ANTIPSYCHOTIC DRUGS: DANGEROUSLY OVERUSED

Antipsychotic drugs, also called neuroleptic drugs or major tranquilizers, are properly and successfully used to treat serious psychotic mental disorders, the most common of which is schizophrenia. Schizophrenia is a disease in which people have lost touch with reality, often see or hear things that are not there (hallucinations), believe things that are not true (delusions), often have severe mood problems such as depression, lose their expressiveness of feeling (“flat affect”), and in general have disorders of thinking. Psychoses include other mental disorders which involve abnormal perceptions of reality such as hallucinations and delusions. Schizophrenia and the other psychoses are much less common in older adults than in younger adults, according to studies done by the National Institute of Mental Health.

Whereas about 1.12% of people aged 18 to 44 have been found to have active schizophrenia (symptoms in last six months) and 0.6% of 45- to 64-year-olds have this diagnosis, only 0.1% of people 65 and older are diagnosed as having active schizophrenia.[1] In other words, active schizophrenia is only one-tenth to one-fifth as common in older adults as in younger adults.

In younger adults, an alarming number of those with schizophrenia who could and often have previously benefited from antipsychotic drugs are not receiving them. They are seen, among other places, on the streets and in homeless shelters. In older adults, the problem is not underuse but, rather, gross overuse by people who are not psychotic.

Drugs That Can Cause Psychoses (Hallucinations) or Delirium

For anyone of any age who has recently become psychotic (has hallucinations, for example) or developed delirium, there should be careful questioning to see if this serious mental problem might have been drug-induced before the person is started on antipsychotic drugs. Drugs that may cause hallucinations or other symptoms of psychosis include many street drugs (e.g., PCP, LSD) as well as many prescribed drugs listed below. In someone who is 60 years old or older, there is a strong likelihood that the recent onset of hallucinations, delirium, or other behavior that is like schizophrenia is due either to the effects of the drugs listed below or withdrawal from addiction to alcohol, barbiturates, or other sleeping pills or tranquilizers. Commonly used drugs that may cause psychotic symptoms such as hallucinations or delirium include the following:[2]

• analgesics/narcotics such as indomethacin (INDOCIN), ketamine (KETALAR), morphine (ROXANOL), pentazocine (TALWIN), propoxyphene (DARVON), and salicylates (aspirin)
• antibiotics and other anti-infective agents such as acyclovir (ZOVIRAX), amantadine (SYMMETREL), amphotericin B (FUNGIZONE), chloroquine (ARALEN), cycloserine (SEROMYCIN), dapsone, ethionamide (TRECATOR-SC), isoniazid (INH), nalidixic acid (NEGGRAM), penicillin G, podophyllum (PODOFIN), quinacrine (ATABRINE), and thiabendazole (MINTEZOL)
• anticonvulsants such as ethosuximide (ZARONTIN), phenytoin (DILANTIN), and primidone (MYSOLINE)
• allergy drugs such as antihistamines (CHLOR-TRIMETON, DIMETANE, etc.)
• antiparkinsonians such as levodopa and carbidopa (SINEMET), bromocriptine (PARLODEL), and levodopa (LARODOPA)
• asthma drugs such as albuterol (PROVENTIL, VENTOLIN)
• drugs for depression such as trazodone (DESYREL) and tricyclic antidepressants such as amitriptyline (ELAVIL) and doxepin (SINEQUAN)
• heart drugs such as digitalis preparations (LANOXIN, etc.), lidocaine (XYLOCAINE), procainamide (PROCANBID), and tocainide (TONOCARD)
• high blood pressure drugs such as clonidine (CATAPRES), methyldopa (ALDOMET), prazosin (MINIPRESS), and propranolol (INDERAL)
• nasal decongestants such as ephedrine, oxymetazoline (AFRIN), phenylephrine (NALDECON), and pseudoephedrine (SUDAFED)
• drugs such as amphetamines, PCP, barbiturates, and powder and crack cocaine
• sedatives/tranquilizers such as alprazolam (XANAX), diazepam (VALIUM), ethchlorvynol (PLACIDYL), and triazolam (HALCION)
• steroids such as dexamethasone (DECADRON) and prednisone (DELTASONE)
• other drugs such as atropine, amino-caproic acid (AMICAR), baclofen (LIORESAL), cimetidine (TAGAMET), ranitidine (ZANTAC), disulfiram (ANTABUSE), methylphenidate (RITALIN), methysergide (SANSERT), metrizamide (AMIPAQUE), phenelzine (NARDIL), thyroid hormones, and vincristine (ONCOVIN)

How Often Are Antipsychotic Drugs Used in Older Adults?

