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Psychoactive drugs - those that affect the brain and mind - can cause harm in two different ways55. Most obviously, they cause direct adverse effects by impairing the function of the brain or body. Drinking alcohol, for example, can result in an intoxication characterized by slurred speech, incoordination, and impaired mental processes. Many psychiatric drugs, especially sedative tranquilizers, have similar effects.
Psychoactive drugs can have equally harmful indirect effects that usually begin to develop after days or weeks of exposure to them. These indirect, delayed effects are caused by the brains attempt to overcome the original drug effect. In essence, by "fighting back" the brain creates its own problems. For example, when a person has been drinking, the brain becomes more excited or energetic in order to overcome the effects of the alcohol. If an alcoholic suddenly stops drinking, he or she can go into a state of withdrawal involving agitation, anxiety, tremors, and, in extreme cases, psychosis and seizures. Again, many psychiatric drugs produce similar withdrawal effects.
All psychiatric drugs produce both direct and indirect adverse effects. This chapter focuses on the direct effects, whereas Chapter 9 concentrates on the indirect effects that often manifest themselves between doses or during and after withdrawal.
The use of psychiatric drugs, especially stimulants, antipsychotics, and anticonvulsants for children and antidepressants for all age groups, has been escalating in recent years (Bender, 1998b [35]). At the same time, there has been growing concern about the adverse effects of prescription medications in general.
A recent study in the Journal of the American Medical Association (JAMA) concluded that the frequency of severe and fatal reactions to prescribed drugs in the United States is "extremely high" (Lazarou, 1998 [247]). More than 100,000 people a year are estimated to die in hospitals from drug reactions, implicating medications as one of the nation's top killers. Depending on the specific estimate, drug reactions in hospitals may constitute either the fourth or the sixth leading cause of death behind heart disease, cancer, and stroke.
The actual figures for drug fatalities are much higher than the estimates in the JAMA report, in part because the study was limited to hospitalized patients. Many patients die of drug-related causes outside of hospitals through suicide, accidents caused by mental impairment, and acute fatal reactions such as heart attack and stroke. The JAMA study also excluded patients who had been given inappropriate prescriptions, such as unusually high doses and unusual drug combinations. Yet inappropriate prescriptions are a very common cause of serious harm to patients. Given the large number of patients who were excluded by the JAMA investigators, it is likely that many more than their estimate of 100,000 Americans die of drug reactions each year.
The data in the JAMA report came as a shock to doctors who, as a group, tend to minimize the dangers of the drugs they prescribe. Death and other tragic outcomes from drug treatment often go unreported in order to protect doctors and hospitals from blame and lawsuits. The JAMA report found that only heart disease, cancer, and stroke likely cause more deaths than adverse drug reactions. There are, of course, famous national associations devoted to reducing the risk of harm and death from these three diseases, as well as from lung diseases, diabetes, and other disorders that may produce fewer deaths than medications. But there are no national associations to prevent death from prescription medication. Motivated by self-interest, drug manufacturers and the medical establishment have little desire to increase the public's awareness of this problem.
True to form, when the JAMA report came out in 1988, the Pharmaceutical Research and Manufacturers Association - an industry lobbying group - warned the public not to make too much of the ominous findings. Rather than showing concern for the safety of patients, some doctors voiced concern that patients would be scared off from taking drugs56.
We previously described how psychiatric drugs in general produce varying degrees of toxic psychoses and other severe mental abnormalities, including anxiety, depression, and mania (see especially Chapter 3). Confirming the frequency of adverse reactions to psychiatric drugs, a German study found that 11 percent of hospitalized psychiatric patients developed adverse drug-induced symptoms that were severe enough to warrant discontinuation (Spieb-Kiefer et al., 1998 [349]). The researchers observed that life-threatening reactions were relatively common, occurring in 1.8 percent of the patients. By far the most common severe reaction was "toxic delirium", a drug-induced state of confusion, disorientation, and generalized mental impairment.
Elderly patients are especially prone to toxic psychoses as well as to less intense mental impairments from almost any mind-altering drug. Typical effects on the elderly include stimulation, excitement, insomnia, depression, and memory problems.
Toxic psychoses, which occur in varying degrees of severity, are also diagnosed as delirium, organic brain syndrome, confusion, or mania. Sometimes a doctor, family member, or patient may notice one or two possible symptoms of toxic psychosis - such as agitation, disorientation, incoherence, disturbed concentration, memory difficulties, or hallucinations - without recognizing the severity of the overall mental dysfunction.
Anxiety and depression are frequently caused by psychiatric drugs. They can appear in either the presence or absence of toxic psychosis.
Mania is a specific toxic psychosis frequently caused by drugs. Based on data gathered from all U.S. trials for the FDA approval of Prozac, the manufacturer reported a 0.7 percent rate of hypomania/mania among Prozac patients57. Internal documents from the FDA, however, show a rate for mania of slightly above 1 percent - a rate much higher than that for the other antidepressants used for comparison in the trials58.
Recall that drug-induced mania is a severe psychotic disorder whose symptoms include extreme overactivity, insomnia, racing thoughts, frantic and exhausting outbursts of energy grandiosity and fantasies of omnipotence that may lead to bizarre and destructive actions, paranoia, and sometimes even suicide (see Chapter 3). People undergoing drug-induced mania have been known to throw away their life's savings on unrealistic schemes or to ruin or quit jobs and marriages that were previously successful. Some end up in mental hospitals or jails. Others commit violence59.
If we accept the estimate that approximately 1 percent of depressed patients treated with Prozac will develop potentially devastating manic reactions, that works out to be a thousand people out of every million. These figures are disastrous in themselves, but in routine clinical practice the reactions would be much more frequent and severe. In the clinical trials used for FDA approval of Prozac, individuals with a history of mania were excluded, while in clinical practice the antidepressant is frequently prescribed to people with a history of, and a potential predisposition to, mania. In the clinical trials, Prozac was not used in combination with stimulants and other antidepressants, while in clinical practice, these other drugs are commonly given along with Prozac, greatly increasing the risk of psychotic mania. And finally, in the clinical trials, patients were typically evaluated once a week by means of checklists and interviews, while in clinical practice, patients frequently go many weeks or months without being seen by a doctor. With less monitoring in clinical practice, patients are likely to become much more psychotic before being detected and removed from the medication60.
Prozac even more commonly induces mania in children. In a study intended to tout the drugs safety and efficacy; 6 percent of the children were forced to drop out due to Prozac-induced mania61. None of the controls became psychotic. A similar drug, Luvox, produced a 4 percent rate of "manic reactions" in children, according to the Physicians' Desk Reference62.
Without a doubt, Prozac and other antidepressants are causing tens of thousands of psychotic reactions that can ruin the lives not only of the afflicted individuals but also of their family members. With the increasing prescription of such drugs to children, we expect the devastation to increase.
In their widely used drug handbook for doctors, J. S. Maxmen and M. G. Ward (1995) [267] summarize the available data regarding estimated rates of various adverse drug effects63. In the sections that follow, our references to these rates for drug-induced psychiatric and neurological disorders are intended to illustrate the frequency with which such disorders are caused by psychiatric drugs64. Even though our own estimates are sometimes higher, the rates reported in Maxmen and Ward's handbook are likely to startle and concern the reader.
Confusion and disorientation (22.8 percent of patients, with some studies reporting nearly 40 percent) and memory impairment (32.5 percent).
