Antipsychotic (Neuroleptic) Drugs and Schizophrenia
The earliest chemical theories of schizophrenia were focused on the neurotransmitter serotonin. This was because LSD and the other hallucinogens that produced mental and perceptual states that resembled schizophrenia blocked serotonin activity. It was hypothesized, therefore, that schizophrenia might be caused by a serotonin deficiency. However, the serotonin theory of schizophrenia was abandoned when it was realized that some hallucinogens did not block serotonin while some drugs that blocked serotonin activity did not produce hallucinations. Furthermore, in time it became clear that the "psychosis" produced by LSD and the other hallucinogens only superficially resembled schizophrenia, and once they had been alerted to the problem, psychiatrists could, in most instances, readily distinguish the real condition from the drug-induced states. 28
The Argument for the "Dopamine Theory of Schizophrenia"
After dopamine was acknowledged to be a separate neurotransmitter, several lines of evidence suggested that it might play the critical role in schizophrenia's etiology and treatment. From the outset, it was observed that practically all of the available antipsychotic drugs used to treat schizophrenia produced motor symptoms that resembled those of parkinsonism. When it was discovered that Parkinson -s patients were suffering from a dopamine deficiency, it was reasonable to hypothesize that antipsychotic drugs must be blocking dopamine activity. These observations led directly to the hypothesis that schizophrenics must suffer from excessive dopamine activity, which antipsychotic drugs correct.
The dopamine hypothesis evolved into a dopamine theory of schizophrenia when it was discovered that there was a strong relationship between the capacity of antipsychotic drugs to block dopamine receptors and their effectiveness (potency) in alleviating schizophrenia. Most antipsychotic drugs bind to dopamine receptors, but they do not trigger the normal physiological response that occurs when these receptors are activated by dopamine. Essentially, antipsychotic drugs are dopamine receptor antagonists - they block dopamine receptors and prevent dopamine (or dopamine agonistic drugs) from acting at these sites. This finding by Seeman and Lee and Snyder, together with their respective colleagues, seemed to be to be a major breakthrough, and it was published at approximately the same time in Nature and Science, the two most widely read scientific journals. 29 When it was later shown that a similar relationship did not hold for drugs that blocked either serotonin or norepinephrine receptors, the dopamine theory of schizophrenia was given a big boost. 30 Thus, although it was not possible to demonstrate any abnormally high levels of dopamine in schizophrenics, it appeared that this mental disorder might be caused by a hypersensitivity to dopamine. As Seeman later explained:
Although the dopamine content is found to be normal in the schizophrenic brain, an elevation in receptor-density would stimulate a "hyperdopamine-like" state. This is in contrast to drug-induced psychosis, as occurs in the hallucinations and delusions brought on by cocaine or high doses of L-DOPA. In these cases, the density of dopamine receptors is normal, but more dopamine is released, creating a hyper-dopamine and psychotic state. 31
A more direct way of determining whether there were excessive numbers of dopamine receptors in the brains of schizophrenics was required. By 1978, a technique for estimating the number of receptors in different regions of the brains of deceased patients was available, and Seeman and Lee and their colleagues reported that they had found a high number of dopamine receptors in the brains of schizophrenics. They concluded that while earlier the evidence supporting the dopamine theory of schizophrenia had only been circumstantial, "We have now obtained direct evidence for some abnormalities in brain dopamine receptors in schizophrenia" 32
Although Seeman and Lee's report of abnormally high numbers of dopamine receptors in the brains of schizophrenics seemed to provide strong support for the belief that these patients must be hypersensitive to dopamine, there were several reasons to have reservations about these initial findings. First of all, there were only twenty schizophrenic brains studied and there was an overlap in the dopamine receptor numbers obtained from the normal and from the schizophrenic brains. More critical, however, was the fact that most of the schizophrenic patients had been treated with antipsychotic drugs for some time before their death, and it is well known that the blocking of dopamine and other receptors produces a compensatory increase in receptor number (see Figure 4-1).
Figure 4-1 Blocking dopamine receptors with antipsychotic drugs leads to a compensatory increase in dopamine receptors. A) The number of receptors before administration of an antipsychotic drug. B) The blocking of the dopamine receptors by an antipsychotic drug produces a proliferation of these receptors. As the blocking of dopamine receptors also results in more dopamine being released (see Figure 3-2, page 86), it is difficult to know whether antipsychotic drugs result in a net increase or decrease in dopamine activity.