There was more than a doubling of the number of prescriptions for antipsychotic drugs in U.S. doctors’ offices between 1989 and 1997. In 1989, such prescriptions were written during 3.2 million office visits, but were written during 6.9 million office visits in 1997. Most of the increase was in the prescribing of the newer, so-called atypical antipsychotic drugs such as risperidone (RISPERDOL) and olanzapine (ZYPREXA). Although the proportions of the various diseases being treated with these drugs remained constant, with 78% of patients being treated for schizophrenia, affective disorders such as depression, or other psychiatric disorders, 22% of patients in 1997 were being prescribed these powerful drugs for a “nonpsychiatric disorder.” The number of office visits in 1997 during which such a prescription was written was 1.5 million.[3]

In nursing homes in the United States, where misuse of antipsychotic drugs has been notorious, antipsychotic drugs were found to be the leading cause of adverse drug reactions, comprising 23% of all adverse drug reactions, and also were found to be the leading cause of preventable adverse drug reactions. Collectively, antipsychotic drugs, sleeping pills, and antidepressants accounted for 48% of all adverse drug reactions in nursing homes and 62% of the preventable adverse reactions.[4]

A recent study in the UK, with findings similar to those in the United States, found that only 17.8% of nursing home residents receiving antipsychotic drugs were getting them for appropriate reasons. The wise advice given by these authors needs to be taken seriously by those in charge of nursing homes worldwide and, moreover, by all who take care of elderly patients. “Before pharmacotherapy is considered for elderly patients with problem behaviour, physical causes, behavioural modification and environmental changes should be explored. [Antipsychotics] can be withdrawn in up to half of recipients with no deterioration or an improvement in resident cognition, memory, or behaviour.”[5]

What Are These Antipsychotic Drugs Being Prescribed For, If Not for Schizophrenia and Other Psychoses?

A group of physicians and other health professionals who specialize in geriatric pharmacology have stated: “The usefulness of antipsychotic medications in nonpsychotic, elderly patients has been questioned....The high frequency of toxic reactions to these drugs is well documented, with many older patients who take them experiencing orthostatic hypotension [low blood pressure on sitting or standing], Parkinson’s syndrome, tardive dyskinesia, akathisia, worsened confusion, dry mouth, constipation, oversedation, and urinary incontinence.”[6]

One of the more common purposes for which antipsychotic drugs are blatantly misused is as a sedative in nursing home patients.[7] Other unjustifiable uses include controlling the overall level of disturbance in older demented (nonpsychotic) patients,[8] and for treating chronic anxiety.[9] Two different studies concluded that often the most mentally alert and least physically disabled people are given these drugs.[10],[11] This is consistent with the charge that these drugs are being used more for the convenience of the nursing home staff or other caretakers than for the needs of the patients.

Another study found that “80% of elderly demented persons are receiving tranquilizers (antipsychotic drugs) unnecessarily.”[12] Other researchers concluded that antipsychotics are “frequently prescribed inappropriately as sedatives to elderly patients” and that “using these drugs incorrectly or for unnecessarily prolonged periods enhances the probability of developing this virtually untreatable, disfiguring syndrome” (referring to tardive dyskinesia).[13]

In other words, medical professionals should attempt to find out what it is in the environment that may be causing or contributing to the problems older people are having and, if possible, change it, rather than endanger their health with these powerful drugs. A perfect example is the use of antipsychotic drugs at the end of the day to treat the so-called sundowner syndrome. As the end of the day approaches, some nursing home or hospital patients become agitated, restless, or confused and may wander about. A careful study of the characteristics of people with this problem found that they were much more likely to have been in their present room for less than one month, to have come to the nursing home or hospital recently, and to be awakened on the evening shift. The implication was that changes in the management of these patients by nurses and other staff could reduce the problem without resorting to the use of antipsychotic drugs.[14]

Has Federal Regulation Improved the Use of Antipsychotic Drugs in Nursing Homes?

The Omnibus Budget Reconciliation Act of 1987 (OBRA-87) included provisions for regulating the use of psychotropic medications, particularly antipsychotics, in long-term care facilities. Several surveys conducted since the enactment of OBRA-87 suggest that the use of these powerful drugs in elderly nursing home residents is being curtailed.