Ritalin. Psychosis (less than 1 percent at normal doses), confusion or dopeyness (2-10 percent), agitation and restlessness (6.7 percent), irritability and stimulation (17.3 percent), and depression (8.7 percent).
Amphetamines. This category comprises Dexedrine and Adderall, among other drugs. Psychosis (less than 1 percent in normal doses), confusion or dopeyness (10.3 percent), agitation and restlessness (more than 10 percent), irritability and stimulation (25 percent), and depression (39 percent!).
Confusion and disorientation (6.9 percent), hallucinations (5.5 percent), anxiety and nervousness (4.1 percent), depression (8.3 percent), and irritability, hostility and anger (5.5 percent). According to Maxmen and Ward, mania is particularly associated with Xanax (Maxmen and Ward, 1995 [267], p. 287).
Confusion and disorientation (11.3 percent) and excitement and hypomania (5.7 percent). However, evidence from other sources suggests even higher rates65.
Confusion and disorientation (1.5 percent) and excitement and hypomania (7.3 percent; Maxmen and Ward also note rates as high as 30 percent). As already noted, 6 percent of the participants in a recent controlled clinical trial involving Prozac for depressed children were forced to drop out due to Prozac-induced mania (Emslie et al., 1997 [142]).
Confusion and disorientation (6.2 percent), mental anxiety and nervousness (2 percent), physical agitation and restlessness (5 percent), excitement and hypomania (17.1 percent, with a range of 10-30 percent), myoclonic jerks (i.e., muscle spasms) (7 percent).
Thorazine. Confusion and disorientation (6.8 percent) and depression (13.9 percent).
Haldol. Confusion and disorientation (4 percent), mental restlessness and agitation (24 percent), physical restlessness and agitation (24 percent), and excitement (12 percent). Rigidity and acute dystonia - disabling, painful muscle spasms - occur at very high rates (30 percent each). The extraordinarily high rates for tardive dyskinesia (TD), as well as the danger of neuroleptic malignant syndrome (NMS), are discussed later in this chapter.
Our review of adverse drug effects across the spectrum of psychiatric medications focuses on neurological and mental malfunctions - that is, on malfunctions of the brain and mind - since these effects are most likely to be confusing to patients, their families, and their doctors. Too often, these effects are mistakenly blamed on the patients, "mental illness".
This category comprises Ritalin and Methylin (methylphenidate), as well as Ritalin SR, Ritalin LA, Concerta, Metadate CD and ER, Methylin ER, and Daytrana (long-acting), Dexedrine and DextroStat (dextroamphetamine or d-amphetamine), Adderall and Adderall XR (dexamphetamine and amphetamine mixture), Vyvanse (lisdexamphetamine), Desoxyn and Gradumet (methamphetamine)66. Both Cylert (pemoline) and, in Canada, Adderall XR, were discontinued or removed from the market in February 2005. For a list of stimulants, see Appendix A.
We are appalled by the widespread use of stimulants to control and suppress the behavior of children diagnosed with ADHD67. The aim is to correct behavior described in terms of hyperactivity, impulsivity, and inattention. In actuality, however, stimulants subdue behavior by impairing mental function, they often cause the very problems they are supposed to correct.
Ritalin and the amphetamines have almost identical adverse effects. Cylert is less addictive, but it has the extreme disadvantage of causing death due to liver failure in a small number of reported cases.
Stimulants have a powerful impact on the functioning of the brain and mind. They can lead to addiction and abuse. Children may give away or sell their stimulants to older children, who use them to get high. Parents may illegally use or sell their children's Ritalin or amphetamine.
In many or most children, stimulants routinely cause rebound, involving a worsening of behavioral symptoms a few hours after the last dose. And especially with larger or more prolonged dosing, they can lead to severe withdrawal reactions such as "crashing", which is characterized by extreme fatigue, depression, and even suicidal feelings (see Chapter 9).
Stimulants can also cause the following: excessive stimulation of the brain, including insomnia and seizures, agitation, irritability, and nervousness, confusion and disorientation, personality changes, apathy social isolation, sadness, and, very commonly, depression. The most characteristic toxic psychosis from stimulants is mania. In addition, stimulants can cause paranoia, involving fearful and even violent feelings toward others. Stimulants such as Ritalin have been used in experiments to worsen the symptoms of patients labeled schizophrenic - a practice that should be considered unethical68.
Furthermore, stimulants can cause a variety of emotional disturbances that are mistakenly considered "therapeutic", including flattened emotions and robotic behavior. Children who take these drugs frequently lose the sparkle in their eyes. The edge comes off their creativity and vitality. Some become zombie-like. When stimulants cause compliance, Obedience, reduced initiative, and reduced autonomy they make children easier to manage. But these "therapeutic" effects, such as compliance or increased obedience, should be viewed as adverse drug effects.
All stimulants can cause the very symptoms they are supposed to treat: hyperactivity, loss of impulse control, and diminished concentration and focus. They can worsen a child's or adult's reactions to stress or anxiety.
Stimulants also cause dizziness, headache, insomnia, palpitations, abnormally increased heart rate, increased blood pressure, cardiac arrhythmias (heart attacks due to arrhythmias have been reported to the FDA), . loss of appetite, weight loss, nausea, vomiting, constipation, and stomach pain, dry mouth, blurred vision, abnormal liver function, muscle cramping, tremor, hair loss, itching and scratching, severe and life-threatening skin eruptions, bleeding problems, weakened immunity, growth hormone disruption and prolactin hormone disruption. In 2006, following a series of reports of sudden deaths of children and adults taking stimulants, the FDA ordered a warning on all stimulant labels for doctors not to prescribe these drugs to those with heart problems. Ritalin causes liver cancer in rats, but this outcome has not been reported in humans. One study published in 2004 found evidence of genetic damage, using three different measures, in each of ten children immediately following a three-month course of Ritalin treatment. All children had tested normal on these measures prior to the treatment, and had undergone no major diet, weight, or environmental changes that could have caused these chromosomal alterations (El-Zein et al., 2004 and 2006 [140]).
Permanent tics, sometimes categorized as Tourette's syndrome, are a serious complication. They often start in the face and neck.
Stimulants suppress the growth of the body, including height and weight. This effect is mainly due not to suppression of appetite but to a disruption of growth hormone production caused by the drugs interference with pituitary function. Because growth hormone affects all organs of the body overall growth is suppressed, including that of the head and its contents, the brain.
Since stimulants disrupt growth hormone and suppress growth during childhood, in addition to causing multiple biochemical imbalances in the growing brain, we believe they should never be administered to children69.
Recently one of the authors had the opportunity to review the animal literature on brain damage and dysfunction caused by stimulant drugs70. All stimulant drugs can produce lasting abnormalities in the brain. The most extensive animal research has been conducted using amphetamines (Dexedrine, Adderall), which have been shown to cause permanent biochemical imbalances and cell death, even in short-term moderate doses. The high risk of permanent injury to the brain is one more reason not to prescribe these drugs to children.
This category comprises Prozac and Sarafem (fluoxetine), Zoloft (sertraline), Paxil and Paxil CR (paroxetine), Celexa (citalopram), Lexapro (escitalopram), Luvox (fluvoxamine), and Effexor (venlafaxine). See Appendix A for a complete list of antidepressants.