It is more than likely, therefore, that the higher receptor number found in some schizophrenic brains was a result of the treatment, rather than the cause of the disorder.
Seeman and Lee made an effort to obtain brains of schizophrenics who had not received any antipsychotic drug treatment, and they have reported that they have found an excessive number of dopamine receptors in the brains of schizophrenics never treated with drugs. Others, as will be described shortly, have not been able to replicate these findings. In the meantime, Seeman and Lee have refined their technique and have estimated the numbers of different dopamine receptor subtypes in the brains of schizophrenics. At least five different dopamine receptors have been identified. Using various radioactive drugs that bind somewhat selectively to one or another dopamine receptor types, Seeman and Lee claimed that the number of D2 receptors was abnormally high in the brains of schizophrenics, even those not treated with drugs. They began to refer to the D2 receptor as the "antipsychotic/dopamine receptor," implying that it was this receptor that was abnormal in schizophrenics and blocking these receptors accounted for the therapeutic effects of antipsychotic drugs.33
Thus, a number of lines of evidence seemingly confirmed the validity of the dopamine theory of schizophrenia. A more critical examination of the evidence, however, indicates that the theory is far from established.
A Critical Examination of the Dopamine Theory
By picking and choosing the evidence to be included, a seemingly convincing argument can be made that schizophrenia is caused by some impairment of a brain dopamine system. However, a more critical examination of the total evidence available reveals that it is far from established that a dopamine impairment underlies schizophrenia. While it is often said that schizophrenics have been found to have an abnormally high number of dopamine receptors, the evidence for this statement is not at all compelling. Even in those studies that found more dopamine receptors in schizophrenics compared to normal, the difference was only on average and did not apply to many schizophrenics. Furthermore, most investigators have not been able to find any evidence of dopamine receptor abnormality in schizophrenics. A multinational research effort involving patients and researchers from Germany, the United Kingdom, and Austria concluded that any difference found in D2 (or any other dopamine) receptors in the brains of schizophrenic is "entirely iatrogenic" meaning that any difference found was totally caused by prior treatment with antipsychotic drugs.34 In another report, Arvid Carlsson, one of the foremost contributors to the field of psychopharmacology in generai, and to our understanding of dopamine mechanisms in particular, concluded that there is:
no good evidence for any perturbation of the dopamine function in schizophrenia. An increased density of dopamine D2 receptors in the brains of schizophrenic patients analyzed postmortem has been reported, and one study with PET [Positron Emission Tomography] scan data showed the same thing, but the data from the Karolinska Institute by Farde and Sedvall show absolutely no difference at all.35
Other (PET) studies failed to find high numbers of any dopamine receptors in schizophrenics.36 Thus there is far ftom any agreement that most schizophrenics have an excess of dopamine receptors other than that caused by antipsychotic drug treatment. Moreover, as will be discussed in the next chapter, it is not clear even in those schizophrenics who do seem to have high number of dopamine receptors, unrelated to drug treatment, whether the dopamine abnormality was the cause or the effect of the disorder.
Studies of dopamine receptors have become more complicated as a result of the discovery that there are more dopamine receptors than just the D1 and D2 types. For example, when Pierre Sokoloff and his colleagues in Paris reported in 1990 that they had identified the D3 receptor, the interest in the report was so enormous that their paper was soon on the Top Ten List of Biology's Hottest Papers as tabulated by Science Watch.37 Five different dopamine receptors (D1-D5) have now been identified, and each of these has a somewhat different anatomical distribution in the brain.
Antipsychotic drugs are claimed to bind mostly to the D2 and D3 receptors and much less so to the D1, D4, and D5 receptors.38 This might seem to implicate the D2 and D3 receptors as the active site for antipsychotic drugs, except that some of so-called "atypical antipsychotics" such as clozapine do not to bind to (or bind very little to) these receptors. (The "atypical antipsychotics" are drugs that do not produce the often irreversible and disfiguring motor symptoms known as "tardive dyskinesia")39 The "atypical antipsychotics" are at least as effective in treating schizophrenia as the more traditional antipsychotics that act primarily on D2 and D3 receptors. It has been shown that 30 percent of patients who did not respond to treatment with three different standard antipsychotic drugs responded to "atypical antipsychotics." A number of clinical investigators have argued that the nonresponding patients may represent a subgroup of schizophrenics who do not have the usual dopamine problem. However, this argument cannot be valid, as "atypical antipsychotics" are also effective with patients who respond to drugs that block dopamine D2 receptors. Therefore, it is difficult to maintain that the antipsychotic drugs work because they correct the D2 receptor abnormality that is the cause of schizophrenia when a diverse group of patients with this illness respond to "atypical antipsychotics" that do not act on this receptor. Furthermore, the fact that some "atypical antipsychotics" have their major effect on serotonin, not dopamine, receptors casts furt~her doubt that any dopamine receptor is critically involved in the efflcacy of antipsychotic drugs.
