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Since I first voiced my concerns and reviewed the subject (Breggin, 1983b [181]), much more evidence has been accumulating that the neuroleplics can cause persistent damage or dysfunction to the highest centers of the brain, including cerebral atrophy. My concept that neuroleptics or antipsychotics are neurotoxic and cytotoxic in general seemed radical at the time, but we will find that it is now an accepted concept by the laboratory researchers who study these toxic effects. In the last few years, laboratories around the world have focused on the mechanisms of how typical and atypical neuroleptics cause neuronal cell death, but textbooks and clinicians have largely turned a blind eye on these critical findings.
A recent study involving primates has demonstrated that both the older and the atypical neuroleptics shrink brain tissue during routine clinical exposure. Dorph-Petersen et al. (2005) [374], from the Department of Psychiatry at the University of Pittsburgh, subjected three groups of six macaque monkeys each to oral haloperidol (Haldol), olanzapine (Zyprexa), or sham for a 17-27 month period. The doses of Haldol and Zyprexa produced plasma concentrations similar to those used in clinical practice with human beings. After exposure, the researchers found an 8% to 11% reduction in brain weight in both drug groups but not in the sham group. Shrinkage of the brain was observed "across all major brain regions (frontal, parietal, temporal, occipital, and cerebellum), but appeared most robust in frontal and parietal regions" (p. 1649). The frontal region is the most critical in producing lobotomy-like brain-disabling effects (chapter 1).
The authors concluded: "In summary, we found that chronic exposure of monkeys to haloperidol or olanzapine in a manner that mimics clinical use is associated with a significant reduction in brain volume that affects both gray and white matter" (p. 1659). A follow-up study conducted by the same research team (Konopaske et al., 2007) [780] and based on the same protocol sought to identify the specific cellular damage associated with the brain shrinkage caused by Haldol and Zyprexa in clinic doses. An examination of the gray matter in the parietal region found that a 14.6% reduction in gray matter was associated with a 14.2% reduction in the glial cells. The numbers of neurons and endothelial cells were unchanged, resulting in their increased density in the shrunken tissue.
The authors concluded that their data raised the possibility that changes seen in the brains of patients diagnosed with schizophrenia might be due at least in part to antipsychotic medication. This was a dramatic suggestion from researchers who were sponsored by both NIH and Eli Lilly, the manufacturer of Zyprexa. As this chapter will confirm, in fact there can be no serious scientific doubt that the destructive changes seen in the brains of patients labeled schizophrenic are wholly attributable to the medications inflicted on them.
By themselves, these studies should have been sufficient to raise warning flags of concern about inflicting these drugs on human beings. NIH, the sponsoring federal agency for the research, held no press conference to warn about these ominous findings. Eli Lilly, the manufacture of olanzapine, sent no "Dear Healthcare Provider" letter warning about widespread shrinkage of the brain resulting from the death of brain cells. Despite this research and the existence of earlier, confirmatory animal studies (see further in the chapter), the medical profession has yet to blink an eye over subjecting its patients to a class of drugs, the neuroleptics that destroy a large percentage of brain cells and substantially shrink the brain size of its patients.
Neuroleptics can damage or destroy brain cells through a variety of mechanisms. They not only suppress the gross function of dopaminergic neurons, they disrupt a variety of metabolic functions within neurons and other cells throughout the body.
It has been known for several decades that these drugs inhibit most enzyme systems in the mitochondria (Teller et al., 1970) [1245], which are the principal sites for many of the most important metabolic processes in the cell. Research by Inuwa et al. (1994) [652] demonstrated that neuroleptics are absorbed into human cell mitochondria, where they interfere with metabolic processes and cause structural abnormalities. The authors suggested, "It is possible that such interaction may be cytopathic leading to premature cell death" (p. 1091) [652].
Recent research has become more sophisticated in studying the toxic effect of neuroleptics on cells of neuronal processes. Ethier et al. (2004) [411] found that haloperidol impairs striatal neuropeptide gene expression. They correlated this in rats with the production of catalepsy - a slowing down of bodily movements - thereby creating a study of the braindisabling effects of neuroleptics. These drugs damage cellular processes and simultaneously inhibit spontaneous movement. The overall reduction of spontaneity in patients is closely related to the so-called therapeutic effect.
Bonelli et al. (2005) [154] observed that "the influence of psychotropic drug medication on acute cell death has not been studied so far in vivo, although some experiments performed in vitro suggest that antipsychotic drugs are neurotoxic". Tissue transglutaminase (tTG) is a marker for apoptosis, a stage in the death of neurons. The researchers studied the occurence of this marker for cell death in the spinal fluid of patients exposed to classic and atypical neuroleptics. Some of the patients had Alzheimer's disease and other neurological disorders, and some did not: "A significant influence (P < 0.01) of antipsychotic drugs for both the Alzheimer's and the non-Alzheimer's group was found with respect to tTG protein levels in cerebral spinal fluid." A variety of other drugs, including tranquilizers and antidepressants, had no such effects on "cerebral cell death". The authors concluded, "The results suggest that typical and atypical antipsychotic drugs may induce cerebral cell death." The results were worse for females than for males.
Consistent with Bonelli et al.'s biochemical finding, Alzheimer patients given the newest neuroleptics have a significantly greater loss of autobiographical memories than untreated patients (Harrison & Therrien, 2007) [601]. Put simply, neuroleptics worsen Alzheimer's dementia.
In an attempt to shed light on the mechanism by which neuroleptics induce extrapyramidal reactions, Bishnoi et al. (2007) [142] chronically administered haloperidol (1 mg/kg) and chlorpromazine (5 mg/kg) to rats, resulting in a time-dependent increase in orofacial hyperkinetic movements. They found a corresponaing time-dependent decrease in extracellular levels of norepinephrine, dopamine, and serotonin in various cortical and subcortical regions of the brain.
Because of their neurotoxicity, neuroleptics probably worsen any brain disorder. A controlled experiment with rats subjected to traumatic brain injury demonstrated that chronic, high doses of risperidone or haloperidol were detrimental, causing persistent cognitive deficits (Kline [771] et al., 2000).
Consistent with my own clinical observation that neuroleptics worsen Alzheimer's disease and other dementing disorders, Bonelli et al. (2005) [154] warned that individuals with Alzheimer's disease are even more vulnerable to neuroleptic-induced cell death. The researchers stated, "A limit on the use of first- and second-generation antipsychotics in elderly patients is proposed." Finally, they saw a possible connection between "the observed increased cerebral cell death and tardive dyskinesia, the most threatening side effect in antipsychotic therapy".
Jarskog et al. (2007) [670] studied the effects of haloperidol, clozapine, and quetiapine on numerous so-called apoptotic markers to study the impact of these drugs on apoptosis. Essentially, they examined the neurotoxicity of neuroleptics, specifically their capacity to induce cell deterioration typical of the process of cell death. They found that the neuroleptics, both the older ones and the atypicals, caused activation of caspase-3, a marker for apoptosis. They tried to reassure their readers that "this activity was probably non-lethal".
Jarskog et al. (2007) [670] did not find evidence for faddish research that tries to prove that neuroleptics actually protect cells from trauma (see chapter 8 for the allegedly protective effects of neuroleptics and mood stabilizers). Indeed, the evidence for the opposite continues to grow, confirming that neuroleptics kill brain cells. Noting that haloperidol causes abnormal motor behavior, Kim et al. (2006) [759] sought to increase knowledge about "how it triggers neuronal impairment". Citing Tseng and Lin-Shiau (2003) [1267], they pointed out that "chronic blockade of dopamine D2 receptors in the striatum results in persistently enhanced release of glutamate, which kills striatal neurons". Using hippocampal neurons from mice, Kim et al. found that haloperidol induces a calcium ion influx into the cell and that this renders neurons more susceptible to oxidative stress. Neuroleptics do not protect cells from stress, they induce toxic processes that render them more susceptible to stress, at times killing them.