Prozac was the first selective serotonin reuptake inhibitor (SSRI) approved for use in the United States. It was followed by Zoloft, Paxil, and Luvox. Luvox was approved for obsessive-compulsive disorder. Effexor is not an SSRI, its direct impact is not limited to serotonin. Nonetheless, its adverse effects are similar to those of Prozac.
Serious criticisms of these drugs have been published for nearly 15 years now71. Despite the great hype surrounding these drugs, and despite their widespread use, there is little scientific evidence for their efficacy as antidepressants. The promise that they would have few harmful effects has not been fulfilled. During the first 12 years after its initial marketing, over 40,000 reports of adverse effects from Prozac were submitted to the FDA. No other drug comes close.
SSRIs were tailored to block the removal of the neurotransmitter serotonin from the synapse in order to cause increased firing of serotonin nerves. However, the brain is much more complex than this description implies. When serotonergic nerves are overstimulated, they tend to become less sensitive. This "downregulation" does not return to normal immediately after the drug is stopped. Whether downregulation can become permanent in this particular system has not been studied, but we believe it poses a serious risk to the brain.
These drugs are capable of producing effects very similar to those of amphetamine or methamphetamine, including an artificial feeling of well-being or energy, anxiety agitation, and insomnia. Prozac and Effexor are especially stimulating. The others can cause somnolence or insomnia. Like the amphetamines and all antidepressants, these drugs cause manic psychoses. As noted earlier, the first published randomized controlled trial of Prozac in children found that 6 percent of children taking it became manic and had to stop the drug (Emslie et al., 1997 [142]). Upon withdrawal, some patients may "crash" into depression and experience suicidal thoughts or commit actions similar to those associated with stimulants (see Chapter 9)72.
We have seen patients become very disturbed and violent, especially when the dosage is changing (as when a patient starts, increases, reduces, or stops the drug). Drug-induced loss of impulse control as well as agitation and mania are among the potential causes. Prozac can also produce akathisia - characterized by a feeling of being tortured from within - which is probably one of its mechanisms for causing self-destructive or violent behavior. Jonathan O. Cole, professor of psychiatry at Harvard and a participant in studies of Prozac, has seen cases of "obsessive suicidal thoughts" related to it73. Cole believes that the adverse reaction is "rare" but adds, "However, some psychiatrists do consider warning patients to check in or stop the medication should new, bizarre suicidal ideation occur".
Numerous suicide and murder cases have involved patients who have taken SSRIs for a few days or longer. The first case to go to court against Eli Lilly the manufacturer of Prozac, was secretly settled by the company during the trial in order to mislead the judge and jury into providing a verdict in its favor. Although the judge changed the jury verdict to "settled with prejudice", Lilly still publicly claims to have won a jury verdict74.
The first case to go to trial against GlaxoSmithKline and Paxil involved a sixty-year-old man who suffered from depression but had never before been violent or suicidal. After his second dose of Paxil, he killed his wife, daughter, and their granddaughter before killing himself. The judge found that there was scientific basis for permitting expert testimony implicating Paxil in murder and suicide, and the jury returned a verdict of $6.4 million against GlaxoSmithKline.
As documented in Peter Breggin's introduction, the FDA has finally admitted that all of the new antidepressants - including the SSRIs, Wellbutrin, Effexor, and Cymbalta - increase suicidal behavior in children and adults. The FDA's advisory committee has suggested limiting the warning about adult suicidality to "young adults", but the distinction is absurdly artificial. The data was generated by very limited controlled clinical trials and the finding must be taken seriously for all ages.
In some ways more important, the FDA now requires a warning about the stimulant or activation syndrome induced by all of the newer antidepressants. Consistent with observations first published by Breggin in a series of books and scientific articles beginning in 1991, this particular group of drug-induced symptoms includes aggression and hostility. Specifically, the antidepressant labels are now required to warn that the drugs are associated with the production of "anxiety agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania".
As noted in the Introduction, the FDA also added a section entitled "WARNINGS - Clinical Worsening and Suicide Risk", stating that adults "should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy or at times of dose changes, either increases or decreases".
There should no longer be any doubt that the antidepressants cause an increase in suicidal and violent behavior, as well as mania, and that they often lead to a general worsening of the patients mental condition. Drastic changes leading to destructive and criminal behavior often happen shortly after starting the drug or around dose changes, up or down; but they can occur at any time.
Withdrawal reactions also occur with these drugs and can be very severe (Chapter 9). Many patients become despondent, tearful, emotionally unstable and suicidal while trying to withdraw from these drugs. A large number suffer from bizarre neurological disturbances such as shock-like pains in the head and weird sensations in the skin. A significant number decide to resume taking the drugs because the process of withdrawal feels too painful to endure.
Because this group of drugs can cause agitation and anxiety they can lead to the increased use of alcohol and other calming drugs. We have seen recovered alcoholics resume their drinking after starting on Prozac.
Patients who take these drugs often experience flattened or dulled feelings. Families report that they are less attentive, caring, or loving. Sexual dysfunctions are common. Some patients become tired and even sleepy instead of agitated, particularly on Paxil and Zoloft.
Especially when combined with other drugs that stimulate serotonin, these drugs can produce serotonergic crises involving agitation, delirium, muscle spasms (myoclonus), various neurological abnormalities, and elevated body temperature. Some reports submitted to the FDA concern Prozac-induced tardive dyskinesia.
Many patients initially experience weight loss when taking SSRIs. While some people may welcome this effect, it can be harmful to those already suffering from lack of appetite and excessive weight loss. Furthermore, over a period of months this drug effect tends to reverse, and many people experience weight gain leading to obesity.
The blunting effects of SSRIs on libido and sexual functioning are now well established. In large surveys of thousands of patients in the United States and abroad, rates of SSRI-induced induced sexual dysfunctions reach upwards of 40 percent (Clayton et al., 2002 [91]; Williams et al., 2006 [390]), and in smaller studies, up to 70 percent of patients on Paxil and Zoloft reported sexual dysfunctions (Kennedy et al., 2000 [225]). Yet, the authors of one such survey concluded that "Physicians consistently underestimated the prevalence of antidepressant-associated sexual dysfunction" (Clayton et al., 2002 [91]). Recently reports of sexual adverse effects-total libido loss, loss of genital sensitivity and genital anesthesia - persisting months and years after cessation of SSRIs have begun to surface, leading some to suggest that these drugs may be permanently altering gene expression75.
This category comprises imipramine (Tofranil, Imavate, Presamine, SK-Pramine, Janimine), desipramine (Pertofrane, Norpramin), amitriptyline (Elavil), nortriptyline (Aventyl, Pamelor), protriptyline (Vivactil), doxepin (Sinequan, Adapin), trimipramine (Surmontil), and Anafranil (clomipramine).
Probably all antidepressants are capable of causing seizures and manic psychoses. Even relatively small doses can result in dulled and flattened feelings or agitated and "wired" feelings. Most tricyclic antidepressants have a variety of anticholinergic effects including blurred vision, dry mouth, constipation, difficulty urinating, and cardiac arrhythmias that sometimes prove fatal, especially among adults with heart problems and among children and the elderly. They frequently cause serious withdrawal reactions (see Chapter 9).
This category comprises Asendin (amoxapine), Desyrel (trazodone), Effexor (venlafaxine), Ludiomil (maprotiline), Remeron, Remeron Sol Tab, Remeron RD, Cymbalta (duloxetine), and Wellbutrin, Wellbutrin SR, Wellbutrin XL or Zyban (buproprion). See Appendix A for a complete list. Following an unexpectedly high number of reports of severe liver injuries, Serzone was withdrawn from the Canadian market in November 2003 and from the United States in May 2004.