A recent report from Japan has described a decrease (not an increase) in dopamine D1 receptors in the prefrontal cortex of schizophrenics, and its authors have speculated that this might underlie some cognitive impairment seen in this disorder.40 Interesting as this finding may prove to be, it would seem to make it even more difficult to explain why blocking dopamine receptors should be helpful to schizophrenics. Perhaps some clarity will eventually emerge from all of these preliminary findings and speculation, but at present the evidence fails to implicate any dopamine receptor as either the cause of schizophrenia or the critical site where an antipsychotic must act in order to be effective.
Another major problem for the theory that schizophrenia is caused by excessive dopamine activity is that antipsychotic drugs, as is also true of the antidepressants, generally take several weeks before they exhibit any significant therapeutic effect.41 This is true despite the fact that it has been demonstrated that the drugs block dopamine receptors in a matter of hours. After several weeks of drug treatment, there is a compensatory increase in the number of dopamine receptors and an increase in the firing rate of dopamine neurons. The increase in the number of receptors should increase the capacity of neurons to respond to dopamine, and when combined with an increase in firing rate of dopamine neurons and a consequent increase in the amount of dopamine released, dopamine activity might be expected to increase rather than decrease at the time that antipsychotic drugs first seem to be working-hardly a change that should correct excessive dopamine activity.
There have been some attempts to resolve this paradox by resorting to explanations based on what is known about the anatomical distribution of many D2 receptors. Many of the D2 receptors, which have been hypothesized to be critically involved in schizophrenia, are "autoreceptors." An "autoreceptor," which is located on the body of dopamine releasing neurons, acts like a brake, slowing the firing rate of dopamine neurons and decreasing the amount of dopamine released. If these autoreceptors are blocked by a drug, it has the effect of removing a brake (or stepping on the gas pedal), and the neuron's firing rate is increased. As most antipsychotic drugs block D2 autoreceptors, this should produce an increase in the firing rate of dopamine neurons and an increase in the amount of dopamine released into synapses. Once again, a paradox appears, as an increase in the firing rate of dopamine neurons would seem to be just the opposite of what a drug should do in order to alleviate a theorized dopamine hyperactivity.
In an attempt to resolve the paradox, it has been suggested that when neurons fire at an abnormaiiy high rate for about a three-week period, their cell membranes "depolarize." Depolarization refers to a reduction in the voìtage differential between the cell membrane and the cytoplasm within the neuron, a condition that blocks the ability of a neuron to fire and to release its transmitter. It has been reported in a recent study that the capacity of chronic administration of different antipsychotic drugs to produce depolarization block of dopamine neurons was related to their antipsychotic efficacy in humans. While the depolarization block phenomenon may prove useful for screening new antipsychotic drugs, its significance for the dopamine theory of schizophrenia is not at all clear. The principal researchers working on the depolarization effects of antipsychotic drugs believe that there is no reason to think that depolarization represents a return to the normal state of the dopamine system, and they conclude that there is probably nothing at all wrong with the dopamine system in schizophrenics.42
Is Schizophrenia One Disease?
It should not be surprising that the search for biological correlates of schizophrenia has consistently produced variable and difficult-to-replicate results. Schizophrenic patients are a very heterogeneous group and most if not all mental health professionais think that it is likely the diagnosis covers several separate disorders with different etiologies. The German psychiatrist Emil Kraepeiin, who provided one of the first classifications of psychiatric disorders around the turn of the century, called schizophrenia dementia praecox because he considered these patients to have "demented" thought processes that first became evident during adolescence.43 Kraepelin divided dementia praecox into four types: simple, hebrephenic, catatonic, and paranoiac.44 Eugen Bleuler, who introduced the term schizophrenia around 1910, referred to "the Group of Schizophrenias" 45 In the 1970s, the label schizophrenia was used so broadly in the United States that it was estimated that it was three times as likely that a patient would be diagnosed as schizophrenic in that country as in Great Britain.46 In recent years, the diagnosis of schizophrenia has been made more objective by listing explicit criteria in the Diagnostic and Statistical Manual (DSM) published by the American Psychiatric Association and in other widely used manuals such as the International Classification of Diseases (ICD) published by the World Heaith Organization. Now that more objective diagnostic criteria are used, the incidence of schizophrenia is estimated at between 1 and 2 percent of the population in most countries.