Neuroleptics are toxic to cells throughout the body. The clinical observations have demonstrated that atypicals cause diabetes and weight gain (Jin et al., 2004) [692] and recently caused the FDA to include warnings in all atypical psychotic labels (package inserts). This has led to research explorations of the underlying cytotoxic processes. Vestri et al. (2007) [1297] compared the effects of two older neuroleptics with the atypicals risperidone, clozapine, olanzapine, and quetiapine in regard to glucose metabolism in cultured cells. All of the medications interfered with some of the intracellular processes. However, only the atypicals "were able to impair the insulin-responsive glucose transport system and to impair lipolysis in adipocytes. ... These effects of SGAs [second-generation antipsychotics] on adipocytes could explain, in part, the association of SGAs with weight gain and diabetes".
Neuroleptics increase the toxicity of the sunlight to human skin, causing discolorations and other adverse dermal reactions. Researchers noted this phenomenon, called phototoxicity, and set out to study its effects on cells loaded with the neuroleptics fluphenazine, perphenazine, or thioridazine (Bastianon et al., 2005) [108]. They found that exposure of these cells to light caused abnormalities in both the plasma membrane and mitochondria.
Clozaril causes potentially fatal agranulocytosis of white blood cells due to bone marrow suppression. The mechanism is probably a direct toxic effect on bone marrow cells. When tested, the neuroleptics chlorpromazine, olanzapine, and quetiapine were also toxic to bone marrow cells (Pereira et al., 2006) [1028].
Neuroleptics can cause sudden death that, at times, is related to cardiac failure. Belhani et al. (2006) [120] demonstrated that numerous classic and atypical neuroleptics produced cardiac lesions and/or hypertrophy in rabbits treated for 3 months. For example, olanzapine (0.30 mg/kg/day) produced ventricular hypertrophy. The lesions were consistent with toxic myocarditis. Again, neuroleptics are generally cytotoxic.
Dwyer et al. (2003) [389] reviewed the literature on antipsychotic cytotoxicity and noted, "The cytotoxic properties of the older phenothiazine antipsychotic drugs are well known." They cited studies confirming that these drugs "inhibit proliferation in a variety of cell lines and alter cell morphology". They set out to compare and evaluate the cytotoxic effects of the newer atypicals by studying the effects of glucose metabolism. They confirmed that antipsychotics produce some of their toxic effect by inhibiting the utilization of glucose in cells. Although generally, the atypicals were less toxic, the results were inconsistent, but all displayed some toxicity. They described the complexity:
"Risperidone was a fairly potent inhibitor of glucose transport but was not very toxic for cells [in their tests] and olanzapine, a modest inhibitor of glucose transport, actually stimulated proliferation of neuronal cells. Haloperidol was toxic for [experimental cells], however, it did not affect glucose transporto On the other hand, this drug inhibited mitochondrial function (energy metabolism), which may explain its toxicity."
The researchers also pointed out that neuronal cells, unlike others, rely exclusively on glucose metabolism, making them especially vulnerable to the effects of antipsychotic drug inhibition of glucose metabolism. However, since multiple toxic effects are produced by the antipsychotics, they concluded: "Taken together, the various data suggest that the cytotoxicity of the antipsychotic drugs may result from a summation of effects on numerous independent pathways that converse to compromise cell viability" (p. 37).
Although the researchers do not discuss it, reduced glucose utilization would produce the reduced metabolic rate and hypoactivity in the frontal lobes caused by neuroleptics, causing or contributing to their brain-disabling, lobotomy-like effect. And they fall prey to wishful thinking, imagining that the abnormal proliferation of neural cells stimulated by olanzapine may be therapeutic.
The reader will find little or nothing in the major psychiatric and psychopharmacological textbooks about these well-documented neuroleptic induced neurotoxic and cytotoxic processes.
In the last two decades, positron emission tomography (PET) scanning has been used to measure the metabolic rate and blood flow of various parts of the brain. This instrument can detect dysfunction that does not necessarily manifest as gross pathology. It can also measure functional changes that have no pathological origin. When an individual pays attention, frontal lobe activity will increase. When the same individual looks at pictures, visual centers of the brain will become activated. Chapter 1 analyzed three PET scan studies involving the effects of risperidone (Lane et al., 2004 [808]; Liddle et al., 2000 [840]; Ngan et al., 2002 [985]). Together these studies demonstrated the brain-disabling concept: first, that risperidone causes a generalized malfunction (suppressed metabolism) in the frontal and temporal lobes; second, that this effect takes place in normal volunteers as well as patients labeled schizophrenic and is therefore not specific for schizophrenia; and third, that this malfunction correlated with so-called improvement in the form of a reduction in communications about symptoms. The suppression of metabolism in the brain is a neurotoxic effect.
From the earliest studies, there has been a somewhat consistent finding of hypoactivity in the frontal lobes and frontal cortex of neuroleptic treated people with schizophrenia (Buchsbaum et al., 1982 [237]; Farkas et al., 1984 [419]; Wolkin et al., 1988 [1358], as reviewed in Andreasen, 1988 [49]; Wolkin et al. 1985 [1359]). In most studies, the patients had long histories of neuroleptic treatment prior to the PET scans, and the drugs were temporarily stopped at the time. However, temporarily stopping neuroleptic treatment would not have reversed its long-standing and persistent suppressive effects on the frontal lobes.
The PET scan has been used to study specific parts of the brain in which the neuroleptics are known to produce dysfunction by blockade of the dopamine neurotransmitter system, including the basal ganglia. A variety of studies show that the basal ganglia of neuroleptic-treated patients develop abnormalities (Farde et al., 1988 [418]). However, there are also many negative PET studies (see Buchsbaum et al., 1992 [236], and a lengthy summary table in Andreasen et al., 1992 [50]; see also Andreasen, 1988 [49]).
One PET study involving unmedicated patients found no frontal hypoactivity (Sheppard et al., 1983 [1169]). Another with unmedicated patients showed increased frontal metabolism (Cleghorn et al., 1989 [288]). The failure to demonstrate hypoactivity in the frontal lobes of unmedicated patients confirms that the effect, when found, is probably caused by the antipsychotic medications. As an exception to this, Buchsbaum et al. (1992) [236] found hypofrontality in never-medicated patients diagnosed with schizophrenia. However, the results were not definitive: "The hypofrontality effect was modestly sensitive and not strongly specific."
Some PET studies have measured cerebral blood flow in patients labeled schizophrenic who had never been exposed to neuroleptics. The PET measurements were made while the subjects were asked to perform a task intended to activate the frontal lobes. Andreasen et al. (1992) [50] found that "decreased activation occurred only in the patients with high scores for negative symptoms. These results suggest that hypofrontality is related to negative symptoms and is not a long-term effect of neuroleptic treatment or of chronicity of illness".
Andreasen et al.'s conclusion has an obvious flaw. Negative symptoms of "schizophrenia" include apathy, indifference, lack of emotion, lack of willpower or volition, lack of verbal communication, and social withdrawal. High scores for negative symptoms mean that the patients were unable or unwilling to cooperate with the demands of the project to perform the requested tests, therefore putting less energy into the task that was supposed to elicit frontal lobe activity. Notice as well that all of these symptoms can be caused by the antipsychotic drugs (chapters 1 and 2), suggesting that these patients may have been especially heavily medicated, resulting in suppression of their frontal lobe activity.
Overall, the finding of subtle differences in energy usage in the brains of any individuals, whether diagnosed schizophrenic or not, could have a psychological origin. It is well known, for example, that different states of consciousness affect the amplitude and frequency of electrical waves in different parts of the brain. For example, visual and auditory activities are reflected in heightened electrical activity in different regions of the brain. Biofeedback experiments have shown that people can consciously control some aspects of brain wave activity.
In most cases, however, the finding of hypoactivity in the frontal lobes of patients diagnosed with schizophrenia results from neuroleptic-induced brain dysfunction and damage. PET scans showing hypoactivity in the frontal lobes of medicated and previously medicated patients confirm the brain-disabling principles of biopsychiatric treatment.
In her review of neuroimaging studies, Jackson (2005) [657] commented on the inconsistency of results. The common finding is that studies of patients exposed to neuroleptics reveal a wide variety of anatomical abnormalities in the brain. As Lang et al. (2004) [810] stated, "Antipsychotic medications are known to alter the structure and metabolism of basal ganglia in humans and animals."