Of extreme importance is the fact that the antidepressant Asendin is converted into a neuroleptic within the body producing the same problems as those associated with other neuroleptics, including tardive dyskinesia and neuroleptic malignant syndrome (see below). For this drug, the FDA requires class warnings regarding TD and NMS.
Ludiomil and Remeron are classified along with Asendin as tetracyclic compounds. Seizures and involuntary abnormal movements (extrapyramidal symptoms) have been reported in association with Ludiomil. Remeron is relatively new; hence its profile of adverse effects is less understood. Many of the adverse effects of other antidepressants, including the tricyclics, should be considered in regard to these three drugs. Remeron, in particular, tends to induce sedation as well as dizziness, weight gain, and low blood pressure. Cardiovascular problems have been reported in connection with both drugs. Like all antidepressants, they can cause toxic psychoses, including mania and delirium.
Effexor (venlafaxine), mentioned earlier as a drug that stimulates serotonin, also stimulates norepinephrine neurotransmission in the brain. However, its effects are very similar to those of Prozac, including stimulation, anxiety nervousness, insomnia, loss of appetite, and weight loss. In addition, it can cause agitation and mania, hostility paranoid reactions, psychotic depression, toxic psychosis, and hypertension.
Serzone (nefazodone) also stimulates serotonin and norepinephrine, but it has other effects as well. It is more likely to cause sleepiness than insomnia. It can produce lightheadedness, confusion, memory impairment, and hypotension. And it can lead to hostility, paranoid reaction, suicide attempts or ideation, derealization and depersonalization, and hallucinations. As he did in regard to Effexor, T. Moore (1997) [286] reviewed the FDA data generated during the approval process for Serzone. He found that suicides and suicide attempts were several times more frequent among patients on Serzone than on placebos.
Desyrel (trazodone) tends to cause sedation, dizziness, and fainting. It can lead to heart problems in cardiac patients. And among men it can cause a potentially serious adverse reaction called priapism - uncontrolled, irreversible penile erection that sometimes requires surgical correction.
Wellbutrin (buproprion) produces an unusually high rate of seizures. It is known to be very stimulating and agitating, causing anxiety, nightmares, and manic psychoses. In 1997, this very same drug, marketed as Zyban, was approved by the FDA as an aid for smoking cessation.
Duloxetine (Cymbalta) arrived on the antidepressant market in August 2004, when it was also approved for the treatment of diabetic neuropathic pain. A recent review summarized its most frequently observed adverse effects as "nausea, dry mouth, constipation, diarrhea, decreased appetite, weight loss, feeling of fatigue, dizziness, somnolence, hypohidrosis [lack of sweating], decreased libido and erectile dysfunction" (Balhara et al., 2007 [26]). A systematic review of its clinical trials by the independent medical journal Prescrire Internacional concluded that "In practice, duloxetine currently has no place in the treatment of depression or diabetic neuropathy. Its efficacy has not yet been demonstrated to be even equivalent to that of other available drugs, and it has too many adverse effects, given this degree of uncertainty"76. Another independent newsletter, noting that the manufacturer Eli Lilly claims that Cymbalta has special value in managing the painful symptoms of depression, concluded, "At this time, any claim that duloxetine is useful for managing pain is groundless" (Wolfe, 2005 [393], p. 3). Even more ominous, in 2004-2005 Cymbalta received considerable negative press surrounding the suicide of nineteen-year-old Tracy Johnson and several other volunteers who took the drug in the initial clinical trials for depression (Lenzer, 2005 [250]). Nonetheless, undoubtedly as a result of Eli Lilly's vigorous marketing and advertising campaign to doctors and the public, sales of Cymbalta jumped 85 percent in 2006 (Russell, 2007 [327]).
This category comprises Parnate (tranylcypromine), Marplan (isocarboxazid), Nardil (phenelzine), Eldepryl (selegiline), and Manerix (moclobemide, available in Canada).
Parnate is chemically similar to amphetamine and is very stimulating. Eldepryl was approved for the treatment of Parkinson's disease, and not for depression.
Although all antidepressants can cause toxic psychoses including mania, the MAOIs are particularly prone to these potentially life-ruining adverse reactions. They often produce mental abnormalities such as dulling of feelings or delirium. Especially when combined with certain foods and drugs, they can also cause life-threatening hypertensive crises (involving violent headaches and possible strokes) as well as serotonergic crises (involving agitation, delirium, muscle spasms, various neurological abnormalities, and elevated body temperature). These food and drug reactions can lead to coma or death. Patients and families should be warned about such problems in advance77. MAOIs interact especially dangerously with stimulants and antidepressants.
MAOIs have many of the same side effects as those typically associated with other antidepressants, but they also include hypertensive crises, low blood pressure, extreme fevers (hyperpyretic reactions), sexual dysfunction, daytime sedation, nighttime insomnia, excessive stimulation, muscle pain, and muscle spasms.
Years ago these drugs went out of favor because of their dangers and questionable efficacy. With the resurgence of biological psychiatry and the disappointing results obtained with other antidepressants, they are again in vogue.
Manerix is currently available in Canada but not in the United States. Although it does not suppress monoamine oxidase for as long as the other drugs in this class and is considered less of a risk for producing hypertensive crises when combined with certain foods, it shares a similar adverse reaction profile with the other MAOIs, including stimulation, insomnia, anxiety and agitation, and occasionally aggressive behavior. Liver problems have been reported in a small percentage of patients.
This category comprises Ativan (lorazepam); Klonopin (clonazepam); Librium, Librax, and Limbitrol (chlordiazepoxide); Paxipam (halazepam), Serax (oxazepam), Tranxene (clorazepate), Valium (diazepam); and Xanax (alprazolam)78.
These drugs are prescribed for anxiety, panic attacks, and related problems. They are also prescribed for insomnia. The benzodiazepines most commonly prescribed for insomnia are Halcion (triazolam), which is banned in England; Dalmane (flurazepam), Doral (quazepam); Prosom (estazolam); and Restoril (temazepam). Versed (midazolam) is also used in injectable form for anesthesia.
When they first came out in the 1960s, benzodiazepines were promoted as relatively safe and free of the well-known addiction problems associated with barbiturates. Nothing could be further from the truth. Consider Xanax, for example. Most patients taking this drug for even a few weeks will develop serious withdrawal problems, and many, if not most, will have trouble discontinuing the medication. In fact, it can be dangerous to stop any benzodiazepine too abruptly (see Chapter 9).
Especially in the case of short-acting agents such as Xanax or Halcion, withdrawal symptoms can occur on a daily basis in between doses. These often manifest as a rebound worsening of the original anxiety symptoms. The individual can end up cycling between withdrawal and intoxication from dose to dose throughout the day.
In addition to addiction and withdrawal reactions, patients taking benzodiazepines face hazards similar to those who abuse alcohol. Intoxication can sneak up on users without their realizing it. They can develop slowed thinking, slurred speech, lack of coordination, clumsiness and impaired walking (ataxia), tremor, poor judgment, and drowsiness. Drugged feelings and hangovers with amnesia are not uncommon.
Benzodiazepines work by producing a continuum of suppression of the brain. Initially, for some people, this suppression is experienced as relaxation or a reduction in anxiety and tension, an effect similar to that of alcohol. As the dose increases, sleep and eventually coma are produced. The drugs work by impairing brain function, which is sometimes experienced as relief from tension or anxiety.
