|Year : 2015 | Volume
| Issue : 1 | Page : 16-29
Adverse drug reactions due to antipsychotics and sedative-hypnotics in the elderly
Natasha S Kate, Shalaka S Pawar, Shubhangi R Parkar, Neena S Sawant
Department of Psychiatry, KEM Hospital, Parel, Mumbai - 400 012, Maharashtra, India
|Date of Web Publication||23-Jul-2015|
Dr. Natasha S Kate
Department of Psychiatry, KEM Hospital, Parel, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Psychotropic drugs are commonly used to manage mental and behavioral problems in geriatric patients. This is, however, accompanied by the risk of developing adverse drug reactions (ADRs), impacting the safety with which the drug can be used. In this article, we provide an overview of the factors associated with the ADRs due to psychotropic medication in the elderly, and the ADRs associated with the use of antipsychotics and sedative-hypnotics in the geriatric population. For this, literature searches were conducted through MEDLINE, PubMed, and Google Scholar using keyword terms: Geriatric, elderly, safety, adverse events, ADRs, antipsychotic, names of individual antipsychotics, benzodiazepine, sedative, hypnotic, zolpidem, zaleplon, zopiclone. Research data indicate that antipsychotics are associated with an increased risk of metabolic syndrome, thromboembolism, cerebrovascular and cardiac events, pneumonia, fractures, and increased mortality. Among antipsychotics, aripiprazole seems to have fewer ADRs while other antipsychotics (typical and atypicals) have reports of troublesome side effect profiles. Sedative-hypnotics are associated with a risk of falls, fractures, cognitive impairment, and may increase the risk of developing dementia with long-term use. The risk of these complications is present with both benzodiazepines and medications such as zolpidem and zopiclone.
Keywords: Adverse drug reaction, antipsychotics, benzodiazepines, elderly, risk, zolpidem
|How to cite this article:|
Kate NS, Pawar SS, Parkar SR, Sawant NS. Adverse drug reactions due to antipsychotics and sedative-hypnotics in the elderly. J Geriatr Ment Health 2015;2:16-29
|How to cite this URL:|
Kate NS, Pawar SS, Parkar SR, Sawant NS. Adverse drug reactions due to antipsychotics and sedative-hypnotics in the elderly. J Geriatr Ment Health [serial online] 2015 [cited 2020 Jan 26];2:16-29. Available from: http://www.jgmh.org/text.asp?2015/2/1/16/161377
| Introduction|| |
The contribution of the elderly to the demographic statistics is increasing each day. Globally, there are around 605 million people who are aged 60 and above.  In India, the elderly comprised 4.5% of the total population in 2001, which increased to 5.3% in 2011 and is expected to be 17.3% by the year 2051.  This increasing proportion of elderly can be attributed to longevity which has become a characteristic of today's world. The life expectancy in India has increased from 32 years in 1947  to 67.46 years for males and 72.61 years for females in the present decade.  The recent advances in the field of medicine have largely contributed to this change which is occurring worldwide. However, with increasing age begins the appearance of symptoms which mark the onset of declining bodily functions. Advancing age also increases the vulnerability to long-term illnesses like anemia, arthritis/joint pain, hypertension, diabetes, cardiovascular disease, cataract, cancers, musculoskeletal illness. Besides physical morbidity, psychiatric morbidity is also common in the older population.  The prevalence of psychiatric morbidity in the elderly is more than 40%, with depression being the most common psychiatric diagnosis,  followed by organic disorders like dementia and delirium, , adjustment disorders, and generalized anxiety disorder.  Few of them also have bipolar disorder, schizophrenia, and substance-related disorder. , While dementia is defined on the basis of cognitive impairment, 60-90% patients experience neuropsychiatric symptoms such as depression, anxiety, apathy, sleep problems, agitation, and psychosis. 
The most common medical intervention for any disorder in the elderly is medication-based therapy. Geriatric patients use 30-50% of all prescription drugs.  Psychotropic medication may be indicated for primary mental illness, or may be prescribed to control behavioral and psychological symptoms of dementia or other organic brain conditions. Use of medications in elderly has its own disadvantages. This group experiences more medication-related adverse drug effects as compared to the younger population. Adverse drug reactions (ADRs), or side effects can be understood as "an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product."  Medication-related side effects are the fifth most common cause of hospitalization in elderly use and accounts for approximately 20% of hospitalizations  and related morbidity and mortality is estimated to cost $76.6 billion in the ambulatory setting in the United States.  Medication-related side effects are also an important reason for discontinuation of medications which further deteriorates the general well-being of the patient. In this review, we shall first discuss the factors associated with ADRs in the elderly. Following this, we shall try to encapsulate the data available on ADRs due to antipsychotics and benzodiazepines.
| Factors associated with Adverse Drug Reactions in the Elderly|| |
The aging body
The elderly should not be viewed simply as "old adults." Advancing age is associated with a number of changes in the changes in the pharmacokinetics and pharmacodynamics of ingested medication. These can have significant repercussions on the action as well as the safety of these medications.