The topic of diagnostic labeling will be discussed more fully in the next chapter, but it is important to recognize that different types of schizophrenia are still recognized, and many peopie believe that different causes may be involved and different treatments called for. The distinctions that are most commonly made today are between acute and chronic schizophrenia and between Type i and Type 2 schizophrenia. Acute and chronic refer, of course, to the duration of the illness, but there are other criteria as well. The acute schizophrenic usually has made a relativety good adjustment up to the time that the symptoms first manifest themselves, and the onset of the disorder is often relativety abrupt, although there are probabiy some early (prodromal) signs that the illness is developing. The symptoms most commonly associated with acute schizophrenia are delusions and hallucinations. Chronic schizophrenics, on the other hand, usually have a long history of marginal adjustment at work (if they can hold a job), and they tend to be socially withdrawn. Chronic schizophrenics often live somewhat isolated lives, have poor personal hygiene, exhibit bizarre behavior, have little affect, and may show signs of disturbed speech and writing, using nonexistent "words" (neologisms) and incomprehensible syntax ("word salad"). As in most typologies, there is a substantial gray area and much overlap, so, for example, there are chronic schizophrenics who have delusional thoughts and hallucinations, and acute schizophrenics may progress into a chronic deteriorated pattern.
Type 1 and Type 2 schizophrenics are distinguished primarily by their predominant symptoms, which overlap to a great extent with the acute chronic distinction. "Positive" symptoms, which predominate in Type 1 schizophrenia, refer primarily to hallucinations and delusions, symptoms not seen in normals. "Negative" symptoms, which predominate in Type 2 schizophrenia, refer to pathology characterized by the absence (or deficiency) of behavior present in normals. Thus, "negative" symptoms include a severe lack of social skill, lack of emotional responses, and a lack of communication skills.47 In general, positive symptoms predominate in acute schizophrenia and negative symptoms are characteristic of chronic schizophrenia.48
It is widely believed that dopamine has a closer relationship to positive symptoms than to negative symptoms. Antipsychotic drugs, which block dopamine receptors, are likely to be more effective in reducing hallucinations and delusions than they are in alleviating negative symptoms. Drugs that increase dopamine activity, such as amphetamine, tend to worsen positive symptoms, but they have little effect, one way or the other, on negative symptoms. Chronic schizophrenics tend to be less helped by antipsychotic drugs.
There has been speculation that different dopamine receptors may be related to positive and negative symptoms, and pharmaceutical companies are hoping that they will be able to develop drugs that will bind to the right combination of dopamine receptors to alleviate both positive and negative symptoms, without producing the adverse motor effects characteristic of most of the antipsychotic drugs. It has been proposed that there is a dopamine hyperactivity only in Type 1 schizophrenics and that is why they respond best to the antipsychotic drugs that block dopamine receptors. However, this hypothesis is contradicted by several lines of evidence. For example, positive symptoms have been shown to respond to those "atypical antipsychotics," such as clozapine, which are not particularly effective in blocking dopamine activity. Moreover, patients do not nicely divide themselves into Type 1 and Type 2 schizophrenia. Many patients exhibit a mixture of positive and negative symptoms, and there are schizophrenic symptoms that do not easily fit into either the Type 1 or Type 2 category.49
Current Status of Antipsychotic Drugs
Our present confusion about what causes schizophrenia and how drugs sometime help is revealed by some of the latest drugs that have been marketed to treat this disorder. Eli Lilly recently started to market the antipsychotic olanzapine (proprietary name Zyprexa), which primarily blocks serotonin and dopamine receptors, but it also blocks some norepinephrine, acetylcholine, and histamine receptors. Olanzapine also binds weakly to some GABA and benzodiazepine receptors. In its package insert Lilly acknowiedges that how olanzapine or any other antipsychotic works is unknown, but it provides some speculation that the antagonism of dopamine and serotonin may be important. Lilly also includes a warning of the possibiity of adverse side effects such as tardive dyskinesia and the potentially life-threatening neuroleptic malignant syndrome (NMS).