Because they suppress overall brain function, all drugs that are used to reduce anxiety or to induce sleep will also impair high mental functions, including thinking and memory. While only a few studies have attempted to examine this danger, the long-term use of any such drug, especially in higher doses, should be viewed as posing a risk of irreversible mental dysfunction. One review of several studies found that after withdrawal from long-term benzodiazepine use, "there remains a significant impairment in most areas of cognition in comparison to controls or normative data". The authors concluded, "there may be some permanent deficit or deficits that take longer than 6 months to completely recover" (Barker et al., 2004 [28]).
Benzodiazepines can cause severe amnesia. Students taking them in order to sleep may lose a substantial part of their memory for the material they studied that same evening. The drugs can produce confusion, paranoia, and paradoxical reactions such as excitement, agitation, and rage and violence. They can cause toxic psychosis. (Xanax is especially known to cause mania). They commonly worsen depression and may lead to suicide. Like alcohol, they often make people irritable and impulsive. We know of individuals who have committed violence after taking just a few doses of these drugs. In cases of longer-term benzodiazepine toxicity users may lose their judgment and perform senseless, out-of-character acts of theft or other criminal activities79.
Halcion, a benzodiazepine used for inducing sleep, has been banned in England because it causes so many mental abnormalities, including depression and paranoia80. Versed, a very short-acting benzodiazepine used for anesthesia, commonly causes behavioral abnormalities following its use for anesthesia. We have seen a case in which the emotionally disturbing effects of Versed appear to have been long-lasting. Versed should be considered a very hazardous drug.
Benzodiazepines can cause muscular twitches and other abnormal movements that are so severe as to be mistaken for seizures. Like many psychiatric drugs, benzodiazepines can also cause headache, visual problems, and a variety of gastrointestinal disturbances.
This category comprises newer drugs such as Ambien (zolpidem), Lunesta (zopiclone), Sonata (zaleplon), as well as drugs on the market for decades, such as Atarax or Vistaril (hydroxyzine), beta-adrenergic blockers (beta-blockers) including Inderal (propranolol) and Tenormin (atenolol), BuSpar (buspirone), Miltown (meprobamate), and Trancopel (chlormezanone).
Drugs such as Lunesta, Sonata, and Ambien have been very widely advertised to the public and to doctors as safe and almost magically effective sleeping pills. Free samples are routinely offered to patients in various promotional strategies, and, as expected, the drugs have become increasingly popular, even among young persons. Unfortunately, virtually every available review of the evidence concludes that their benefits may be mostly illusory but their risks quite real. In clinical trials heavily biased in favor of these drugs, they succeed in adding mere minutes of sleep in comparison to placebo, while carrying much more risk of daytime fatigue, memory loss and other cognitive impairments, as well as morning-after difficulties with motor coordination (Glass et al., 2005 [177]). Older people, especially those over 70 and 80 years of age, remain the most frequent and long-term users of sedatives and hypnotics, but non-drug methods to induce and maintain sleep in older persons are consistently found to be superior, safer, and more durable (Sivertsen et al., 2006 [346]).
A variety of non-benzodiazepines are used for sleep and for the control of anxiety. Miltown is addictive and subject to abuse, and is very much like the benzodiazepines in its profile of adverse reactions. Trancopel can cause many of the adverse effects associated with other sedative drugs, including confusion and depression. Severe skin rashes have also been reported.
Ambien, like the benzodiazepines, can cause drowsiness, confusion, awkward gait, fatigue, headache, nausea, and memory problems. It can also cause dizziness and incoordination, resulting in falls, toxic psychosis, hallucinations, and nightmares, various sensory disturbances, and disinhibition (bizarre or dangerous behavior). Occasional reports and our own clinical experience suggest that it can produce dependence. In 2003, Ambien appeared on the list of psychotropic drugs of abuse of the United Nations' Vienna convention.
Atarax or Vistaril is an antihistamine with sedative qualities. We have seen cases of abuse of this drug, usually in combination with multiple addictions.
BuSpar can cause headaches, dizziness, and nausea. It can also produce tension or anxiety, abnormal dreams, delirium, and psychotic mania.
Barbiturates, which are prescribed to induce sleep and, sometimes, to reduce anxiety, include Amytal (amobarbital), Butisol (butabarbital), Mebaral (mephobarbital), Nembutal (pentobarbital), phenobarbital (generic), and Seconal (secobarbital).
Barbiturates are highly addictive and produce toxic symptoms similar to those of alcohol and the benzodiazepines, including sedation, clumsiness, slurred speech, and poor judgment. They also produce a withdrawal syndrome similar to that of alcohol and the benzodiazepines. They can cause paradoxical reactions such as excitement, hyperactivity and aggression. They can also cause hallucinations and depression. Extreme behavioral abnormalities are especially common among children and the elderly.
Other common problems associated with the use of barbiturates include dizziness or lightheadedness, nausea and vomiting, diarrhea, muscle cramps, and hangovers. According to one of the few studies of long-term adverse effects on mental function, relatively small doses of phenobarbital in children resulted in a measurable reduction in IQ. The drug had been administered over the long term for the prevention of seizures induced by high fevers. As emphasized earlier in the chapter, all drugs that suppress anxiety or induce sleep should be suspected of causing irreversible mental dysfunction when used over the long term.
Any drug associated with reduction of anxiety or increased sleep should also be suspected of causing tolerance - an increasing need for larger doses - as well as dependence. This is especially true of the benzodiazepines and barbiturates, but caution is suggested in cases of sedation or tranquilization from almost any drug. There is no "free ride". If the drug has a significant impact, the brain will likely try to compensate, producing the potential for rebound and withdrawal symptoms.
Beta-blockers suppress the heart rate, thereby reducing one of the most disturbing symptoms associated with acute anxiety - the pounding heart. They are also used in medicine to slow the heart rate.
Beta-blockers have more negative effects on brain function than many doctors realize. Drugs such as Inderal can cause serious depression in some patients (Bender, 1998 [34]). More commonly, they can cause sedation and slow down the thinking process in a manner that physicians describe as "clouding the sensorium". They can bring about a feeling of being "washed out" or lethargic. They can cause overstimulation, delirium, anxiety, nightmares, and more extreme psychotic symptoms such as hallucinations. They can also produce impotence, gastrointestinal upsets, low blood pressure, and slowed heart rate. A dangerous possibility is the constriction of the respiratory tract (bronchospasm). Withdrawal can be a problem as well, in that it can result in rebound or increased heart rate and blood pressure.
This category comprises several different drugs from different classes. They include Lithium (Eskalith, Lithane, Lithobid, Lithotabs) and the anti-epileptic or anticonvulsant medications, including Tegretol (carbamazepine), Depakene (valproic acid) and Depakote (divalproex sodium), Neurontin (gabapentin), Lamictal (lamotrigine), Topamax (topimarate), and Trileptal (oxcarbazepine). Other drugs prescribed as mood-stablizers include Klonopin (clonazepam), Calan (verapamil), and Catapres (clonidine). See Appendix A for a complete list.