A review of prescription and medical records in eight nursing homes conducted between August 1994 and March 1996 found that of a total of 1,573 residents, 279 were taking antipsychotic drugs (17.7%). Of these 279, 70.9% were receiving the drug for an appropriate reason, 90.1% were prescribed the drug within the recommended dosage limits, and appropriate target symptoms were documented in 90.4% of these residents.[15]

Benefits and Risks of Antipsychotic Drugs

For the small fraction of older adults taking antipsychotic drugs appropriately, that is for the treatment of psychotic illnesses such as schizophrenia, the significant risks are more than balanced out by the proven benefits for those people who respond. But at least 80% of the use of these drugs in older adults is inappropriate. Either the drugs are ineffective, as in the treatment of senile dementia, or unnecessary, as in their frequent uses to sedate or control nonpsychotic behavior that is often responsive to nondrug approaches.

What Are the Main Adverse Effects of Antipsychotic Drugs?

Falls and hip fractures

Approximately 16,000 older adults a year suffer from drug-induced hip fractures, attributable to the use of antipsychotic drugs. In one study, the main category of drugs responsible for falls leading to hip fractures was antipsychotic drugs.[7] Fifty-two percent of those hip fractures attributable to the use of mind-affecting drugs were due to antipsychotic drug use. (Also, see section on minor tranquilizers and sleeping pills)

Nerve problems

Tardive dyskinesia: This is the most common, serious, and sometimes irreversible adverse effect of antipsychotic drugs. It is characterized by involuntary movements of the lips, tongue, and sometimes the fingers, toes, and trunk.[2] Older adults are at increased risk for this adverse effect, and it may occur in as many as 40% of people over the age of 60 taking antipsychotic drugs.[16]

Tardive dyskinesia is more common and more severe in older adults. The majority of cases are irreversible and often result in immobility, difficulty chewing and swallowing, and eventually weight loss and dehydration. None of the antipsychotic drugs has a lower chance of causing this problem than others.[12]

In most studies of elderly patients, the incidence of tardive dyskinesia in people taking antipsychotic medications is between 30 and 35%. However, a recent study found that in those elderly patients who had never before been given an antipsychotic drug, the incidence of tardive dyskinesia was 60% in those patients given the drugs for depression, significantly higher than in older adults getting these drugs for other purposes.[17] Most studies find that increased age and long duration of therapy are important predictors for increased rates of tardive dyskinesia. Another variable between studies is the differing definitions of tardive dyskinesia. The risk of tardive dyskinesia is somewhat less for the newer, atypical antipsychotic drugs.

Another study estimated that there were 192,718 people in the United States who had developed tardive dyskinesia attributable to antipsychotic drugs.[17] Of these, 54,284 cases occurred in nursing homes. If 80% of these exposures to antipsychotic drugs were unnecessary, more than 43,000 people in nursing homes developed tardive dyskinesia unnecessarily because they should not have been given these drugs. An additional 112,854 people not in an institution also suffered from tardive dyskinesia induced by antipsychotic drugs. According to national drug prescribing data, approximately 33% of the prescriptions for the drugs were in people over the age of 60.[7] Thus, an additional 37,000 noninstitutionalized older adults appear to have developed tardive dyskinesia from these drugs. If the prescriptions for 80% of these people are unnecessary, another 30,000 cases of tardive dyskinesia that should have been avoided have occurred. Thus, there are approximately 73,000 cases of tardive dyskinesia in older adults that are the result of poor prescribing practices by physicians.

To date, no drug has been found to be effective in treating tardive dyskinesia, thus making its prevention extremely important.

Drug-induced parkinsonism: Drug-induced parkinsonism involves the following symptoms: difficulty speaking or swallowing; loss of balance; masklike face; muscle spasms; stiffness of arms or legs; trembling and shaking; unusual twisting movements of body.

Although many people believe that parkinsonism is one of the inevitable consequences of growing old, a large proportion of the cases seen in older adults are caused by drugs. A study found that 51% of 93 patients referred for evaluation of newly developed parkinsonism had drug-induced diseases.[18] One-fourth of patients with drug-induced parkinsonism could not walk when first seen by their doctors, and 45% required hospital admission. The parkinsonism cleared in 66% of the patients, but 11% continued to have the disease a year after the drug was stopped. An additional 25% who had cleared initially went on to develop classic Parkinson’s disease, leading the authors to speculate that, for this latter 25%, these drugs were “unmasking” a disease that might have showed up later.