Absorption of the medication from the stomach is decreased due to decrease in gastric acid secretion which results in increase in intra-gastric pH. Decrease in gastrointestinal motility causes delayed gastric emptying time and overall blood flow to the gastrointestinal tract is also reduced.  Progressive reduction in total body water and lean body mass causes important changes in the volume of drug distribution. Total body water content of the body declines with age, and may fall by 10-15% until the age of 80. Furthermore, total body fat increases with age and this increase may be as high as 18-36% in men and 33-45% in women.  Lipid soluble drugs such as diazepam, nitrazepam, amitriptyline, haloperidol, and chlorpromazine have increased half-life with prolonged action in elderly and water soluble drugs like lithium have an initial increase in plasma concentration following administration due to decreased volume of distribution. ,, Furthermore, there is age-related decrease in protein binding which causes increased fraction of unbound drug.  First pass metabolism by liver is an important step in drug pharmacokinetics. Though aging does not cause much of a change in the cytochrome P450 enzyme system,  the live mass is reduced by 30% and the hepatic blood flow by 40%. This is enough to significantly reduce the hepatic drug clearance. , Benzodiazepines undergo both phase I (oxidation) and phase II (conjugation) reactions. Therefore, the side effect profile of benzodiazepines when used in the older population depends on the elimination half-life and type of metabolism that it undergoes. Lorazepam and oxazepam undergo conjugation only and do not have any active metabolite. They may hence be preferred in elderly population, especially those with hepatic impairment. Many drugs which are excreted by the kidney require appropriate dose adjustment because as age progresses, there is 30-50% reduction in glomerular filtration rate along with compromised tubular function and reduced renal blood flow. , The presence of chronic kidney disease only compromises kidney function further.  These changes ultimately cause prolongation of the drug half-life with an increase in serum drug concentration of drugs such as risperidone and amisulpride, which in turn are responsible for increased risk adverse reactions. The half-life of drugs like lithium can, therefore, increase significantly.
The action of any drug is related to its interaction with its target receptor which brings about its intended effect. Some drugs have different pharmacological actions in elderly than in the young. This is due to change in the number of receptors and binding affinity. The number of dopaminergic receptors in the central nervous system (CNS) decreases with age.  In vivo brain imaging has demonstrated an age-related reduction in striatal D2 binding sites. This deterioration occurs at the rate of 4-13% per decade.  The availability of D2 receptors in the caudate and putamen also decline with age. This decreased dopamine activity in striatal regions of the brain is associated with impaired cognitive and motor performance. Increased antipsychotics sensitivity occurs in older patients and, as a result, extra pyramidal side effects with risperidone occurs at 32-79% D2 receptor occupancy,  whereas in the young population, this side effect is usually observed when 80% of D2 receptors are occupied. In addition, there are age-dependent changes in the GABA A-benzodiazepine receptor complex in the form of altered subunit composition and decrease in the number of receptors. This results in increased sensitivity to the action of benzodiazepines and similar drugs, resulting in psychomotor dysfunction even at lower doses.  There is also age-related increase in cellular monoamine oxidase B enzyme due to compartmentalization within cell bodies of glial cells and the numbers of glial cells increase with age in the normal human brain.  The loosening in tight junctions of the blood-brain barrier and decline in the function of p-glycoprotein may also be the reason for increased access of the drug into the CNS.  There are also deficits in hormonal, biochemical, and nervous reflexes which causes impaired homeostasis leading to an altered drug effect. For example, there is desensitization of the β-adrenoreceptors resulting in impaired baroreflexes. This increases the risk of developing postural hypotension. 
The presence of co-morbidities is one of the reasons for increased risk of adverse effects in the elderly population. The prevalence of co-morbidities increases with increasing age. Thirty-five percent of persons aged between 45 and 65 years have two or more chronic conditions, whereas this number increases to 85% in the age group above 65 years.  Nineteen percent of the elderly have presence of three co-morbidities, and 24% have four co-morbidities.  The presence of three or more co-morbidities increases the risk of having a severe ADR by 2.9-12.6-folds. 
Polypharmacy and drug interactions
The average number of drugs used concomitantly, in persons aged above 65 years is two to nine. Fifty-seven percent of the patients are prescribed more than five drugs and 12% more than 10 drugs.  Patients taking two drugs have 13% risk of adverse drug effect while those taking four drugs have 38% and those taking seven drugs have 82% risk of experiencing an adverse drug effect.  Polypharmacy also causes drug-drug interactions which again increases the chances of adverse reaction. Frequency of drug-drug interaction depends on the age as well as the number of drugs. The frequency is 24% in those aged between 60 and 74 years and 36% in those above 80 years.
