mirsky, 1970 [933]; Slikker et al., 1976 [1188]). Jarvik (1970) [671] pointed out that the neuroleptics produce diminished spontaneous activity and emotional indifference in all animal species, including man, but he nonetheless argued for a specific antipsychotic effect.
Not surprisingly, a variety of studies on human beings, including normals, has also shown impairment of mental functioning, including memory and learning (DiMascio et al., 1970 [363]; Fischman et al., 1976 [443]; Gillis, 1975 [520]; Seppala et al., 1976 [1156]; Tecce et al., 1975 [1242]).
Many former psychiatric patients and inmates have described the brain- and mind-numbing effects of the neuroleptics (Burstow et al., 1988 [243]; Chamberlin, 1978 [272]; Frank, 1980 [483]; Grobe, 1995 [568]; Hudson, 1980 [637]; Millett, 1990 [930]; Modrow, 1992 [938]).
I am not the first to suggest that neuroleptic medications are highl toxic. In fact, it was considered common knowledge in the first decades of their use (Hunter et al., 1964 [642]; Hunter et al., 1968 [641]). In support of the use of lithium, a number of investigators have criticized the neuroleptic for their stupefying effects. Fieve [432] (cited in Shah, 1973 [1160]), for example, said that neuroleptics "zonk a person out" and put them in a "mental straight jacket". Fieve (1989) also referred to the "zombielike appearance" ([432] p.4) produced by neuroleptics. A NIMH (1970 [971]) brochure compared the drug unfavorably to lithium because of their effect of "wrapping the patient entire mind in a cocoon of stupefaction". Similarly, Prien et al. (1972) [1055] found that "most patients receiving chlorpromazine were sluggish or fatigued". Wittrig and Coopwood (1970) confirmed the lobotomy-like effect of impaired "initiative and planning" ([1352] p. 488), which they called the chemical straightjacket. Robitscher (1980) noted that patients frequent feel "dead or `like a zombie' " ([1091] p. 90).
Perhaps in response to growing professional and public criticism, psychiatrists have become much more reluctant to publish criticism of any treatments or to mention their brain-disabling effects. Nowadays the neuroleptic drugs are always described as having a specific antipsychotic effect, rather than a numbing, lobotomy-like deactivation effect. In the words of my research assistant, Ian Goddard, "This remarkable difference between historic and contemporary commentary on the effects of neuroleptics clearly reveals the existence of an all-pervasive denial that has consumed the profession in modern times" (2007, unpublished).
Some proponents of brain disability as therapy assume that a little toxicity is helpful and that only excessive toxicity is harmful. They bring up precedents in medicine for drugs that reduce function of one organ or another to improve its effectiveness. Thus some cardiac medications actually weaken heart muscle function in the interest of preventing , rhythmias. But the analogy falls short when dealing with the brain. When the strength of the heart muscle is reduced, nothing substantial is done to the mind or personality of the person - unless, of course, the patient goes into heart failure. But when brain function is reduced, the individual's capacities as a sentient being are directly and proportionally reduced. He or she becomes less able to think, feel, choose, and initiate activities - and ultimately spellbound.
Beyond this, one must also look at the purposes of medical and psychiatric interventions. The medical intervention that disrupts one kind of heart function is intended to improve overall heart function. The psychiatric intervention that disables the brain is aimed at suppressing certain thoughts, emotions, or behaviors at the cost of reducing overall mental function. In doing so, it renders the individual less self-aware and less self-determining, more helpless, and more manageable. The individual may appear to be less emotionally disturbed when he or she is, in reality, less emotionally aware or vital.
In summary, consistent with the brain-disabling principles of biopsychiatric treatment presented in chapter 1, the neuroleptic or antipsychotic drugs produce a lobotomy-like deactivation syndrome characterized by emotional indifference or apathy, reduced spontaneity, and docility. This is the primary or "therapeutic" impact of all neuroleptic drugs including Haldol, Risperdal, Zyprexa, Geodon, and Seroquel.
This clinical result is obvious in the great majority of patients, some of whom are reduced to a zombielike state. It is documented by recent research studies involving the atypical antipsychotic Risperdal and other neuroleptics. It is also confirmed by studies of animals, normal human beings, political dissenters, and rebellious children as well as by studies of the inmates of mental hospitals, institutions for the developmentally disabled, nursing homes, and prisons. Given an effective "therapeutic" dose, all human beings and animals alike are emotionally stifled and subdued by antipsychotic drugs.
Pioneers in the field recognized and wrote about the lobotomy-like effects of the neuroleptic drugs when they first came into use, but in recent years drug advocates have promoted the false impression that these medications have a specific antipsychotic or antischizophrenic effect. In reality, the overriding clinical effect of these highly toxic chemical agents is to render patients and inmates more emotionally flat and indifferent, more apathetic and docile, and less autonomous and self-directed.
As a result, these patients and inmates some times seem less obviously in emotional pain, and they are almost always much more manageable. But the effect has nothing to do with treating a psychiatric disorder. Instead, the patients have been rendered emotionally and neurologically disabled by the drugs.