Meanwhile, considerable evidence has accumulated that neuroleptics cause enlargement (increased volume) of the striatum (caudate, putamen, and globus pallidus; study results and review in Lang et al., 2004 [810].) Dopaminergic nerves predominate in this area, and the enlargement may represent proliferation within the dopaminergic system in response to neuroleptic blockade. On the other hand, the neuroleptics cause shrinkage of brain tissue in the frontal regions, with a compensatory increase in the volume of the ventricular spaces. This probably results from the destruction of brain cells.
Magnetic resonance imaging (MRI) has been replacing CT scans in recent years for studying brain morphology. Lieberman et al. (2005b) [843] assessed brain volume changes in first-episode patients diagnosed with schizophrenia and treated with haloperidol or olanzapine. The patients treated with haloperidol "exhibited significant decreases in gray matter volume, whereas olanzapine-treated patients did not". The authors suggested that the haloperidol "effects on brain morphology could be due to haloperidol-associated toxicity". They cited three studies showing that haloperidol can "induce oxidative stress and excitatory neurotoxicity". That, of course, is the only reasonable conclusion, given that neuroleptics are toxic to brain cells. In addition, they observed an increase in the size of the caudate, which they acknowledge is known to be due to treatment effects of conventional drugs causing ultrastructural changes in striatal neurons" (p. 368).
However, Lieberman et al. (2005b) [843] waffle, suggesting that the "greater therapeutic effects of olanzapine" threw off the results. The second author of the study, Gary Tollefson, has been a longtime consultant and then staff member of Eli Lilly, the manufacturer of olanzapine (Breggin et al., 2004 and author affiliations at the end of the article). Another author, Mauricio Tohen, is also a Lilly employee, and the project received partial funding from the Lilly Foundation.
The summary in the abstract of the article is also misleading. Olanzapine did cause some degree of reduction in the volume of the frontal lobes, but it was relatively less. In addition, the doses of olanzapine were relatively mild compared to those for haloperidol. The range of olanzapine doses (5-20 mg) was similar to that of haloperidol (2-20 mg), but milligram for milligram, haloperidol is much more potent and hence toxic. The recommended initial dose of olanzapine is 10-15 mg/day, and for haloperidol, the initial recommended dose is a fraction of that amount at 1-6 mg/day (Drug Facts and Comparisons, 2007 [379]). The comparative doses of haloperidol were thus much larger, indicating why it was causing more damage to the frontal lobes. This is a common trick used by drug companies when trying to show that their drug is less toxic than a competitor's drug: utilize a comparatively lower and hence less toxic dose for your drug.
Khorram et al. (2006) [757] found that conventional antipsychotics caused a dose-dependent increase in the volume of the thalamus compared to normal volunteers. The thalamic volumes returned to normal when the patients were switched from the older antipsychotic drugs to olanzapine. However, the doses of olanzapine are not provided. The authors conclude, "Antipsychotic medication could contribute to the wide range of thalamic volumes reported in schizophrenia" (p. 2007). In other words, the drugs and not the disorder are causing the brain structure abnormalities. This, of course, confirms the brain-disabling principles of neuroleptic effects.
Many older studies involved computerized axial tomography (CT) scans of psychiatric patients, most but not all of whom were diagnosed schizophrenic. They have found enlarged lateral ventricles and sometimes enlarged sulci, indicating shrinkage or atrophy of the brain. Nearly all these studies involved patients heavily treated with neuroleptics.
A number of the CT scan studies have found a correlation between atrophy and persistent cognitive deficits or frank dementia in these neuroleptic-treated patients (DeMeyer et al., 1984 [348]; Famuyiwa et al., 1979 [413]; Golden et al., 1980 [539]; Johnstone et al., 1976 [697]; Lawson et al., 1988 [817]). Some of these studies used the Nebraska and Halstead-Reitan batteries, considered among the most sensitive for detecting brain damage and dysfunction.
While some of the studies claimed that drugs could not have caused the observed brain abnormalities, they did not provide evidence that confirmed this viewpoint (e.g., Johnstone et al., 1976 [697]; Johnstone et al., 1978 [698]; Lawson et al., 1988 [817]; Shelton et al., 1988 [1166]; Weinberger et al., 1980 [1323]; Weinberger et al., 1979 [1326]).
Two studies that evaluated relatively young and relatively untreated patients diagnosed with schizophrenia found enlarged ventricles, a marker for brain atrophy (Schulz et al., 1983 [1144]; Weinberger et al., 1982 [1324]; reviewed in detail in Breggin, 1990 [187]). However, very small numbers of patients were involved, and other studies have not confirmed their findings (Benes et al., 1982 [126]; Iacono et al., 1988 [646]; Jernigan et al., 1982 [678]; Tanaka et al., 1981 [1238]).
Surprisingly few studies have attempted to correlate brain scan findings with the presence of tardive dyskinesias (TD). Bartels and Themelis (1983) [105] found abnormalities in the basal ganglia of TD patients, but overall, the results have been mixed and inconclusive (Besson et al., 1987 [137]; Goetz et al., 1986 [534]; Jeste et al., 1980 [686]; Koshino et al., 1986 [782]). However, as noted in chapter 4 in regard to neuroleptic malignant syndrome (NMS), patients with these more extreme reactions to antipsychotic drugs often show gross brain damage (Zarrouf and Bhanot, 2007 [1379]).
Mounting radiological evidence from PET, MRI, and CT scans confirms the presence of chronic brain dysfunction (PET scans) and brain atrophy (MRI and CT scans) in neuroleptic-treated patients diagnosed with schizophrenia. It also confirms the brain-disabling concept.
By 1988, Kelso et al. [751] estimated the total number of relevant CT scan studies to be over 90, most of which show damage. Some studies implicate the total lifetime amount of neuroleptic intake (DeMeyer et al., 1984 [348]; Lyon et al., 1981 [859]). A number of researchers try to attribute the findings to schizophrenia, but there is little justification for this (see subsequent discussion).
Studies indicate that the percentage of drug-treated patients diagnosed with schizophrenia who demonstrate atrophy on CT scans varies from 0% to over 50%. If treatment has been lengthy and intensive, as in Suddath et al. (1990) [1226], most patients may show brain atrophy. Reported rates are substantial, typically in a range of 10% to 40%. Coming to a similar conclusion, Andreasen (1988) [49] reviewed the literature and found a range of 6% to 40%. Andreasen noted that higher rates were reported with increasing severity and length of illness. However, severity and length of "illness" would also correlate with intensity and duration of treatment with neuroleptics.
Evidence from several different clinical sources confirms that the neuroleptics can permanently impair mental functioning.
The term dementia will be defined as a syndrome of organically based multiple cognitive deficits, including memory impairment as well as other brain dysfunctions, such as emotional lability, personality change, or impairments in abstract thinking, judgment, and other higher cortical or executive functions (see American Psychiatric Association, 2000 [44]). The chapter focuses on gradually evolving persistent brain damage and dysfunction associated with chronic exposure to neuroleptics.
An earlier review (Breggin, 1983b [181]) disclosed that many patients with TD are also suffering from severe cognitive dysfunction (e.g., Edwards, 1970 [393]; Hunter et al., 1964 [642]; Ivnik, 1979 [656]; Rosenbaum, 1979 [1102]). Often the data had to be culled from charts and footnotes because most of the studies relegated this correlation to obscurity within the article. Other studies concluded, without evidence, that the brain damage must have predated the TD. However, multiple subsequent studies have confirmed my initial observations, and the correlation between tardive dyskinesia and cognitive function is now well established. (See subsequent sections).
Many clinical studies have now confirmed the existence of persistent cognitive deficits and dementia in association with neuroleptic use. However, to some extent, researchers have lost their enthusiasm for demonstrating over and over again that neuroleptics cause cognitive deficits, and textbooks of psychiatry simply do not want to mention it (e.g., Hales et al., 2003 [589]). This is reminiscent of the history of research into the brain-damaging effects of shock treatment (chapter 9). When repeated animal studies showed that electroconvulsive therapy caused brain damage, including scattered small hemorrhages and cell death, the research stopped, and textbooks ignored or denied its existence.