Given these considerations, pharmacotherapy in the elderly is often fraught with risks. However, the elderly are frequently excluded from phase II and phase III clinical trials and hence research data regarding the safety and ADRs in this age group are not so easily available. In addition, current research that does look at the use of psychotropics in the elderly is often done in hospital inpatients, nursing home residents, and through retrospective chart analysis, thereby rarely representing the general population. Despite these methodological limitations, there is a slowly increasing database that provides information regarding the safety of pharmacological agents in this age group. In the following sections, research data regarding ADRs in the elderly following the use of antipsychotics and sedatives-hypnotics shall be discussed. For this purpose, peer-reviewed literature searches were conducted to obtain published literature for this review. The following bibliographic databases were searched: MEDLINE, PubMed, and Google Scholar. Google and other Internet search engines were used to search for additional information. The search strategy comprised of controlled vocabulary, such as the National Library of Medicine's MeSH (medical subject headings), and keywords including the terms geriatric, elderly, safety, adverse events, ADRs, antipsychotic, names of individual antipsychotics, benzodiazepine, sedative, hypnotic, zolpidem, zopiclone. Methodological filters were applied to limit the retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, economic studies, and guidelines. Two independent reviewers screened the titles and abstracts of the retrieved publications and independently evaluated the full-text publications for final article selection. Articles were considered eligible for inclusion if they involved adults who were 60 years or older, provided outcome data regarding safety or ADRs due to use of antipsychotics (individual drugs or as a group, atypical or atypical), benzodiazepine, and other sedatives/hypnotics.
| Antipsychotics|| |
Antipsychotic medications are used for various indications in the elderly. The most common ones are delirium, dementia, agitation, psychosis, and affective disorders.  Often, the use of antipsychotics in elderly is disproportionate and unjustified. This practice significantly increases the risk of adverse effects in this population.  However, most of the research with regards to ADRs in the elderly has been done in patients of dementia. The use of antipsychotics is commonplace in delirium but shall not be included in this review as they are often used for extremely short durations and it is difficult to assess ADRs in patients who already have a number of medical morbidities. There is very little work on the safety and side effect profile of antipsychotics in elderly patients without cognitive impairments. Chief concerns with antipsychotic use include increased risk of death, metabolic syndrome, increased risk of cerebrovascular accidents (CVAs) and venous thromboembolism (VTE), and other ADRs such as pneumonia, fractures, and extrapyramidal symptoms. Again, most of these ADRs have been described in patients with dementia, yet may be applicable in all elderly patients.
The use of antipsychotics in the elderly has become a controversial issue secondary to research data that implicates them in increasing the risk of death in the elderly population. Though the precise mechanism of death remains unclear, most of the deaths in clinical trials were due to cerebrovascular, cardiovascular or infectious causes. In the year 2005, a pooled analysis of 17 short-term randomized controlled trials involving elderly patients with dementia, it was found that compared to placebo, use of atypical antipsychotics increased the risk of death by 60%.  Following this, the USA Food and Drug Administration issued a Public Health Advisory stating that all atypical antipsychotics must carry a black box warning stating that the drug carries a significant risk of serious or even life-threatening adverse effects and advised against the use of atypical antipsychotics in treatment of dementia in 2005. By 2007, the black box warning extended to the use of typical antipsychotics as well. The risk of increased mortality following antipsychotic use has been heavily researched. A retrospective cohort study reported that all groups taking antipsychotic medications had significantly higher mortality rates (22.6-29.1%) than those taking other medications (14.6%).  A cohort study which included 22,890 USA Medicare patients (state funded low-income pharmacy assistance program) showed that compared to atypical antipsychotics, the typical antipsychotics were responsible for 37% increase in 180 days mortality.  However, since the patients involved were enrolled in a state-funded pharmacy assisted program, they were not representative of general elderly population as on average they belonged to the lower income group and had higher morbidity and mortality. Similar findings were replicated in another cohort study which was carried out in elderly residents. All-cause mortality over 6 months was compared between patients taking typical and atypical antipsychotics. Around 14% patients taking typical antipsychotics died as compared to 9.6% in the atypical group (mortality ratio 1.47, 95% confidence interval [CI] 1.39-1.56). The other findings in this study included that compared to risperidone, haloperidol carried a greater risk of mortality (relative risk [RR] 2.14, 95% CI 1.86-2.45). The greatest increase in mortality occurred when the patients received higher doses of antipsychotics and during 1 st 40 days after starting the drug therapy.  A large meta-analysis of 15 placebo-controlled trials found similar mortality rates among patients receiving olanzapine, risperidone, quetiapine, and aripiprazole.  The overall odds ratio (OR) for death in atypical antipsychotic users compared to placebos was 1.45 (95% CI 1.06-2.23). However, a more recent retrospective cohort study found that the mortality rate was highest for haloperidol (RR 1.54, 95% CI 1.38-1.73) which was followed by risperidone (reference medication). Lowest rates were those for quetiapine (RR 0.73, 95% CI 0.67-0.80) among the atypicals. The mortality risk for haloperidol was greatest in the 1 st 30 days which later declined significantly and that for other agents was highest during the 1 st 120 days.  The above studies confirm that the concern for mortality with use of antipsychotics is apparent in elderly, especially in those having dementia , but also in those without cognitive impairment. 