Even more disturbing is the finding in another study in which 36% of patients with drug-induced parkinsonism had been started on antiparkinson drugs to treat the disease! Because the doctors had not considered the possibility that a drug was responsible for the disease, they assumed that the patients had classic Parkinson’s disease and treated the parkinsonism with another drug instead of stopping the one responsible for the disease in the first place.[9]

Another way of looking at this serious problem is to ask what proportion of patients who take antipsychotic drugs or other drugs that can also cause these problems (Phenergan, Compazine, and Reglan) get drug-induced parkinsonism. In various groups of patients in whom this has been studied, the range is from 15 to 52%.[9] In one study, 26% of older adults (60 and over) taking haloperidol (HALDOL) developed drug-induced parkinsonism.[19] Other studies have shown an overall incidence of 15.4%, but among patients over 60, the incidence was approximately 40%.[20] In the same study, 90% of the cases of drug-induced parkinsonism began within 72 days after starting the drug.

In older persons the symptoms of an adverse drug reaction may be mistaken for a new disease or attributed to the normal process of aging. The chance of such misinterpretation is more likely when symptoms of an adverse reaction are indistinguishable from an illness common in the elderly, such as Parkinson’s disease.

A study published in the Journal of the American Medical Association reported that the likelihood of being treated for Parkinson’s disease increases threefold in elderly patients taking the antinausea drug metoclopramide. The most troubling finding of this study, according to the authors, was the extent to which adverse metoclopramide reactions were treated with levodopa-containing drugs, carrying increased risk of toxicity at greater cost, but offering little likelihood of benefit.[21]

Restless leg (akathisia): Another very common adverse effect of these drugs is the restless leg syndrome, in which the person restlessly paces around and describes having the “jitters.” When seated, the patient often taps his or her feet. Not infrequently, this might be interpreted as needing more antipsychotic medicine. Instead of reducing the dose of the drug or stopping it entirely, more of the drug causing the problem may be used.

Weakness and muscle fatigue (akinesia): The most common of this group of drug-induced nerve problems (extrapyramidal reactions) is when the patient appears listless, disinterested, and depressed. This drug-induced problem is often misdiagnosed as primary depression, and the patient is put on antidepressant drugs. Giving these drugs along with the antipsychotic drugs even further increases the risk of serious adverse effects. Once again, instead of recognizing a drug-induced problem and either stopping or lowering the dose of the drug, another drug is added, making things even worse.

Although seen as a component of parkinsonism, akinesia can also occur on its own. Additional problems can include infrequent blinking, slower swallowing of saliva with subsequent drooling, and a lack of facial expression.

As a general rule, if any elderly person on psychoactive medication—sleeping pills, antianxiety tranquilizers, antidepressants, or antipsychotic drugs—appears to be doing poorly, first think about reducing the dose or stopping the drug rather than adding another drug.

Anticholinergic adverse effects

The two types of Anticholinergic effects are those affecting the brain, such as confusion, delirium, short-term memory problems, disorientation, and impaired attention, and those affecting the rest of the body. The latter type includes dry mouth, constipation, retention of urine (especially in men with an enlarged prostate), blurred vision, decreased sweating with increased body temperature, sexual dysfunction, and worsening of glaucoma. These adverse effects are much more common in the so-called high-dose antipsychotic drugs (see chart below).

Sedation

Sedation is one of the most common adverse effects of the antipsychotic drugs, especially with the high-dose drugs. Since these drugs are often improperly prescribed as sleeping pills, older adults will often have a decreased level of functioning during the day. In nonpsychotic older adults, the largest group being given these drugs, the quality of sleep is extremely unpleasant. The frightening aspects of this drug-induced disturbed sleep can last up to 24 hours after a single dose.

Hypotensive effects: lowering of blood pressure to levels that are too low

Orthostatic (postural) hypotension, or the fall in blood pressure that occurs when someone stands up suddenly, is a common adverse effect of antipsychotic drugs, especially in older adults. It can be even more troublesome if the person is already at increased risk for this problem because he or she is taking other drugs to treat high blood pressure. As a result of such a drug-induced drop in blood pressure, falls that result in injury, heart attacks, and strokes can occur. For this reason, before starting one of these drugs, the person’s blood pressure should be taken both in the lying position and after standing for two minutes. This should be repeated after the person has used the drug for several weeks. People taking these drugs should rise slowly from a lying position and wear supportive stockings to help prevent hypotension. This adverse effect is also seen more often with the use of the higher-dose drugs, such as chlorpromazine (THORAZINE), but occurs with all of the antipsychotic drugs.

Blood sugar elevation and diabetes mellitus

Elevations in blood sugar (glucose),[22],[23],[24] in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics that include aripiprazole (ABILIFY), clozapine (CLOZARIL), olanzapine (ZYPREXA), quetiapine (SEROQUEL), risperidone (RISPERDAL), and ziprasidone (GEODON).

The relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia, including polydipsia (excessive thirst/drinking of liquids), polyuria (excessive urination), polyphagia (excessive eating), and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

For a variety of reasons, including increased appetite, the newer, so-called atypical antipsychotic drugs commonly cause a significant increase in weight that can be troublesome to and dangerous for patients using these drugs. For various drugs in this group, the usual range of weight gain is from 5 to 20 pounds, but there are a large number of reports of people gaining much more than 20 pounds, especially with longer-term use of the drugs. In addition to and related to weight gain are metabolic disorders including elevated blood sugar, the onset of diabetes, and abnormalities of fat metabolism such as elevated triglyceride levels. Patients should be informed of these effects to help prevent excessive body weight gain.[25]

Cerebrovascular adverse events, including stroke, in elderly patients with dementia

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in clinical trials of the atypical antipsychotics in elderly patients with dementia-related psychosis.[26] In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with these drugs compared to patients treated with placebo. The atypical antipsychotics are not approved for the treatment of patients with dementia-related psychosis.

Other adverse effects

Other adverse effects include weight gain, poor ability to withstand high or low temperatures (because these drugs affect the body’s temperature regulation center), increased sensitivity to sunlight and other skin problems, bone marrow toxicity, and abnormal heart rhythms.

How to Reduce the Risks of These Antipsychotic Drugs

• Give antipsychotic drugs only to people who need them. The majority, at least 80%, of older adults being prescribed these drugs should not be getting them, and the serious adverse effects are just as harmful in them as in the small fraction of people for whom the drugs are appropriate (people with schizophrenia). Thus, the most effective way of reducing the risk of these drugs for most older adults is to stop using them. Unless the patient has schizophrenia or another psychotic condition, beginning to use them or continuing to use them provides significant risks without compensating benefits. These drugs are also not effective for psychoses seen with senile dementia.[11] As discussed above, the use of these powerful drugs for older people who have depression is fraught with a high incidence—60%—of tardive dyskinesia.
  
  Antipsychotic drugs should never be used as sleeping pills or to treat anxiety.

• Start with the lowest possible dose. For older adults this is usually one-tenth to two-fifths the dose for younger adults. Use the drug for as short a period of time as possible.[27] If, however, the use of antipsychotic drugs is indicated, the first thing to realize is that as is the case for many drugs for older adults, the starting dose and, very likely, the eventually used dose should be lower than the dose for younger adults. There are three reasons why this is so for the antipsychotic drugs:
  
  First, kidney function in older adults decreases, which means that the drugs last longer in the body. They get more “mileage” out of a given dose. Second, because of a decrease in an important brain chemical—dopamine—as people age, there is an increased risk in older adults of the adverse effects, such as drug-induced parkinsonism or akinesia. Third, because of another change in brain metabolism with aging, there is an increased sensitivity to the anticholinergic effects of these drugs, such as confusion, delirium, dry mouth, difficulty urinating, constipation, and worsening of glaucoma.[28]
  

• Pay attention to the adverse effect profile of the drugs (see comparison chart below). As mentioned previously, the antipsychotic drugs are all quite similar in their effectiveness for treating psychoses, but differ mainly in the spectrum of their adverse effects. The chart shows a great difference in the severity of the adverse reactions, depending on whether the drug is a less potent or more potent one.
  
  At the top of the list is the less potent, higher-dose chlorpromazine (THORAZINE). It causes more sedative, anticholinergic, and hypotensive effects but has a relatively lower risk of the extrapyramidal effects, such as restless leg and drug-induced parkinsonism. In the middle of the list are more potent, lower-dose drugs, such as haloperidol (HALDOL) and thiothixene (NAVANE). They cause fewer sedative, anticholinergic, and hypotensive adverse effects but have a higher risk of the extrapyramidal adverse effects, such as drug-induced parkinsonism. At the bottom of the list are drugs that have more recently come on the market.
  
  Since all of these drugs are equally effective, the choice depends on which adverse effects would likely be or are most intolerable. For a person with a tendency to become faint or dizzy upon standing (orthostatic, postural hypotension), the addition of Thorazine, with its high risk of lowering blood pressure, would not be a good idea. Instead, if drug treatment is really necessary, one of the more potent drugs with fewer hypotensive and sedative effects might be a better choice. Similarly, people who already have trouble walking or who have trouble with their posture would be at much greater risk if they developed one of the extrapyramidal adverse effects of Haldol, Navane, or the other more potent antipsychotic drugs. Therefore, these people would probably do better on one of the less potent drugs with fewer extrapyramidal adverse effects, such as clozapine or olanzapine. The most important consideration is to adjust the dose, or change or discontinue drugs when and if adverse effects occur. This is especially true when the adverse effects are as bad as or worse than the original reason for starting the drug.