A clinical study of hospitalized drug-treated patients found many suffering from mental deterioration typical of a chronic organic brain syndrome that the researchers labeled dysmentia (Wilson et al., 1983 [1346]). Tardive dysmentia consists of "unstable mood, loud speech, and [inappropriately close] approach to the examiner". It is probably a variant of hypomanic dementia10. The mental abnormalities in the study by Wilson et al. (1983) [1346] correlated positively with TD symptoms measured on the Abnormal Involuntary Movement Scale. In addition, length of neuroleptic treatment correlated with three measures of dementia: unstable mood, loud speech, and euphoria. The authors stated, "It is our hypothesis that certain of the behavioral changes observed in schizophrenic patients over time represent a behavioral equivalent of tardive dyskinesia, which we will call tardive dysmentia" (p. 188). The tendency in the literature, perhaps in search of a euphemism, has been to use the term tardive dysmentia even when a full-blown dementing syndrome is described.
A variety of studies confirmed the existence of tardive dysmenia (dementia; Goldberg, 1985 [536]; Jones, 1985 [700]; Mukherjee, 1984 [958]; Mukherjee et al., 1985 [959]; Myslobodsky, 1986 [965]). Myslobodsky (1993) [966] summarized the triad of features of tardive dysmentia as "occasional excessive emotional reactivity, enhanced responsiveness to environmental stimuli, and indifferent or reduced awareness of abnormal involuntary movements". He reviewed a study indicating that patients diagnosed with schizophrenia with TD score significantly higher on measures of aggression and tension than similar patients without TD. He pointed out that some of these patients suffer from typical frontal lobe signs. He also warned that routine neuropsychological testing can miss the frontal lobe syndrome associated with TD11.
In addition to Wilson et al. (1983) [1346], several other studies reported an association between TD symptoms and generalized mental dysfunction (Baribeau et al., 1993 [97]; DeWolfe et al., 1988 [358]; Itil et al., 1981 [655]; Spohn et al., 1993 [1208]; Struve et al., 1983 [1224]; Waddington et al., 1986a&b [1305] & [1306]; Wolf et. 1982 [1356]; many reviewed in Breggin, 1993 [194]). After eliminating schizophrenia as a causative factor, Waddington and Youssef (1988) [1307] also found increased cognitive deficits in neuroleptic-treated bipolar patients with TD in comparison to those without the disorder.
Wade et al. (1987) [1308] pointed out that Huntington's and Parkinson's diseases provide a related model for TD, including the development of cognitive impairments (see Koshino et al., 1986 [782]; Breggin, 1993 [194], for similar discussions). They studied 54 patients who were diagnosed with mania or schizophrenia with TD and concluded that TD is one expression a larger "chronic neuroleptic-induced neurotoxic process" (Wade et al., 1987, p. 395 [1308]).
Paulsen et al. (1994) [1022] reviewed the literature and found that "TD was generally reported to be associated with cognitive impairment". Krabbendam et al. (2000) [785] found a particular correlation between orofacial TD and cognitive impairment, especially delayed memory that may be caused by a "frontal subcortical disturbance" related to orofacial TD. It is apparent that TD is not merely a motor disorder but afflicts a range of cognitive and emotional functions.
Palmer et al. (1999) [1017] focused on extrapyramidal symptoms (EPS) rather than TD and found that severity of EPS correlated with the severity of neuropsychological deficits, especially in the areas of learning and motor skills. Krausz et al. (1999) [788] found a similar correlation between EPS and cognitive deficits on a self-rating scale. They believed the deficits were sufficient to cause potential difficulty with insight and everyday life skills.
Gualtieri and Barnhill (1988) [576] pointed out, "In virtually every clinical survey that has addressed the question, it is found that TD patients, compared to non-TD patients, have more in the way of dementia" (p. 149). They believed that the dememia results from damage to the basal ganglia caused by the TD (see subsequent discussion)12. Gualtieri (2002) [575], one of the most experienced researchers in the field, has continued to make the point that TD patients have more "signs of dementia" (p. 401) than similar patients who do not have TD.
Since the rates of TD are so high (see chapter 4), affecting a large proportion of neuroleptic-treated patients, its association with cognitive dysfunction and dementia is especially ominous. These data by themselves provide sufficient evidence to conclude that neuroleptics frequently and irreversibly impair mental function. Once again there is ample reason to be cautious about prescribing these toxic agents to adults and to prohibit giving them to children and youth.
A multisite national research project evaluated brain dysfunction caused by polydrug abuse, including street drugs (for a more detailed analysis, see Breggin, 1983b [181]). Using the Halstead-Reitan Neuropsychological Battery, the study unexpectedly uncovered a significant correlation between generalized brain dysfunction and total lifetime psychiatric drug consumption in patients diagnosed with schizophrenia (Grant et al., 1978a&c [553] & [555]). More than one-fourth of the neuroleptic-treated patients had persistent brain dysfunction. The chronic brain dysfunction was related more to lifetime neuroleptic intake than to the diagnosis of schizophrenia: "Neuropsychological abnormality was associated with greater antipsychotic drug experience" (Grant et al., 1978c, p. 1069 [555]). Indeed, patients diagnosed with schizophrenia who abused street drugs rather than taking neuroleptics showed no correlation between the diagnosis of schizophrenia and increased brain dysfunction. None of the patients had been exposed to neuroleptics for more than 5 years.
In an unpublished version of the paper presented at a professional meeting (Grant et al., 1978a [553]), the authors underscored the connection between TD and cognitive deficits and warned in their concluding sentence, "It is also clear that the antipsychotic drugs must continue to be scrutinized for the possibility that their extensive consumption might cause general cerebral dysfunction" (p. 31). The version published in the Archives of General Psychiatry (Grant et al., 1978c [555]) warned of the possibility of long-term cognitive deficits associated with neuroleptic use, but in somewhat less threatening language. The danger of neuroleptic-induced chronic brain dysfunction was expurgated from the American Journal of Psychiatry version (Grant et al., 1978b [554]). The misleading correlation with schizophrenia was highlighted. Prodrug editing made the risk disappear from the supposedly scientific article.
Reports by Gualtieri and his colleagues (Gualtieri, 2002 [575]; Gualtieri et al., 1988 [576]; Gualtieri et al., 1984 [577]; Gualtieri et al., 1986 [578]) indicated that many institutionalized children and young adults go through a persistent period of worsening psychiatric symptoms after withdrawal from neuroleptics, typically impairing them more than their original symptoms prior to treatment. This occurred in developmentally disabled patients in whom schizophrenia had not been diagnosed. The researchers attributed the withdrawal-emergent problems to a drug-induced dementing process. Some patients stabilized or improved if kept medication-free, but others seemed permanently worsened by the medications. They required increased medication to control their drug-induced symptoms.
Clinical reports of denial or anosognosia among TD patients also confirm that they are suffering cognitive dysfunction and, in more severe cases, a dementing process. Anosognosia involves denial of impaired or lost function following neurological injury (chapter 1). My experience coincides with that of Fisher (1989) [444], who stated that anosognosia "may qualify as one of the general rules of cerebral dysfunction" (p. 128). Thus the presence of anosognosia in TD patients tends to confirm the existence of generalized cerebral dysfunction in these patients. Anosognosia, as described in chapter 1, is an aspect of the broader concept of intoxication anosognosia or medication spellbinding. The spellbinding effect of neuroleptics is caused by their direct toxic effects and also by the irreversible damage that they inflict upon the brain.
Multiple publications confirm that most TD patients do not complain about their symptoms and will even refuse to admit their existence when confronted with them (Alexopoulos, 1979 [23]; Breggin, 1983b [181], 1993 [194]; Chard et al., as cited in Myslobodsky, 1993 [966]; DeVeaugh-Geiss, 1979 [357]; Smith et al., 1979 [1194]; Wojcik et al., 1980 [1354]).