Essentially the same statements about pharmacological action and possible adverse side effects are made about the new antipsychotic risperidone (Janssen Pharmaceutical's Risperdal) and about other new antipsychotic drugs. Much current antipsychotic drug development is influenced by the action of "atypical antipsychotic drugs," which tend not to produce the same adverse motor effects as do most antipsychotics, but some of them have their own problems.50 New antipsychotic drug development is often guided by an attempt to duplicate the profile of activity of the "atypical antipsychotics," but by making small chemical changes, it is hoped that it will be possible to improve efficacy and decrease the incidence of adverse side effects. Many of the newer antipsychotics tend to block the D2 dopamine receptor and the 5-HT2A serotonin receptor and are called "D2/5-HT
All of the antipsychotics fail to help a significant number of schizophrenic patients. John Kane, a professor of psychiatry at the Albert Einstein College of Medicine, has studied the effectiveness of antipsychotic drugs and has concluded that only about 50 percent of schizophrenic patients show any improvement after four weeks of treatment with these drugs.51 Moreover, if the nonresponders are continued at the same dose of medication, or if the dose is increased, or if they are switched to another antipsychotic drug, only 9 percent of these nonresponders show any improvement after an additional four weeks of treatment. Clearly, the drugs do not help a substantial number of people, and the honest answer is that we don't know why.
Those who respond to antipsychotic drug treatment are often caught in a "Catch 22" dilemma. If the drug treatment is stopped even after the patient's condition has been in remission for over a year, over three-quarters of them will relapse. However, if the drug treatment is maintained, the patients run a 25 to 40 percent risk of developing tardive dyskinesia.52 Moreover, there are several reports that schizophrenics treated with antipsychotic drugs that block dopamine activity are more likely to relapse into chronicity than patients not given drugs. A World Health Organization (WHO) study reported that schizophrenics in developing countries where drugs tend to be less prescribed do not relapse as often after a remission.53 As will be discussed in the next chapter, it has been demonstrated that repeated exposure to stress and such drugs as amphetamine, cocaine, and opiates, which stimulate dopamine activity, can produce long-lasting and perhaps permanent sensitization of dopamine circuits. This raises the possibiity that prolonged treatment with antipsychotics may also produce permanent changes in the brain that might increase the possibiity of a relapse.
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NOTES for chapter 5 of "Blaming The Brain"
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28. This tale is slightly modified from one described in Kety, S. S., A biologist examines the mind and behavior, Science, 1960,132.
29. Diamond, M. C., Enriching Heredity: The Impact of the Environment on the Anatomy of the Brain (New York: The Free Press, 1988).
30. Suddath, R. L., et al., Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia, New Engiand Journal of Medicine 1990,48,357-61.
31. LeVay, S., The Sexual Brain (Cambridge, Mass.: MII Press, 1993); Ward, L., and Ward, O. B., Sexual behavior differentiation: Effects of prenatal manipulations in rats, in Adler, N., Pfaff, D., and Goy, R., eds., Handbook of Behavioral Neurobiology, vol. 7 (New York: Plenum, 1985), pp. 77-98.
32. Alzheimer, A., Beitrage zur pathologischen Anatomie der Dementia praecox, Allgemeine Z. Psychiatrie, 1913, 70, 8 10-12.
33. Plum, E, Neuropathological findings, in Kety, S. S., and Matthysse, S., eds., Prospects for Research on Schizophrenia, Neuroscience Program Research Bulletin,1972, 10, 384-88.
34. Wyatt, R. J., Neurodevelopmental abnormalities and schizophrenia, Archives of General Psychiatry, 1996, 53, 11-15.
35. There have also been some studies of the brains of patients with obsessive-compulsive disorder. These studies used positron emission tomography (PET) scans, computerized-tomography (C-T) scans, and computerized averaging of magnetic resonance imaging (MRI) scans. For brief reviews of this literature and references to specific research see Williamson, E C., Schizophrenia as a brain discase, Archives of Neurology, 1993,50, 1096-97; Taubcs, G., Averaged brains pinpoint a site for schizophrenia, Science, 1994, 266, 221.
36. Weinberger, D. R., Berman, K. E., and Zec, R. F., Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia: I, Regional blood flow cvidence, Archives of General Psychiatry, 1986, 43, 114-24.
37. Goldman-Rakic, P., Dissolution of cerebral cortical mechanisms in subjects with schizophrenia, in Watson, 5., ed., Biology of Schizophrenia and Affective Disease (Washington, D.C.: American Psychiatric Press, 1995), 113-27.