Risk of metabolic syndrome
Metabolic side effects are a matter of special concern when using antipsychotics in the elderly. There a number of studies which highlight significant changes in the metabolic parameters when adult patients are treated with antipsychotics, atypicals more than typicals. , Weight gain is an important reason for discontinuation of medications seen in patients on antipsychotics, but the risk is high for clozapine and olanzapine (more than 4 kg).  In Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease trial, 186 male and 235 female Alzheimer's disease outpatients were studied in relation of the duration of antipsychotics (olanzapine, quetiapine, and risperidone) with parameters of metabolic syndrome.  Duration of antipsychotic use was associated with an increase in body mass index after adjustment for age (0.02 kg/m 2 /week of antipsychotic use, P = 0.006). Subjects with at least 24 weeks of antipsychotic use were more likely to have clinically significant weight gain defined as at least 7% increase from baseline (OR = 3.38, P = 0.02). Female gender had a marginally increased likelihood for significant weight gain than males (OR = 1.79, P = 0.051). A significant average weekly weight gain was observed in the olanzapine and quetiapine groups (0.12 pounds/week, P = 0.03 and 0.14 pounds/week, P = 0.02), but not in the risperidone group (0.10 pounds/week, P = 0.07). Olanzapine treatment was also significantly associated with increased waist circumference (0.07 inches/week, P = 0.004) and decreased high-density lipoprotein cholesterol (0.19 mg/dL/week, P = 0.004). No effects of antipsychotic treatment were noted for changes in systolic and diastolic blood pressure, glucose, and triglycerides. However, some degree of conflicting data also exists with regards to metabolic parameters and antipsychotic use in the elderly. When compared to the general adult population, the risk of weight gain is smaller in the elderly prescribed antipsychotics. A recent retrospective review of residents in a nursing home found no association between short-term use of antipsychotics and either weight gain or diabetes mellitus.  Similar findings were noted in nursing home residents having Alzheimer's disease.  A large retrospective cohort study which involved patients above the age of 65 years compared the incidence of diabetes in those receiving antipsychotics with those on benzodiazepines and corticosteroids. The incidence was significantly lower in those on antipsychotics and benzodiazepines as compared to those on corticosteroids. No difference of incidence of diabetes was found in those on antipsychotics or benzodiazepines. Similarly, a subanalysis showed no difference in between typical and atypical antipsychotics with regard to the development of metabolic syndrome.  A pooled analysis of seven olanzapine clinical trials in patients of Alzheimer's, vascular and mixed dementia noted an overall increased risk of diabetes. However, there was no difference in the incidence between patients receiving olanzapine and those receiving placebo.  These findings have been replicated in other studies as well. , Hence, while weight gain may occur with patients on antipsychotics, all patients may not be equally affected. More factors are possibly at play when it comes to antipsychotic-induced weight gain in the elderly.
With older age comes higher risk of deep vein thrombosis which leads to pulmonary embolism, collectively known as venous thrombo-embolism (VTE). A clear association between VTE and antipsychotic use has been seen in literature.  A large retrospective cohort study of 19,940 new users of antipsychotic agents and 1, 12, 078 nonusers found that the rate of hospitalization for VTE was 0.91/100 person-years. The rate of hospitalization for VTE was found to be more for atypical antipsychotics, risperidone (hazard ratio [HR] = 1.98), olanzapine (HR = 1.87), clozapine, and quetiapine (HR = 2.68). No increased rate with phenothiazines (HR = 1.03) or other conventional agents (HR = 0.98).  A nested case-control study found that prochlorperazine and risperidone were both associated with elevated risks of VTE OR = 2.18, (95% CI 1.47-3.25), and OR = 1.83 (95% CI 0.88-3.81), respectively. This risk is highest just after starting the drug.  Other studies have observed higher risk for clozapine, olanzapine, and low potency first generation antipsychotics and the risk seem to be associated with higher doses. The proposed hypotheses for VTE are increased sedation and body weight gain, enhanced platelet aggregation, and increased levels of antiphospholipid antibodies, hyperprolactinemia, and hyperhomocysteinemia.  As old age is usually associated with an increased risk for coagulopathies, it is essential to do baseline blood investigations ruling out the same. There should also be a regular weight monitoring and patient should be advised to exercise regularly, and immobility must also be avoided.