Patients with TD not only display indifference toward their symptoms, they sometimes confabulate about them. Smith et al. (1979) [1194] cited several studies showing that TD patients typically refuse to recognize their symptoms. They observed,
"We were so convinced that many patients were aware of their symptoms but unwilling to report them that toward the end of the project we started to ask patients at the completion of the examination if they noticed any abnormal movements in other patients. Several of the patients described the symptoms of tardive dyskinesia in other patients in great detail. Although it is conceivable that these patients might have been unaware of their own tongue or mouth movements, it is difficult to see how they could not have observed their own hand, feet, or leg movements."
DeVeaugh-Geiss (1979) [357] confirmed denial of symptoms as well as lobotomy-like indifference in TD patients. Despite repeated inquiries,
"Seven of these [fifteen TD] patients consistently and repeatedly denied that they had abnormal or involuntary movements, despite the fact that most of them had symptoms that were severe enough to cause some difficulty with speech, ambulation, or coordination of ordinary motor movements such as those used in eating or dressing."
Wojcik et al. (1980) [1354] found that 44% of patients with TD denied awareness of their abnormal movements. Joyce Kobayashi (as cited in Patient May Not Be Cognizant, 1982) described the lack of awareness or concern about their symptoms found in more than half the TD patients selected from four words at the Bronx Veterans Administration Medical Center.
Myslobodsky et al. (1985) [967] found that 88% of the TD patients "showed complete lack of concern or anosognosia with regard to their involuntary movement" (p. 156). The study also found other indications for cognitive deficits in these patients. Myslobodsky (1986) [965] reported "emotional indifference or frank anosognosia of abnormal movements" in 95% of TD patients. He theorized that the most probable cause was "some form of cognitive decline associated with dementia disorder, probably owing to some neuroleptic-induced deficiency within the dopaminergic circuitry" (p. 4). In 1993, Myslobodsky [966] pointed out that patients suffer from denial of TD even while they remain able to voice complaints about their other medical problems and symptoms. He postulated at that time that "TD patients lose the motor part of their 'road map of consciousness.' "
These studies of denial in TD patients strongly confirm the association between TD and cognitive dysfunction. As mentioned earlier, the cause is probably twofold: the spellbinding effect of the drugs themselves, when the patients are still taking them, and the persistent effect of the brain damage caused by the drugs.
Chapter 2 described and documented the primary lobotomizing or deactivating effect of the neuroleptics. The anosognosia or denial exhibited by so many TD cases probably reflects a permanent deactivation phenomenon as well as a more specific intoxication anosognosia (medication spellbinding).
Bleuler (1978) [148] suggested that long-term exposure to neuroleptics can produce an irreversible frontal lobe syndrome with apathy and indifference. The syndrome would seem an inevitable consequence of the permanent dysfunction of dopaminergic neurons that frequently results from neuroleptic treatment. Some of these neurons (originating in the ventral tegmentum) project to the limbic system and frontal lobes. Others (from the substantia nigra) project to the striatum, where they also interconnect with the limbic system as well as with the reticular activating system (Alheid et al., 1990 [24]; see also Ethier et al., 2004 [411]; Seeman, 1995 [1150]). Injury in any of these regions of the brain tends to lead to deactivation of the brain and mind (chapter 1).
Chapter 3 documented that the neuroleptics can produce acute depression and psychosis. This chapter has documented the existence of tardive dysmentia and tardive dementia as well as tardive behavioral abnormalities in children. There is further evidence that the neuroleptics can also produce irreversible, schizophrenic-like psychoses, variously called supersensitivity psychosis, tardive psychosis, and rebound psychosis.
When Chouinard and Jones [281] first announced their discovery of tardive or supersensitivity psychosis at the annual meeting of the Canadian Psychiatric Association (see Jancin, 1979 [664]), one psychiatrist in the audience protested,
"I put my patients on neuroleptic drugs because they're psychotic. Now you are saying that the same drug that controls their schizophrenia also causes a psychosis and that on top of that the drug causes tardive dyskinesia one third of the time. It's a Hobson's choice. My patients are going to lose in the end either way."
One of the panelists, Barry O. Jones, warned, "Some patients who seem to require lifelong neuroleptics may actually do so because of this therapy."
In the published version (Chouinard et al., 1980 [281]), the authors suggested that the irreversible supersensitivity psychosis results from rebound hyperactivity of the blockaded dopamine receptors in the limbic system. They compared the mechanism of supersensitivity psychosis to that of TD. Tardive psychosis may be a mental manifestation of the same processes that cause the motor phenomena of TD.
Chouinard and Jones (1980) [281] noted that both the TD and the supersensitivity psychosis are masked, or hidden, when the patient is taking drugs. They further stated that continuous use of the drugs tends to worsen both diseases. Neuroleptic-treated patients have often developed tardive psychoses that became more severe than their original psychiatric disorders (Chouinard et al., 1980 [281]; Chouinard et al., 1982 [282]; Chouinard et al., 1978 [283]; Csernansky et al., 1982 [324]; Hunt et al., 1988; Mayerhoff et al., 1992 [894]; see also news reports by Jancin, 1979 [664]; "Supersensitivity Psychosis," 1983). Tragically, patients can require lifetime medication for a disorder that could have had a much shorter and more benign natural history.
Although Chouinard and Jones (1980) [281] found a prevalence of 30% to 40%, Hunt et al. (1988) reviewed the charts of 265 patients and located only 12 probable and no definite cases of tardive psychosis. Kirkpatrick et al. (1992) [764] cast a critical eye on the existence of tardive psychosis. Research commonly fails to detect even the most obvious adverse drug effects, resulting in so many drugs reaching the market without their most serious side effects being detected. That so many researchers have documented tardive psychosis should, by now, confirm its existence.
Since my lengthy review of the subject in Psychiatric Drugs: Hazards to the Brain (1983b), and then in the 1997 edition of this book, the literature on tardive psychosis has become sparser. After an initial burst of research in this arena, much like in research concerning cognitive disorders and dementia, there has been a slowing down of interest. Not surprisingly, the psychopharmaceutical complex discourages research that undermines its products.
The 2003 edition of The American Psychiatric Publishing Textbook of Clinical Psychiatry makes no mention of tardive psychosis or supersensitivity psychosis in the discussion of adverse neuroleptic effects, including in the section "Tardive Disorders" (Hales et al., 2003 [589]). Nor is there any discussion of the many studies on cognitive deficits associated with neuroleptics and in particular with TD. The only mention of tardive psychosis occurs within a discussion of mood disorders with citations to three studies spanning 1991-1993. The 1993 study points to a possible biological mechanism in the death of striatal cholinergic neurons, caused by prolonged exposure to neuroleptics (Miller et al., 1993 [929]).
It is as if the profession has found the concept intolerable - that taking so-called antipsychotic drugs for prolonged periods of time causes a persistent psychosis worse than the original disorder - so it has chosen to ignore it. It is similar to the resistance we will find to admitting that so-called antidepressants, even in the short run, cause depression and suicidality (chapters 6 and 7).
Nonetheless, some studies continue to crop up, and concerns continue to be expressed. Llorca et al. (2001) [848] described a case of supersensitivity psychosis following abrupt olanzapine withdrawal. Lu et al. (2002) [856] reported two cases of older patients who developed hallucinations and delusions following withdrawal from metoclopramide (Reglan).
Stanilla et al. (1997) [1212] described three cases of delirium with psychotic symptoms due to clozapine withdrawal (see also Adams et al., 1991 [13], for an early report of clozapine withdrawal psychosis). They believed that clozapine produces more severe withdrawal symptoms than typical antipsychotic agents. In a 3-year open label study of quetiapine, Margolese et al. (2004) [875] switched 23 male patients from classical antipsychotics and risperidone to quetiapine: "Six of the seven patients who relapsed after being stabilized on quetiapine for at least three months met the criteria for supersensitivity psychosis." This is a very high rate, again raising questions about whether atypicals may be more prone to cause tardive psychosis.