38. There are reports that the amygdala, hippocampus, entorhinal cortex, and parahippocampal gyrus in the brains of schizophrenics tend to be significantly smaller than they are in normals. For one example, see Suddath, R. L., et al., Anatomic abnormalitics in the brains of monozygotic twins discordant for schizophrenia, New Eng. I. Med., 1990, 62-67.
39. Andreasen, N. C., et al., Thalamic abnormalities in schizophrenia visualized through magnetic resonancc image averaging, Science, 1994, 266, 294; Taubes, G., Averaged brains pinpoint a site for schizophrenia, Science, 1994, 266, 221.
40. A recent article has reviewed a number of the reports of brain anomalies claimed to have been found in schizophrenics and depressed patients. Sec Andreasen, N. C., Linking mmd and brain in the study of mental illness: A project for a scientific psychopathology, Science, 1997,275,1586-93. Sec also the study by Eric Hollander of the Mount Sinai Medical Center in New York in the February 1996 issue of the Archives of General Psychiatry
41. Andreasen, N. C., op. cit., p. 1590.
42. There is an eminently readable review of the genetics of mental disorders in Chapter 9 of Steen, R. G., DNA & Destiny, Nature and Nurture in Human Behavior (New York: Plenum, 1996).
43. This figure may be on the high side. More recent estimates of the concordance rate for identical twins are between 25 and 29 percent, and an estimate of a maximum of 2 percent (not far from the base rate for the general population) for second-degree relatives (nieces, nephews, aunts, and uncles). Walker, E., and Grimes, K., Gcnetic counseling for schizophrenia, Clinical Advances in the Treatment of Psychiatric Disorders (A KSF Publication), 1991, 5, 1-10.
44. A study had reported that a gene marker had been found on chromosome 11 in a population of Old Order Amish (Egcland, J. A. ct al., Bipolar affective disorder linked to DNA markers on chromosome 11, Nature, 1987,325,783-87). Several other studies failed to replicate these results and several of the original authors rctracted their original report. Sec Steen, R. G., op. cit., pp. 142-46, for references and a more complete discussion of these studies.
45. Sec Healy, D. T., op. cit., pp. 155-56.
46. Healy, D., Psychopharmacology in the new medical state, in Healy, D., and Doogan, D. P., eds., Psychotropic Drug Development: Social, Economic and Pharmacological Aspects (London: Chapman & Hall Medical, 1996), pp. 13-40 (quotation from pp. 30-31).
47. Solomon,A.,Anatomy ofmelancholy, The New Yorker, 12 January 1998, pp.46-61.
48. Shorter, E., A History of Psychiatry: From the Era of the Asylum to theAge of Prozac (New York: John Wiley, 1997), p. 296.
49. Szasz, T. 5., The Myth of Mental Illness: Foundations of a Theory of Personal Conduct (New York: Hoeber-Harper, 1961; revised 1974); Szasz, I. S., Law, Libcrty, and Psychiatry: An Inquiry into the Social Uses ofMental Health Practices (New York: Macmillan, 1965); Szasz, T. 5., Psychiatric Justice (New York: Macmillan, 1965); The Manufacture of Madness:A Comparative Study of the Inquisition and the Mental Health Movement (New York: Harper & Row, 1970); Law, Liberty and Psychiatry (New York: Macmillan, 1963); Psychiatric Slavery (New York: Free Press, 1977).
50. Szasz, T. 5., What counts as a disease? Canad. Med. Assoc. Journal, 1986, 135, 859-60. The views of the psychiatrist Peter Breggin are quite similar to those of Thomas Szasz. Breggin believes that psychiatric institutions and drug treatment are often used to incarcerate and subdue people who are unwanted and inconvenient, rather than for treating people with illnesses. See Breggin, P., Psychiatric Drugs: Hazards to the Brain (New York: Springer, 1983), pp. 5 5-56.
51. Szasz, T. S., The Myth of Psychotherapy (New York: Anchor/Doubleday, 1978), Preface, p. xv.
52. Szasz, T. 5., What counts as a disease? Canad. Med. Assoc. Journal, 1986,135,859-60.
53. Clouston, T. 5., Clinical Lectures on Mental Disease, 6th ed. (London: Churchill, 1904).
54. Moore, J. W, The syphilis—general paralysis question, Review of Neurology and Psychiatry, 1910, 8, 259-7 1; Noguchi, H., and Moore, J. W, Demonstrations of Spirochaeta pallida in brain in cases of general paralysis,J. Exper. Mcd., 1913,17,232.