Cerebrovascular accidents and cardiac effects
By 2003, reports regarding the risk of strokes following the use of antipsychotic medications began to trickle in. A case-control study which studied the temporal relationship between exposure to antipsychotic and CVAs, found an association between treatment duration and risk, with the risk of CVAs elevated with <1-week of use (OR, 1.7; 95% CI, 5.7-17.2) and this risk subsequently decreasing to a nonsignificant level across a 3-month period (OR, 1.0; 95% CI, 0.7-1.3). Exposure to antipsychotic drugs (either current or recent) was associated with an overall 70% increase in the risk of cerebrovascular adverse events (OR, 1.7; 95% CI, 1.4-2.2).  In a case-control study that looked at hospital admissions secondary to stroke or transient ischemic attacks following use of atypical and typical antipsychotics (vs. nonusers) found that compared to nonusers, risk of developing a cerebrovascular event was increased. The risk was greater for olanzapine (OR 1.32, 95%CI 0.83-2.11) and other atypicals (OR 1.57, 95% CI 0.65-3.82) compared to risperidone (OR 0.87, 95% CI 0.67-1.12).  In a population-based retrospective cohort study which looked at 32,710 dementia patients who were admitted to the hospital for strokes found that RRs for atypical antipsychotics compared with typical antipsychotics was equal (OR 1.01, 95% CI 0.81-1.26).  In a large retrospective cohort study done in Italy  that studied 74,162 elderly patients, it was seen that use of antipsychotics increased the risk of developing the first episode of stroke. When antipsychotics were compared, it was seen that phenothiazines have the greatest risk (OR 5.79, 95% CI 3.07-10.9), followed by butyrophenones (OR 3.55, CI 1.56-8.07) and atypical antipsychotics (OR 2.46, CI 1.07-5.65).
Antipsychotics also increase the risk of cardiac complications. In a case-control study in geriatric nursing home residents that were hospitalized for cardiac arrest or ventricular arrhythmias, it was seen that typical antipsychotics increased the risk of developing these side effects (OR 1.86, 95% CI 1.27-2.74).  Users of atypical antipsychotics did not seem to have an increased risk for the same. Patients using older medications like pimozide, sertindole, droperidol, or haloperidol have an increased risk of sudden death due to torsade de pointes. The risk is maximum with thioridazine. 
Other side effects
Other problems with the use of antipsychotics in the geriatric group are the risks of developing pneumonia, extrapyramidal symptoms, and fractures. Trifirò et al.,  found that use of antipsychotic medication increased the risk of community-acquired pneumonia. Current use of typical (OR 1.76, 95% CI 1.22-2.53) or atypical antipsychotic (OR 2.61, 95% CI 1.48-4.61) was associated with a risk of development of pneumonia in a dose-dependent pattern. However, atypical antipsychotics were associated with an increased risk for fatal pneumonia (OR 5.67, 95% CI 1.49-23.98). All antipsychotics (typical more than atypical) can cause dystonias, akathisia, tardive dyskinesia, and antipsychotic-induced Parkinsonism More Details/extrapyramidal symptoms (EPS). There is an inverse relationship between age and medication induced dystonia, whereas the prevalence of akathisia is same across all age groups (3.3%). The risk of tardive dyskinesia and Parkinsonian features increases with increasing age.  The prevalence of extrapyramidal side effects in elderly using atypical antipsychotics at higher doses is similar to those using typical.  Though the incidence for tardive dyskinesia is lower in elderly on atypical antipsychotics, this lower incidence does not extend to the elderly having a diagnosis of dementia. , The occurrence of tardive dyskinesia also increases as the duration of treatment increases. Furthermore, the presence of Parkinsonian features, organic brain syndrome, negative features, diabetes, and female gender increases the vulnerability to develop tardive dyskinesias. Antipsychotics have been associated with an increased risk of hospitalization for fractures as well.  This risk was more for haloperidol (OR 1.53), followed by risperidone (OR 1.42) and then olanzapine (OR 1.34).
Almost all of the literature that look at the safety and the ADR profile of individual antipsychotic drugs focus on the atypical antipsychotics. There are very few controlled trials that look at typical antipsychotics in the elderly, and almost all of them use haloperidol as a reference drug that too in comparison to other atypical antipsychotics. Hence, we have not included the typical antipsychotics separately, and studies with the use of typical agents have been incorporated where relevant. The atypical antipsychotics have a varied side effect profile, which are specific to the individual drug. This needs a separate mention in this review.