British psychiatrist Moncrieff (2006b) [941] reviewed the literature and found especially strong evidence that clozapine causes withdrawal psychoses. She observed that some reported cases occurred in people without a psychiatric history and concluded, "These effects require further urgent research." In another article discussing why it is so difficult for patients to stop psychiatric medication, Moncrieff (2006a) [940] warned, "The implications of these effects include the possibility that much of the research on maintenance treatment is flawed and that the recurrent nature of psychiatric conditions may sometimes be iatrogenic." She noted studies indicating that 20% to 40% of people with severe psychotic disorders "can stop long-term treatment without difficulty" and urged consideration for the careful management of neuroleptic withdrawal.
Gualtieri (1993) [574] observed that the anxiety and emotional tension suffered by tardive akathisia patients are primary emotional and cognitive components of the disease. After reviewing the functional neuroanatomy, Gualtieri concluded,
"One is entitled to surmise, therefore, that affective instability and intellectual impairment may be the consequence of neuropathology at the level of the basal ganglia. ... TDAK [tardive akathisia] is one manifestation of that effect. There are probably others."
In other words, the existence of the syndrome of tardive akathisia demonstrates that the neuroleptics can produce irreversible damage to the mental life of the individual.
Animal autopsy data provide strong evidence that the neuroleptics frequently cause brain damage. Human autopsy studies are too few and contradictory to lead to a definite conclusion. Once again, interest in them has declined.
Earlier in the chapter 1 summarized the findings of Dorph-Petersen et al. (2005) [374] that clinical doses of haloperidol and olanzapine in monkeys produced marked shrinkage of the brain tissue with cell death through the brain, but most markedly in the frontal and parietal lobes. Multiple earlier controlled animal studies indicate that long-term, and sometimes short-term, neuroleptic treatment cause brain damage. Evidence of structural damage, including cell degeneration and death in the basal ganglia, is especially consistent after chronic administration of neuroleptics (Coln, 1975 [304]; Jeste et al., 1992 [685]; Mackiewicz et al., 1964 [862]; Nielsen et al., 1978 [988]; Pakkenberg et al., 1973 [1016]; Popova, 1967 [1045]; Romasenko et al., 1969 [1095]; reviewed in Breggin, 1983b [181]). Far fewer studies have been negative (Fog et al., 1976 [452]; Gerlach, 1975 [511]).
After one "comparatively low" dose of chlorpromazine, 0.5-5 mg/kg, Popova (1967) [1045] found structural changes in rat brains, including "swelling, chromatolysis and vacuolization of the nerve cell bodies" (p. 87) in many regions, including the sensory-motor cortex, midbrain, hypothalamus, thalamus, and reticular formation. In 1992, Jeste et al. [685] reviewed the literature and published the results of exposing rats to fluphenazine decanoate (5 mg/kg, intramuscular) every 2 weeks for 4, 8, or 12 months. The density of large neurons in the striatum was measured after sacrifice by a computerized image analysis system. This team found a reduced density by 8 months of treatment.
Most animal studies report irreversible neuronal damage, including cell death, after relatively brief exposure to neuroleptics. Of great importance, animal studies with longer durations of exposure to neuroleptics - 1 year (Pakkenberg et al., 1973 [1016]), 8 months (Jeste et al., 1992 [685]), and 36 weeks (Nielsen et al., 1978 [988]) - show the expected neuronal deterioration in the basal ganglia.
Animal research provides definitive and apparently incontrovertible evidence that neuroleptics often cause irreversible brain damage. This is consistent with more recent studies reviewed earlier in the chapter that demonstrate how both older and newer atypical neuroleptics are highly toxic to living cells in animals.
There are surprisingly few human autopsy reports examining the effects of chronic neuroleptic therapy. Older studies have been reviewed by Bracha and Kleinman (1986) [165], Brown et al. (1986) [231], Jeste et al. (1986) [687], and Rupniak et al. (1983) [1113]. Although somewhat inconclusive, autopsy evidence does suggest that the neuroleptics can damage the basal ganglia, an area potentially critical in the production of both TD and tardive dementia. But the literature, overall, is scant, contradictory, and not conclusive. The studies of Arai et al. (1987) [63], Brown et al. (1986) [231], Christensen et al. (1970) [286], Forrest et al. (1963) [479], Gross and Kaltenback (1968) [569], Hunter et al. (1968) [641], Jellinger (1977) [674], Roizin et al. (1959) [1094], and Wildi et al. (1967) [1342] are reviewed in more detail in Breggin (1990 [187]).
Chapter 3 mentioned the similarity between neuroleptic malignant syndrome and an acute episode of the viral disorder, lethargic encephalitis (encephalitis lethargica, or von Economo's disease). The parallel suggests that the neuroleptics, in their primary impact, produce a controlled chemical encephalitis, which, when out of control, becomes neuroleptic malignant syndrome, indistinguishable from a fulminating viral encephalitis (Breggin, 1993 [194]).
There are many other ways in which neuroleptic drug effects closely mimic those of lethargic encephalitis, as reported during and after World War I (Breggin, 1993 [194]). Both the neuroleptics and the viral disease produce mental apathy and indifference. In a 1970 retrospective, Deniker observed,
"It was found that neuroleptics could experimentally reproduce almost all symptoms of lethargic encephalitis. In fact, it would be possible to cause true encephalitis epidemics with the new drugs."
The parallel between lethargic encephalitis and neuroleptic toxicity is remarkable in several respects. Both groups of patients initially display apathy or disinterest, followed by the onset of various dyskinesias. After a delay, the dyskinesias sometimes become permanent in both groups. Many lethargic encephalitis patients seemed to recover, only to relapse into devastating neurological disorders years later. While a Parkinsone like disorder was the most common tardive, or delayed, motor disorder associated with lethargic encephalitis, other dyskinesias more similar to drug-induced TD were also known to develop.
After an apparent recovery, many of the encephalitis victims later went on to develop severe psychoses and dementia (Abrahamson, 1935 [6]; Matheson Commission, 1939 [884]). Thus the completion of the parallel between lethargic encephalitis and neuroleptic effects awaited the discovery that in addition to TD, tardive psychosis and tardive dementia could follow the exposure to neuroleptics.
The parallel between the medication effects and the viral encephalopathic effects sounded a warning that similar mechanisms - and hence similar adverse outcomes - were possible. Only a few years after the advent of the neuroleptics, Paulson (1959) [1023] raised this concern when he wrote,
"The sequelae of encephalitis include many muscular, psychic and autonomic responses; and most of the neurologic complications from the phenothiazines are within the range of post-encephalitic Parkinsonism. (p. 800)"
Other investigators also noticed comparisons between neuroleptic toxicity and lethargic encephalitis (Brill, 1959 [226]; Hunter et al., 1964 [642]). Brill (1959) [226] documented that the hardest hit areas in lethargic encephalitis are the cells of the basal ganglia and the substantia nigra, the areas most affected by the neuroleptic medications in the production of TD (see Breggin, 1993 [194], for a further discussion of the anatomic pathways). There are multiple interconnections between the basal ganglia, reticular activating system, limbic system, and cerebral cortex, involving both motor and mental functions (e.g., Adams et al., 1989 [13]; Alheid et al., 1990 [24]; Brodal, 1969 [229]). As a result of the interconnections, neuroleptic-induced damage to the basal ganglia, if severe enough, would be expected to produce persistent cognitive deficits and dementia.
The association of mental deterioration with diseases of the basal ganglia and substantia nigra led to the concept of subcortical dementia (Huber et al., 1985 [636]), that is, dementia arising from damage to the basal ganglia and surrounding structures. Patients with subcortical dementia tend to be more depressed and apathetic, without as much evidence gross impairment to higher cortical functions. Subcortical damage to the basal ganglia is one of the brain-disabling mechanisms that make neuroleptic-treated patients more docile and less troublesome to others. Because higher cortical functions are less obviously damaged, observers can reassure themselves that the patients are not being grossly harmed, when in fact their overall energy level and quality of life are impaired by damage to subcortical functions.
Marsden (1976) [878] observed, "If long-term neuroleptic therapy can cause an apparently permanent change in striatal dopamine-receptor action, then one must assume that the same can occur in the mesolimbic cortical dopamine receptors" (p. 1079), that is, the highest centers of the brain. Marsden and Obeso (1994) [879] pointed out the complex interconnections between the basal ganglia and the frontal lobes and their possible role in higher mental functioning.