These drugs are supposed to control mania or to reduce mood swings, which psychiatrists commonly call "bipolar disorder". Faced with disappointing results from the use of lithium, psychiatry turned to the use of anticonvulsants, three newer ones of which were approved by the FDA for the treatment of acute mania and bipolar disorder between 1994 and 2000. These drugs probably all have their effect by causing sedation and overall depression of the central nervous system. In 2006, however, as discussed in David Cohen's Introduction, there appeared several reports on the largest-ever study (nearly 1,500 patients) of the drug treatment of bipolar disorder. The study was unusual in that it was not funded by the drug industry, and it enrolled a broadly representative sample of patients diagnosed with bipolar disorder from across the country. The patients were seen as often as clinically desired, and the study claimed to use the "best available" drug treatments (mostly anticonvulsants, antipsychotics, lithium, and clonazepam) in addition to a standard psychosocial intervention. The results: only 28 percent of treated individuals achieved remission without experiencing a recurrence of major symptoms during the two-year follow-up (Perlis et al., 2006 [304]).
Lithium flattens emotions by blunting or constricting the range of feeling, resulting in varying degrees of apathy and indifference. It also slows down the thinking processes. This drug-induced mental and emotional sluggishness should be considered lithiums primary "therapeutic" effect. Lithium sometimes reduces the likelihood that a patient will become "high" or manic - but at the cost of brain dysfunction81.
Many people experience increasing memory problems after taking lithium for months or years. Their ability to work can become impaired.
Doctors and patients often mistakenly attribute these problems to other causes such as chronic fatigue syndrome, depression, or "old age". When the lithium is reduced or stopped, many people experience a rebirth of their cognitive and emotional capacities. Some patients, however, find that their mental faculties do not fully recover after years of lithium treatment.
Lithium can cause hypothyroidism, cardiac arrhythmias, weight gain, stomach discomfort and diarrhea, skin diseases such as severe acne and rashes, hair loss, tremor, an awkward gait, and serious disorders of the kidneys. It can cause serious, life-threatening toxicity of the brain, which may creep up on users whose judgment has become impaired by the same toxic process. For these reasons, routine blood levels are required to keep track of potential intoxication. It can cause an increased white count; concern has been expressed about its possibly causing leukemia. And, finally, lithium is known to cause birth defects, including heart malformations, and to suppress the brain of the fetus or nursing baby, leading to flaccidity and lethargy. Withdrawal from lithium commonly results in mania (see Chapter 9).
Depakote (Depakene) is somewhat similar to benzodiazepines and alcohol in that it can cause sedation, tremor, and difficulty walking. It can also cause behavioral abnormalities, including confusion or delirium. Over the long term it may impair mental abilities, and on rare occasions it has been known to cause liver failure. It can also cause weight gain, stomach upset, hair loss, rash, pancreatitis, and blood clotting problems.
Clonidine (Catapres) is an antihypertensive drug that can cause sedation and thus has found a place in psychiatric use. If withdrawn too quickly, it can produce rebound hypertensive crises. It can also cause many psychiatric problems including insomnia, nightmares, anxiety restlessness, depression, and, more rarely, hallucinations.
Klonopin, a benzodiazepine, can cause all the problems associated with this class of drugs, including dependence (see above). It is FDA approved for both seizures and panic attacks.
Tegretol is closely related to the tricyclic antidepressants and can cause all of the problems associated with them (see above). It poses a special danger of bone marrow suppression, involving loss of blood cells. Patients and their families need to be alert to early signs of this condition, including fever, sore throat, and tiny bleeding spots (petechiae) in the skin. Other side effects include sedation, fatigue, nausea, and lightheadedness. Higher doses can produce signs of neurological intoxication, including lack of coordination of the muscles. When the muscles of the eyes are affected, seeing double may result. Liver functions may show up as abnormal upon testing, and, more rarely liver toxicity may develop. Cardiac function can also be impaired. Rashes are common.
Calan, a calcium-channel blocker, is an agent used to treat cardiac disorders, but it can cause a variety of cardiovascular problems. Dizziness, headache, and nausea are common; high doses can result in sedation and lethargy. More rare are such serious adverse effects as cardiac arrhythmias that don't respond well to treatment, liver toxicity, and severe low blood pressure with fainting. The heart and blood pressure status of patients taking this drug should be checked for baseline and then for potential adverse drug effects.
Many benzodiazepines, anti-seizure medications and anti-hypertension drugs are used as mood stabilizers because of their sedating effects. The benzodiazepines and anti-seizure drugs should be gradually tapered to avoid withdrawal seizures, and the anti-hypertension drugs should be gradually tapered to avoid rebound spikes in blood pressure. An experienced health professional should be consulted about the length of time and dose schedule required for withdrawing from these drugs, many of which are listed in Appendix A.
The available neuroleptics or antipsychotics - previously called major tranquilizers - include phenothiazines and other drugs82. The phenothiazines include Compazine (prochlorperazine), Etrafon (antidepressant plus Trilafon), Mellaril (thioridazine), Prolixin (fluphenazine), Serentil (mesoridazine), Stelazine (trifluoperazine), Thorazine (chlorpromazine), Tindal (acetophenazine), Trilafon (perphenazine), and Vesprin (triflupromazine).
Other neuroleptics include Haldol (haloperidol), Inapsine (droperidol), Loxitane (loxapine), Moban (molindone), Navane (thiothixene), and Taractan (chlorprothixene).
"Atypical" or "second- or third-generation" antipsychotic drugs currently include Clozaril (clozapine), Risperdal and Risperdal Consta (risperidone), Seroquel (quetiapine), Zyprexa (olanzapine), Geodon (ziprasidone), Abilify (aripriprazole), and Invega (paliperidone, approved by the FDA in December 2006). Serlect (sertindole) was approved by the FDA in 1996 but never actually marketed in the United States because of later concerns over major cardiac effects. See Appendix A for a list of most antipsychotic drugs.
Orap (pimozide) is a neuroleptic that causes an especially high rate of adverse effects. In one clinical trial involving twenty patients, reported in the 1998 Physicians' Desk Reference [307], many of the patients suffered serious neurological impairments, including sedation (fourteen patients), akathisia or inner agitation causing hyperactive movements (eight patients), akinesia or slowed movements (eight patients), adverse behavior effects (five patients), and impotence (three patients). Orap was approved by the FDA for treating tics associated with Tourette's disorder, but not for treating psychosis. Nonetheless, the manufacturer, in its drug label, refers several times to Orap as an "antipsychotic", and some doctors use it for that purpose.
Sertindole and ziprasidone are other atypical neuroleptics currently undergoing or having recently undergone the FDA approval process. These drugs are intended for use in the control of psychotic patients, usually those diagnosed with schizophrenia or acute mania.
Neuroleptics have their main impact by blunting the highest functions of the brain in the frontal lobes and the closely connected basal ganglia. They can also impair the reticular activating or "energizing" system of the brain. These impairments result in relative degrees of apathy, indifference, emotional blandness, conformity and submissiveness, as well as a reduction in all verbalizations, including complaints or protests. It is no exaggeration to call this effect a chemical lobotomy.
Contrary to claims, neuroleptics have no specific effects on irrational ideas (delusions) or perceptions (hallucinations). Like all other psychiatric drugs, they have the same impact on healthy animals, healthy volunteers, and patients - namely, the production of apathy and indifference. They are even used in veterinary medicine to control violent animals. Most veterinarians, however, do not use them for long periods of time because they are considered too dangerous.
All neuroleptics produce an enormous variety of potentially severe and disabling neurological impairments at extraordinarily high rates of occurrence; they are among the most toxic agents ever administered to people.