Clozapine is associated with serious adverse effects like agranulocytosis, myocarditis, seizures, and metabolic syndrome. Other common side effects are sedation, constipation, urinary incontinence, and hypersalivation. These side effects are particularly important in the older population who are more susceptible to them.  Research regarding adverse effects of clozapine in elderly is scarce, however, decreased clearance of clozapine and norclozapine with age results in increased blood concentrations and hence, the potential for ADRs.  A review by Barak et al.,  showed that out of 139 elderly patients on clozapine, side effects were observed in 11.5%, with leukopenia present in 33%, hypersalivation in 26%, and orthostatic hypertension in 20%. Hematological disturbances were present in 5% patients which exceeded the rates reported for the young population. However, in this study, the mean dose of clozapine was 134 mg/day.
Olanzapine is widely used among the elderly. After correcting for body weight and smoking, concentration per dose ratio increases by 9.4% for each decade of life.  A randomized controlled trial of 105 patients on olanzapine with a control group of 30 patients on risperidone/other typical antipsychotics found that 5% of patients receiving olanzapine experienced adverse events cystic fibrosis 8% in control group. Patients on olanzapine had reduced incidence of akathisia (P = 0.021) and tremor (24.5% vs. 60.0%; P = 0.026). The most common adverse effects associated with olanzapine are somnolence, weight gain, and malaise, but these were not statistically significant.  In a double-blind randomized control trial (RCT) on elderly patients randomized to olanzapine (n = 83) or haloperidol (n = 34) found olanzapine to be superior to haloperidol on the Simpson-Angus Scale, Barnes Akathisia Scale, and had lower propensity to cause hyperprolactinemia.  A study of 94 elderly patients who were having psychosis and were treated with olanzapine (mean dose 10.1 ± 5.3 mg/day) found that 48% experienced some side effects and 17% reported more than three side effects.  The most common ones were somnolence (18.1%), dizziness (18.1%), and bradykinesia (16%). The other side effects were significant increases in body weight, fasting triglycerides, and fasting blood sugar (2.2, 39.9, and 8.9% from baseline, respectively). In a prospective, open-label study carried out in patients with Parkinson's disease (with or without dementia), olanzapine was used for treating psychosis. It was found that drowsiness is one of the main reasons for discontinuation of medication.  Sedation as an important adverse effect with olanzapine was also found in another study comparing various antipsychotics for managing behavioral problems in the medical setup in elderly patients. 
Although the use of atypical antipsychotics to control behavioral and psychotic symptoms of dementia is considered "off-label," risperidone is one of the commonly used antipsychotics in such patients. A double-blind randomized control study in 330 elderly patients with dementia on risperidone reported the incidence of emergent persistent dementia was 5.5% in patients taking 1.5 mg/day and 1.7% in those taking 0.75-1.5 mg/day. Around fifteen percent had worsening of tardive dyskinesias.  In a study conducted by Hwang et al.,  80 patients having psychosis were treated with risperidone 2.1 mg/day. Twenty percent patients experienced one ADR, and 22% reported more than three side effects, with gait problems (39.1%) and dizziness (29.1%) being the most common ones. A population-based retrospective cohort study from Canada found that the use of risperidone was associated with lower risk of extrapyramidal symptoms as compared to the use of typical antipsychotics.  A meta-analysis of 1,721 patients found the risk of mortality in patients on risperidone was 4% whereas in those receiving placebo was 3.1% (RR = 1.21). The most common adverse events associated with death were pneumonia, cardiac failure or arrest, and CVAs.  At present, risperidone is also available as a long-acting injection (LARI). Lasser et al.,  conducted a 1-year open-label multicenter trial in 725 stable patients of which 57 were elderly with an average age of 70.9 years. Adverse events were reported by 74%, which included 74% of the 25 mg group, 71% of the 50 mg group, and by 78% of the 75 mg group. No cases of emergent tardive dyskinesia were reported. ADRs reported were insomnia (14%), constipation (12%), bronchitis (12%), psychosis (11%), and rhinitis (11%). The incidence of adverse events was not dose-related. The average increase in body weight was 0.3 kg at end-point. Kissling et al.,  also performed subgroup analysis on 52 geriatric patients in the Switch to Risperidone Microspheres study. This was an open-label study for 6 months, nonrandomized, investigating the efficacy and safety of LARI in clinically stable patients with schizophrenia or another psychotic disorder. ADRs reported were Parkinsonism (n = 8), extrapyramidal disorder (n = 8), tremor (n = 4), depression (n = 3), diarrhea (n = 3), dizziness (n = 3), and insomnia (n = 3). Serious adverse events were reported by 11 patients, and the most common were psychiatric disorders and general medical conditions (n = 3each). There were no cerebrovascular adverse events. There was one case of new onset diabetes mellitus.