Animal research confirmed that supersensitivity of dopamine receptors develops in the mesolimbic and cerebral cortical areas, much as it does in the striatum (Chiodo et al., 1983 [277]; White et al., 1983 [1339]), and that it can become chronic after termination of neuroleptic treatment (Jenner et al., 1983 [675]; Rupniak et al., 1983 [1113]). While TD is difficult to reproduce in animals, Gunne and Haggstrom (1985) [582] were able to create both acute and irreversible dyskinesias in monkeys and rats. With persistent dyskinesias, they found evidence of irreversible biochemical changes in the basal ganglia and related areas (substantia nigra, medial globus pallidus, and nucleus subthalamicus).
Many researchers remarked on the relationship between neuroleptic-induced inhibition in the mesolimbic and cortical dopamine system and the clinical production of blunting or apathy (Lehman, 1975 [825]; White et al., 1983 [1339]). Irreversible changes to these biological systems account for many findings of permanent cognitive dysfunction.
Gualtieri and Barnhill (1988) [576] confirmed these observations:
"Persistent TD is probably the consequence of irreversible striatal damage. But the corpus striatum is responsible for more than motor control; it is a complex organ that influences a wide range of complex human behaviors. No disease that afflicts striatal tissue is known to have only motor consequences; Parkinson's disease and Huntington's disease are only two examples." (p. 150)
It is tragic that psychiatry persists in promoting the antipsychotic or neuroleptic drugs as specific treatments for "psychosis," "schizophrenia," and "mania," when in fact the drugs cause severe brain damage and dysfuction, effectively disabling the brain and mind, rendering individuals more docile as well as relatively indifferent to their own needs or suffering. The use of the neuroleptics is, to a great extent, a convenience for physicians and caretakers at the expense of the patients' well-being.
There is a very cogent reason to believe that the atrophy found on CT scans cannot be the product of schizophrenia. Brain atrophy is far more accurately and definitively evaluated by a direct postmortem pathological examination than on a CT or MRI brain scan. The actual pathology, if it exists, can more easily be identified and accurately measured by direct observation and microscopic analyses.
The CT scan and the MRI scan capture images in the range of the human eye. The MRI scan, for example, examines a slice of brain approximately 1-3 mm thick (Innis et al., 1995 [651]). That is the width of one to three pencil leads. Furthermore, the images are limited to black and white. The best MRI resolution only begins to approximate what can be seen with the naked eye on autopsy (Innis et al., 1995 [651]).
An autopsy can also obtain tissue slices for examination with a light microscope or an electron microscope. Furthermore, on gross examination of the brain, instead of estimating tissue loss from MRI pictures, an autopsy can actually weigh and measure the brain and examine cell density under the microscope. As a result, many diseases of the brain, such as Alzheimer's, require an autopsy rather than an MRI or CT scan to make the definitive diagnosis (Caine et al., 1995 [249]).
Despite the infinitely greater sensitivity, usefulness, and relevance of autopsy examinations and microscopic pathology studies, no consistent finding of brain atrophy or any other pathology has been made despite hundreds of these studies performed on thousands of patients diagnosed with schizophrenia prior to the use of neuroleptics (e.g., Bleuler, 1978 [148]; Nicholi, 1978 [986]; Noyes et al., 1958 [996]). Arieti (1959) [66] concluded that hopes for finding a neuropathology of schizophrenia "have remained unfulfilled" (p. 488). Weinberger and Kleinman (1986) [1325] estimated that by 1950, more than 250 studies had claimed to find a gross pathological defect in schizophrenia, and "the overwhelming majority of these claims were either never replicated, unreplicable, or shown to be artifacts". The task proved so frustrating that "the effort stalled in the 1950s" (p. 52). When the Task Force on Tardive Dyskinesia (American Psychiatric Association, 1980b [35]) made a brief reference to the initial CT scan findings of brain atrophy in neuroleptic-treated patients, it remarked, "This observation is quite surprising as it is not consistent with earlier neurologic evaluations of chronic schizophrenics; it requires further critical evaluation" (p. 59).
Furthermore, prior to the neuroleptics, there was no consistent dementia syndrome that could be clinically identified in association with so-called schizophrenia. In other words, until the advent of neuroleptic treatment, clinical examination of patients labeled schizophrenic had always failed to reveal anything that looks like a brain disease such as Alzheimer's or Huntington's chorea. That is why schizophrenia became known as a functional, rather than an organic, disorder and why a diagnosis of schizophrenia in fact requires first ruling out an underlying organic disorder. Schizophrenia is a diagnosis of exclusion-meaning that real diseases have been ruled out before making the diagnosis.
Meanwhile, as this chapter and earlier chapters document, the neuroleptics have indeed produced identifiable physical or organic disorders in patients labeled schizophrenic. Ironically, psychiatry has created what it always sought to find-something wrong with the brains of people diagnosed with schizophrenia. Having found it, psychiatry tends to deny the reality or to claim, once again, that the problem must emanate from the patients' preexisting schizophrenia. This claim is made despite a mountain of evidence proving that these same drugs are also toxic to the brains of animals.
In reply to the question, Do patients diagnosed with schizophrenia have cerebral atrophy, dilated ventricles, neurological deficits, or dementia? Lidz (1981) [841] observed, "For 100 years investigators have reported a neuropathological or physiopathological cause of schizophrenia. The trouble is that no such findings have been replicated. If the patient suffers from dementia, the diagnosis is not schizophrenia" (p. 854). Lidz recommended taking into account the impact of medications and shock treatment on the brain.
In summary, the failure to obtain consistent findings of cerebral pathology on postmortem examination prior to the drug era strongly indicates that more recent findings of atrophy on brain scans are the result not of so-called schizophrenia but of some new threat to the brains of these patients. The new threat is the widespread use of the neuroleptic drugs that are already known to cause brain diseases, including TD, neuroleptic malignam syndrome, and tardive dementia.
Other reasons to doubt that patients with schizophrenia have a deteriorating brain disorder were reviewed years ago by Manfred Bleuler (1978) [148]. First, unless caused by a toxic agent, which is then removed, organic disorders characterized by brain atrophy and dementia are usually progressive. Yet it is well documented by Bleuler and others that many patients diagnosed with schizophrenia improve over time; up to one-third or one-half show significant recovery over the years. They do not tend to show the physical signs of deterioration usually associated with progressive neurological losses, such as premature aging, infirmity, seizures, or neurological signs and symptoms. They die of the same diseases that afflict normal people. In following 208 patients for decades, Bleuler found that most of them remained in generally good health, "in spite of advanced age" (p. 450). Nowadays, of course, the widespread of neuroleptics results in anything but "generally good health" for those unfortunate enough to experience months and years of exposure to these toxic agents.
Second, a dementing disorder, once it has progressed, would rarely, if ever, clear up spontaneously. Yet there are many examples, even before the advent of medications, of patients abruptly and spontaneously improving for years at a time or for a lifetime. In addition, many patients wax and wane, showing great clarity at one moment and extreme irrationality at another (see Bleuler, 1924 [147]; Bleuler, 1978 [148]). These older observations are entirely consistent with my own clinical experience. Without using drugs, I am often able to help patients recover from hallucinations, delusions, and other symptoms that would have earned them a diagnosis of schizophrenia and a lifetime of drug treatment from most psychiatrists. Nor am I alone in finding that this supposed biological disorder can often be reversed by psychosocial interventions (chapter 16).
As another confirmation that these patients do not suffer from an irreversible physical disorder of the brain, sometimes an emergency will temporarily arouse a seemingly chronic and incapacitated patient into a state of acute awareness and rational behavior. As a resident, I was the admitting doctor for a patient diagnosed paranoid schizophrenic. She refused to let me perform a routine physical examination as a part of her admission to the psychiatric ward, until I noticed from her breathing that she had signs of pneumonia. When I told her, in effect, "You are really sick; I need to examine you," she stopped abehaving irrationally and allowed me to listen to her lungs, confirming my suspicion of pneumonia. When the exam was over, she reverted to her previous nearly catatonic behavior.