Tardive dyskinesia (TD) is a common and yet potentially disastrous adverse reaction to all of the antipsychotic or neuroleptic drugs. TD involves irreversible abnormal movements of any of the voluntary muscles of the body. It commonly afflicts the face, eyes, mouth, and tongue, as well as the hands and arms, feet and legs, and torso. It can also affect breathing, swallowing, and speech. In some cases, spasms of the eyes are so severe that the person cannot see.
One variant of TD is tardive dystonia, which involves painful spasms, often of the face and neck. Tardive dystonia can be disfiguring and disabling, potentially impairing even the ability to walk.
Another variant of TD is tardive akathisia. The individual is virtually tortured from inside his or her own body as feelings of irritability and anxiety compel the person into constant motion, sometimes to the point of continuous suffering. We agree with T. van Putten and S. Marder who observe that akathisia, "in the extreme case, can drive people to suicide or to homicide"83.
Neuroleptics actually suppress the symptoms of tardive dyskinesia while the disease is developing. As a result, the afflicted individual, the family or the doctor may not recognize the impairment until the symptoms break through or until the drug dosage is reduced.
The rates of TD are extremely high. Many standard textbooks estimate a rate of 5 percent to 7 percent per year in healthy young adults. The rate is cumulative so that 25 percent to 35 percent of patients will develop the disorder in five years of treatment. Among the elderly rates of TD reach 20 percent or more per year84. For a variety of reasons, including the failure to include tardive akathisia in estimates, the actual rates are probably much higher for all patients85.
We have seen the lives of numerous individuals and their families wrecked by tardive dyskinesia. In many cases, patients and their families were not informed by doctors about the dangers of TD86. In other instances, several doctors - one after another - ignored obvious symptoms of the disorder. Often the drug dose was mistakenly increased instead of being reduced and stopped. The failure to stop the drugs at the first sign of the disorder resulted, in these cases, in painful, severely incapacitating, disfiguring twitches and spasms. The afflicted individuals were unable to work or to carry on a normal family or social life. Often they became depressed, felt humiliated by their physical appearance, and withdrew from loved ones.
Another disastrous reaction caused by neuroleptic drugs is neuroleptic malignant syndrome (NMS). Similar to viral brain inflammation (encephalitis), NMS is characterized by severe abnormal movements, fever, sweating, unstable blood pressure and pulse, and impaired mental functioning. Delirium and coma can also develop. NMS can be fatal, especially when doctors fail to recognize it in time. Patients who recover may be left with varying degrees of irreversible mental impairment as well as permanent abnormal movements87. This drug reaction looks so "bizarre" that many doctors initially, and even persistently, attribute it to the patient's "mental illness". In such cases, of course, it will go untreated - with tragic results.
Although many doctors and even some textbooks say that neuroleptic malignant syndrome is "rare", others such as A. F. Schatzberg, J. O. Cole, and C. DeBattista (1997) [331] give a more realistic estimate of 0.7 to 2.4 percent of hospital admissions treated with neuroleptics. The higher rate of 2.4 percent is probably the more accurate88. The FDA considers a rate of 1 percent to be "common" or "frequent". Like tardive dyskinesia, neuroleptic malignant syndrome may be caused by atypical antipsychotics. One review conducted in January 2003 located 68 published cases, most of which were caused by Clozaril, Risperdal, and Zyprexa (Ananth et al., 2004 [10]).
Using a low-end rate of 1 percent, Maxmen and Ward (1995 [267], p. 33) estimate that 1,000-4,000 deaths occur in America each year as a result of neuroleptic malignant syndrome. The actual number is probably much greater.
If such high rates for a dangerous and disabling adverse reaction were reported in relation to drugs used in general medicine, such as antibiotics or blood pressure medication, they would probably be removed from the market. Vulnerable mental patients, by contrast, are purposely exposed to brain-damaging treatments such as electroshock, psychosurgery, and neuroleptics.
A number of reports confirm that these drugs can cause very disabling withdrawal reactions, including irreversible psychosis (tardive psychosis) and irreversible deterioration of the mental processes (tardive dementia) (see Chapter 9). Tragically individuals treated for an acute and perhaps short-lived emotional disturbance can end up with a chronic drug-induced psychosis.
Unexplained sudden death is another adverse effect of neuroleptic drugs, especially among chronically hospitalized patients. It may be due to an increased rate of convulsions, impaired swallowing reflex, or heart attacks caused by arrhythmias. These medications also reduce the capacity to handle heat, resulting in numerous deaths in urban centers during heat waves. Because people on neuroleptics are less sensitive to signals from their body, they may become dangerously ill before they realize it.
All of the antipsychotics can cause a Parkinsonism syndrome, involving flattened emotions, stiff facial features, tremors, and a characteristic stooped and shuffling walk. The term akinesia, referring to the slowing down of emotions and movements, is used to describe an aspect of this syndrome. Antipsychotics can also produce acute and painful muscular spasms (dystonias) and very disturbing emotional agitation accompanied by a compulsive need to more about (akathisia). Studies indicate very high rates - sometimes exceeding 50 percent - for these acute adverse reactions. As we have described, such reactions can become permanent in a large percentage of patients.
Although there is some variation among medications in this class, all of them can cause toxic psychoses with delirium, confusion, disorientation, hallucinations, and delusions. The atypical antipsychotics are no exception. One article published at the time Abilify (aripiprazole) first appeared on the United States market, in 2004, described four cases of exacerbation of psychosis after starting on this drug. The report bears the unusually informative title "Aripiprazole possibly worsens psychosis" (Ramaswamy et al., 2004 [314]). Invega (paliperidone) was recently approved by the FDA. The agency described the drug as a new molecular entity, meaning that its active substance has never been approved for marketing in the United States. Nonetheless, every person who has ever taken Risperdal has had Invega coursing through his or her body - because Invega is simply the main active metabolite of Risperdal, on the market since 1994. Invega is now described in some publications as a unique antipsychotic, but many if not all of Risperdal's adverse effects can be expected to occur with Invega.
Probably all antipsychotics can also cause depression; Prolixin, in the long-acting intramuscular form, appears to be a special offender in this regard. Most of them can cause sedation and fatigue, seizures, weight gain, dangerous cardiac problems, hypotension (especially upon the patient's attempt to stand up), a variety of gastrointestinal problems such as paralysis of the bowels, hormonal abnormalities including swelling of the breasts and even lactation, sexual dysfunctions, disfiguring facial hair growth, skin rashes and sensitivity to sunlight, eye disorders, allergic reactions that can become serious, and disorders of body temperature regulation that can lead to fatalities on hot days.
Most neuroleptics can also cause bone marrow suppression (agranulocytosis or aplastic anemia), involving immunological suppression and the risk of serious, intractable infections. Though seemingly rare, except in the case of Clozaril, these blood disorders are potentially lethal. Families need to be alert to early signs, such as elevated temperature, and immediately seek medical evaluation, including a blood count. Unfortunately, many different kinds of psychiatric drugs can cause bone marrow suppression.
Although the reader may be feeling overwhelmed by the data presented thus far, this summary has only touched on the enormous range of often serious adverse effects associated with neuroleptics. These drugs subject almost every system of the body to impairment. Research, including a recent study, indicates that these drugs are toxic to cells in generals89.
Anyone, as well as their relatives and friends, taking these drugs should review the adverse effects listed in the Physicians' Desk Reference and other sources.