Given its lower propensity to cause extrapyramidal symptoms, the use of quetiapine is popular in the elderly age group, especially for those with compromised brain functions. An RCT used quetiapine in doses 100 mg/day, 200 mg/day versus placebo for agitation in patients of dementia. Incidences of cardiovascular accidents, postural hypotension, falls were similar across all groups. The mini-mental status examination score did not change in any group. Mortality was numerically higher in the quetiapine groups, however, rates were not statistically different from placebo.  In 81 patients with geriatric psychosis treated with quetiapine, most common adverse effects were somnolence (30.0%), lower-limb weakness (28.0%), and dizziness (27.0%). Weight (2.2%) and fasting triglycerides (8.9%) were also significantly elevated.  When used in 403 elderly patients of bipolar affective disorder, the incidence of side effects was 10%, with dry mouth, somnolence, postural hypotension, weight gain, and dizziness, the commonly encountered adverse events in older adults. 
Phases II and III trials of aripiprazole showed a favorable safety and tolerability profile which makes it one of the frequently used drugs in elderly patients. A placebo-controlled study carried out in 256 elderly subjects having Alzheimer's disease with psychosis showed that the incidence of extrapyramidal side effects in patients on aripiprazole was 5% as opposed to 4% in the placebo group. The incidence of somnolence was 14% and 4% in aripiprazole and placebo group, respectively.  Researchers have also studied the rate of discontinuation for different doses. The rates of discontinuation were found to be 8% (2 mg/day), 18% (5 mg/day), and 25% (10 mg/day). The most common reason for discontinuation was dose-related asthenia.  In a meta-analysis assessing safety and tolerability data from the Phase II and Phase III trials, 1539 patients receiving aripiprazole (n = 926), haloperidol (n = 200), or placebo (n = 413) were assessed. They reported the incidence of common adverse effects with aripiprazole was comparable to that of placebo. The most common side effects reported with aripiprazole were headache, insomnia, agitation, and anxiety. Discontinuation due to adverse events occurred at an incidence rate of 7% with aripiprazole compared to 8% with haloperidol and 10% with placebo. The most frequent adverse events leading to discontinuation of aripiprazole included psychosis (3.6%), agitation (0.6%), and akathisia (0.6%). There was no significant difference in the incidence rate of EPS-related adverse events, and tardive dyskinesias were only reported by two of the aripiprazole-treated patients. Patients showed minimal mean increase in body weight from baseline (<1 kg) on aripiprazole. There was no dose-response relationship between aripiprazole and changes in the QT interval (QTc). The median increase in fasting total cholesterol from baseline observed with aripiprazole treatment was low and did not differ significantly from placebo. Only 5.5% of patients on aripiprazole had abnormally elevated fasting glucose levels and only 1.4% of the patients on aripiprazole had random levels of glucose above 200 mg/dL. 
No RCTs studies were found with elderly subjects with dementia on ziprasidone. In a study with 21 elderly patients with schizophrenia, 40 mg of ziprasidone was the maximum daily dose with no significant side effects.  Another study also did not find any significant QTc prolongation. 
We did not find any controlled studies related to use of amisulpride, paliperidone, asenapine, and lurasidone in elderly. Amisulpride has a lower incidence of EPS because of its preferential binding to dopamine receptors in extrastriatal regions rather than in the striatum.  A recent study assessing the short-term tolerability of sublingual asenapine in older patients with psychosis described hypertension, headache, and somnolence as the most frequently reported adverse event. The study also reported that the incidence of EPS related adverse events was 5.7%. The mean weight gain at the end of 6 weeks was found to be 0.4 kg. However, the study concluded that in spite of the slower clearance of asenapine in elderly it was well-tolerated, and doses need not be adjusted for older patients. 
A drug report of lurasidone for use in schizophrenia stated that the dosing of lurasidone need not be modified for elderly patients (ages 65-85 years) with psychosis, as lurasidone concentrations when dosed at 20 mg/day were found to be similar to those in young subjects. The report also mentions a boxed warning for increased mortality in elderly patients with dementia-related psychosis. 
Given the propensity for antipsychotics to cause multiple ADRs in the elderly population, it is recommended that they be given in lower doses, especially in cases with cognitive impairment. Doses recommended for antipsychotics in this population ,, are given in [Table 1].
| Sedatives-Hypnotics|| |
In the elderly population, benzodiazepines are most commonly used sedatives used for anxiety and insomnia and also for the treatment of alcohol withdrawal, seizure disorders, and controlling agitation. Recently, there has been a trend toward development and use of nonbenzodiazepine hypnotics that represent a safety advantage with respect to residual effects and withdrawal symptoms. These nonbenzodiazepine hypnotics are zopiclone, eszopiclone, and zolpidem (popularly known as the Z-drugs/Z-medications). These hypnotics were found to be most effective in reducing sleep latency and improving sleep efficiency with minimal effect on total sleep time.  The prevalence of dispensing benzodiazepines and other similar medication increases with increasing age.  Benzodiazepines can be short, intermediate or long-acting based on their elimination half-life. In the elderly population, long-acting benzodiazepines are avoided as the accumulation of the drug over long periods of use can lead to various adverse effects.  Anterograde amnesia can be seen with all benzodiazepines.  Adverse effects that may be associated with benzodiazepine use in the elderly include falls, cognitive impairment, sedation, and impairment of driving skills, all of which are particularly related to the long half-life of benzodiazepines.  Short-acting benzodiazepines are mostly associated with rebound insomnia and withdrawal symptoms, whereas the long-acting benzodiazepines are more likely to produce residual daytime sleepiness. These side effects increase the propensity of falls and cognitive impairment in the elderly, resulting in significant morbidity in this vulnerable age group. 