Third, patients diagnosed with schizophrenia do not suffer from the typical signs of the earlier stages of a dementing disorder such as short term memory dysfunction. They are usually easy to distinguish, for example, from victims of Alzheimer's disease, multi-infarct dementia, and the dementias associated with Parkinson's disease, Huntington's chorea, or multiple sclerosis.
Fourth, instead of deteriorating, the intellectual functions in patients diagnosed with schizophrenia become misdirected or psychologically irrational. As I describe in Toxic Psychiatry, patients diagnosed with schizophrenia often speak in unusual and complex metaphors dealing with psychological and spiritual conflicts over the meaning of love, life, or God. Often they display enormous passion around the concept of the own presumed evil or exalted nature. Quite frequently, only one or two specific false ideas (delusions) will appear in an otherwise normal mental life. These delusions will be defended with intellectual vigor and, a high degree of mental acuity, indicating that overall brain function itself is normal and often above average. Unless there has been exposure to neuroleptics, the patient diagnosed with schizophrenia will have an unimpaired IQ and no signs of neuropsychological deficits. For this reason, neuropsychological testing aimed at discovering organic brain deficits are of no use in diagnosing so-called schizophrenia, except to rule out other "real" diseases such as dementia.
In summary, there is little or no reason to believe that findings of brain atrophy and dementia are caused by so-called schizophrenia, while there is overwhelming evidence to indict neuroleptic therapy.
Meanwhile, the question "What is schizophrenia?" remains complicated and largely unanswered. In contrast to the biological theories now in vogue, many researchers have found that diagnosis holds little or no scientific validity, while others believe it reflects profound psychological disturbances reaching back into early childhood. This is not the place to discuss this question in any depth. However we view the diagnosis of schizophrenia, people given the label deserve to be protected from neuroleptics, a class of drugs that would probably be taken off the market if they weren't aimed at defenseless, stigmatized mental patients.
It took psychiatry 20 years to recognize TD as an iatrogenic illness, even as it afflicted half or more of hospitalized patients (Gelman, 1984 [506]). As noted in chapter 4, resistance to dealing adequately with TD continues (Breggin, 1983b [181]; Brown et al., 1986 [230]; Cohen et al., 1990 [295]; Wolf et al. 1987 [1355]). An even greater reluctance to recognize tardive dementia and brain atrophy was to be anticipated since the damage is still more catastrophic. Furthermore, it is easier to overlook cognitive deficits and dementia than to ignore dyskinesias, and easier as well to mistakenly attribute the mental symptoms to the patient's psychiatric disorder.
A variety of drugs are used to control neuroleptic-induced acute extrapyramidal effects such as tremors, rigidity, akathisia, and dystonia. Most of these agents suppress the cholinergic nervous system. They include benztropine (Cogentin), biperiden (Akineton), procyclidine (Kemadrin), and trihexyphenidyl (Artane). These agents produce multiple anticholinergic side effects, including glaucoma, severe constipation, ileus, and the inability to empty the bladder. Since many of the neuroleptics also produce anticholinergic effects, the likelihood of these adverse reactions is increased when they are combined.
From the brain-disabling viewpoint, anticholinergic drugs can cause confusion, organic brain syndromes, and psychoses. Far too little attention has been paid to their adverse effects on memory and learning, which can interfere with everyday living, rehabilitation, or school (Marcus et al., 1988 [873]; McEvoy, 1987 [905]). Furthermore, there is concern that the use of these drugs increases the risk of TD (APA, 1992 [41]).
As described in chapter 4, the difficulties associated with neuroleptic ithdrawal have led me to raise the issue of their potential to cause dependence (Breggin, 1989a [185], 1989b [186]). Meanwhile, clinicians have become increasingly aware of the difficulty of removing patients from neuroleptics, partly because of tardive psychosis. Withdrawal from the drugs can also produce transient or persistent dyskinesias, dysphoria, and autonomic imbalances, resulting in nausea and weight loss. In addition, underlying cognitive deficits become more apparent to the patient and other observers as the neuroleptic fog is lifted. As previously described, neuroleptics possessing marked anticholinergic effects can cause a severe flulike syndrome.
Since neuroleptics are extremely spellbinding, during or more likely after withdrawal the individual will have to face a variety of persistent or permanent adverse drug effects that went unnoticed during months and years under the influence of the drugs. Many former psychiatric patients feel betrayed by the doctors who inflicted these drugs on them, sometimes against their expressed will, and almost always without fully informing them about the risks. Am I going too far in suggesting that patients and their families are almost never fully informed by prescribing physicians about the risks associated with neuroleptics? I don't believe that I am exaggerating. Years of experience reviewing the medical records and treatment histories of other doctors, as well as their sworn depositions in legal cases, have confirmed the common sense conclusion that prescribing physicians cannot fully inform patients about the risks associated with neuroleptics because no one except the most self-destructive patient would knowingly take such toxic drugs. Doctors have to hide the mountain of risks associated with these drugs in order to get their patients to take them. In this sense, informed consent is largely a sham in regard to antipsychotic drug administration.
Chapter 15 describes how to withdraw from psychiatric drugs.
The neuroleptic drugs, including the newer atypicals, are highly toxic to brain cells. They cause cell death and tissue shrinkage throughout the brain and especially impair dopamine neurons in the basal ganglia. As a result, they produce a variety of potentially irreversible motor abnormalities in the form of TD, tardive dystonia, tardive akathisia, tardive dementia, and tardive psychosis, as well as the potentially lethal neuroleptic malignant syndrome. They frequently cause a parkinsonian syndrome with retardation of both mental and motor processes. Long-term treatment frequently produces irreversible mental dysfunction in the form of cognitive deficits, dementia, a worsening mental condition, and psychosis.
The most consistent information on the prevalence of marked or obvious brain damage has been generated by animal studies that demonstrate the mechanisms of toxicity within the cells as well as cell death and brain shrinkage. The animal research findings are confirmed in humans by brain scans measuring brain atrophy. We can estimate a prevalence of 10% to 40% among neuroleptic-treated patients. It probably exceeds 50% in older patients and after more intense, long-term treatment. Not surprisingly, these figures are somewhat parallel to those for TD, which strikes the same anatomical region of the brain, and can be found in 40% to 50% or more of relatively young long-term neuroleptic-treated patients.
In addition, numerous life-threatening adverse reactions have come to the forefront with the newer atypicals, such as hypertension; cardio vascular disease, including stroke in the elderly; obesity; elevated serum cholesterol; elevated blood sugar; diabetes; and pancreatitis. Finally, there is compelling new evidence linking neuroleptic use to premature death.
As described in earlier chapters, the "antipsychotic" effect of neuroleptics such as Haldol, Zyprexa, Risperdal, Seroquel, Abilify, and Geodon is mythical. All of the neuroleptics, including the so-called atypicals or second-generation drugs, produce a lobotomy-like disability of the brain, reducing the individual's emotional responsiveness and willpower, and causing apathy and indifference (chapter 2). Consistent with the brain disabling principles of biopsychiatric treatment described in chapter 1, these effects render the patient more manageable, less troublesome to others, and less aware or able to respond to his or her own needs and suffering. The supposed treatment in reality entails the infliction of a toxic disease process upon the patient remarkably similar to the viral disorder called lethargic encephalitis that afflicts the same regions of the brain and also caused apathy and indifference, as well as EPS.
All of the neuroleptics are profoundly medication spellbinding (chapter 1), rendering the user unable to perceive the damage being done to his or her brain, mind, and body. Because of this, the neuroleptics readily lend themselves to the creation of iatrogenic denial and helplessness, in which the doctor uses drug-induced brain damage and dysfunction to produce a more docile, less troublesome patient.
Since the mid-1950s, neuroleptic drugs have been prescribed to hundreds of millions of patients worldwide, producing an epidemic of iatrogenic brain damage, a broad spectrum of diseases, and an increased death rate among its victims. As suggested at the conclusion of chapter 4, an ethical and scientific psychiatry would devote itself to ending the use of these highly toxic agents. Instead, organized psychiatry and the pharmaceutical companies, supported by the FDA, continue to push successfully for an expanded use of these drugs, even in the treatment of children and youth.