Loxitane, Moban, Navane, Orap, and Haldol essentially pose the same dangers as the phenothiazines, especially in regard to tardive dyskinesia and neuroleptic malignant syndrome. Haldol and Orap are especially prone to causing severe and painful neurological problems.
The atypical antipsychotics, touted for the past decade as breakthrough drugs in terms of improved efficacy and superior safety are not so atypical after all. All of these drugs have been shown to cause the range of neurological and psychological disorders associated with the other neuroleptics (antipsychotics) including tardive dyskinesia and neuroleptic malignant syndrome (see Chapter 9). One careful review concludes that "atypical antipsychotics continue to have notable risks of [abnormal movement disorders], particularly akathisia" (Shirzadi and Ghaemi, 2006 [344]). One of their best-documented adverse effects is commonly called "metabolic syndrome", which consists of abnormal sugar and/or insulin metabolism, weight gain, elevated cholesterol levels, and high blood pressure. Approximately 50 percent of patients on atypicals gain an average of 20 percent of their weight (primarily fat), and some gain much more. Weight gain can predispose individuals to various problems, including coronary artery disease, high blood sugar, and sleep apnea. In addition, atypical drugs are relatively stimulating drugs with a tendency to cause agitation and other behavioral abnormalities.
Clozaril (clozapine) is a more sedating drug than most in this class. Many patients who take it can expect to become lethargic, subdued, and sleepy. Some reports indicate that it can cause obsessive-compulsive disorder (OCD). Among antipsychotics it also has a special reputation for causing withdrawal problems, including agitation, anxiety and toxic psychosis (see Chapter 9).
Clozaril has many adverse effects, including low blood pressure and a 4-5 percent rate of seizures, especially at higher doses. Although we found only one published case of TD due to Clozaril, the FDA requires that the drug carry the standard class warning for TD. The drug's pharmacological actions are consistent with the production of this disorder. In addition, Clozaril is known to cause neuroleptic malignant syndrome, the more drastic and potentially lethal acute neurological impairment associated with neuroleptics.
Clozaril also poses a special danger of bone marrow suppression, which is potentially fatal. In such cases, the immune system is compromised, leading to fatal infections. Rates approach 1 out of 100 patients. Years ago, this drug was banned in some European countries because it caused so many fatalities; but the escalating power of drug companies subsequently led to its approval by the FDA. Patients and families should seek immediate medical attention if a fever or other signs of infection develop during the administration of any neuroleptic drug, especially Clozaril.
The neuroleptics or antipsychotics are extraordinarily dangerous drugs. If they were not highly profitable drugs used to control a rather helpless, stigmatized, or troubling population, often including involuntary patients, these drugs would not be so freely prescribed. They might even be taken off the market.
This category comprises Symmetrel (amantadine), Sinemet (carbidopalevodopa), Cogentin (benztropine), Akineton (biperiden), Kemadrin (procyclidine), Artane (trihexyphenidyl), and Parsidol (ethopropazine).
Here we describe various drugs used to treat the abnormal movements that are produced during treatment with the neuroleptics. Although they are often effective in reducing some of these acute neurological reactions before they become permanent, they may increase the likelihood that the neurological impairments will become permanent in the form of tardive dyskinesia. Once tardive dyskinesia develops, they can worsen it.
All of these drugs can also cause a range of effects described as anticholinergic, because they suppress the function of the neurotransmitter acetylcholine. Anticholinergic effects include potentially severe constipation with bowel obstruction and difficulty urinating, dry mouth, blurred vision, light sensitivity dizziness, and stomach upset. The drugs can also worsen glaucoma.
The use of these drugs is hazardous in psychiatry because they can mimic symptoms of severe psychiatric disorders, including toxic psychosis, delirium, confusion, excitement, euphoria or giddiness, hallucinations and delusions, insomnia, paranoia, agitation, depression, apathy or listlessness, and bizarre behavior. They can also cause more subtle interference with memory and thinking processes. Although no studies of this phenomenon have been conducted, we agree with other clinicians who believe that these drugs may cause irreversible mental deterioration when used over the long term.
Neuroleptic malignant syndrome has been reported in connection with Symmetrel and Sinemet. Because both of these drugs bring about their impact by stimulating dopamine, they can also cause twitches, spasms, and other involuntary movements (dyskinesias).
Although it is common practice to combine these anticholinergic drugs with neuroleptics and antidepressants, which often share their anticholinergic action, we have seen severe toxic psychoses develop under these conditions. The neuroleptics with especially strong anticholinergic tendencies include Thorazine and Clozaril, followed by Serentil, Mellaril, and Orap. Tricyclic antidepressants with strong anticholinergic effects include Elavil and Vivactil, followed by Anafranil, Trazodone, Surmontil, and Tofranil.
Now that we have reviewed many of the dangers associated with taking psychiatric drugs, it should be apparent that the fetus or infant needs maximum protection from these agents. Lithium, as already noted, causes heart malformations. It is contraindicated in pregnancy. But parents should be very cautious about exposing the unborn or the newborn to any psychoactive medications.
All psychiatric drugs cross the placenta and enter into the fetal blood stream. They do so "readily rapidly, and without limitation"90. Once the drug has entered the fetal bloodstream, it has easy access to the brain. Furthermore, after the child is born, the child's liver will have less capacity than the mothers to metabolize or break down the drug, increasing the length of time it will remain present and active in the newborns body91.
Psychoactive substances can also pass to the infant through the mothers milk, although the concentrations may be higher or lower than those in the mothers blood. For example, the plasma level of clozapine in fetal blood exceeds that in the mother. But regardless of the relative tendency of the drugs to cross into the fetal blood stream, nursing mothers should avoid exposing their unborn infants to such toxic substances with their harmful effects on multiple organ systems. In addition, after birth the infants immature liver will be less able to metabolize or break down whatever amount of drug remains in its body. Some drugs ingested by a nursing mother, such as lithium, can make the infant become flaccid. Other drugs, such as valproic acid (Depakene), can make the infant hyper-excited and may cause brain dysfunction detectable up to six years later (Koch et al., 1996 [234]). Special caution should be shown in the first trimester, when malformations are most commonly caused by toxic agents. The use of all psychiatric drugs should be avoided during pregnancy92. See Chapter 9 for a discussion of drug withdrawal reactions in neonates whose mothers took antidepressants during pregnancy.
To date, the FDA has not approved any psychiatric drug for use during pregnancy or lactation. Some physicians try to reassure pregnant or nursing mothers about their baby's safety while they are taking psychiatric drugs. But there is no scientific basis for offering this reassurance in regard to any drug that affects the brain.
There are many reasons not to start taking psychiatric drugs and many reasons to stop taking them once you have begun. The choice to taper off or to stop a drug is a personal one; but ideally it should be made with the help of an experienced clinician who can provide advice about strategies to make withdrawal as safe as possible. Unhappily it is often difficult to find health professionals who do not advocate such drugs and who know how to withdraw patients from them. We know that this book has helped to inform many people and the health professionals with whom they are working.
Our approach is based on the principle that individuals and families have the right to make their own decisions about psychiatric drug use. But, equally important, we believe that informed decisions can be made only on the basis of full disclosure, including critical viewpoints from experts who do not advocate drugs. In Chapters 3 and 4 we have examined some of the physical dangers of psychiatric drugs. In the next chapter, we look at the psychological and moral hazards of relying on these mind-altering agents.