Falls and fractures
A major cause for concern with the use of benzodiazepines in the elderly is the increased risk of falls and the subsequent development of fractures. A retrospective study designed to identify the falls leading to hospitalization and death found that in the geriatric population, use of benzodiazepines daily increased the risk of falls (RR = 1.83).  In another case-controlled study of 181 elderly males, it was established that 46% of the geriatric patients with falls were taking a benzodiazepine compared with 27% of control patients (P < 0.001). Taking a benzodiazepine increased the overall risk of falls (OR = 2.3).  The Z-group medications are also associated with an increased risk of falls. In some studies, the risk of falls and fractures after use of the Z-group medications was comparable to benzodiazepines, contrary to the previous belief that these medications are safer. A case-control study done of hip fracture cases and controls showed that zolpidem was associated with a significant increased risk of hip fracture (adjusted OR = 1.95, 95% CI = 1.09-3.51).  A double-blind randomized control trial established that the risk of adverse effects was 26.1% with zolpidem when compared to placebo (21%). There was a significant increase in body sway with eyes closed and open (P < 0.001). Around 9% of patients experienced dizziness with zolpidem (4.3% with placebo).  A study from South Korea reported that the use of zolpidem increased the risk of fracture significantly (OR = 1.72; 95% CI, 1.37-2.16). However, the association between benzodiazepine hypnotics and the risk of fracture was not statistically significant.  A large nested case-control study with 17,198 patients with a hip fracture leading to hospitalization and 85,990 controls matched on hospitalization found that the RR for overall benzodiazepine use and hip fracture was 1.2 (95% CI 1.1-1.2), the RRs for use of lorazepam, alprazolam, and zolpidem were 1.9 (95% CI 1.7-2.2), 1.5 (95% CI 1.3-1.7), and 1.7 (95% CI 1.4-2.0), and 2.1 (95% CI 1.5-2.8) when the medication was started within 14 days preceding the index date. The risks increased with increasing benzodiazepine dose and was the most for those who took more than one daily benzodiazepine dose/day (RR = 1.3,95% CI 1.2-1.5).  A retrospective cohort study that looked at the risk of fractures requiring hospitalization after an initial prescription for zolpidem, lorazepam, alprazolam, or diazepam in the geriatric age group found the RR for the development of fractures for 90-day posttreatment with these agents was 2.55 (95% CI 1.78-3.65; P < 0.001) for zolpidem, 1.53 (95% CI 1.23-1.91; P < 0.001) for lorazepam, 1.14 (95% CI 0.80-1.64; P = 0.42) for alprazolam, and 1.97 (95% CI 1.22-3.18; P = 0.01) for diazepam. In addition, the RRs was 1.68 (95% CI 1.12-2.53; P = 0.02) for zolpidem relative to lorazepam, 2.23 (95% CI 1.36-3.66; P = 0.006) for zolpidem relative to alprazolam, and 1.29 (95% CI = 0.72-2.30; P = 0.32) for zolpidem relative to diazepam. The study concluded that in older adults, the risk of injury along with zolpidem was more than alprazolam and lorazepam and was similar to that with diazepam.  Overall, current literature seems to indicate that both benzodiazepines and Z-group medications increase the risk of falls in the elderly population.
Cognitive side effects and risk of accidents
Sedative-hypnotics may also impair cognition, and this is a major cause for concern in the geriatric population wherein patients may already be suffering from cognitive deficits. A retrospective cohort of study of 1,389 people aged 60-70 years which assessed the long-term benzodiazepine use and cognitive decline showed that when compared to the nonusers, chronic users had performed poorly on several cognitive tests and also scored less on mini mental state examination. Episodic and recurrent users also had lower cognitive scores than nonusers, but the difference between the two groups was not statistically significant.  A double-blind, balanced, cross-over study that compared zolpidem and zopiclone to placebo in daytime driving performance after a single night time dose found that both zolpidem and zopiclone impaired the driving performance in healthy older middle-aged subjects after a single dose and in the absence of any other medication, with difficulty in maintaining vehicular speed and trajectory. Moreover, they had difficulty maintaining the car in the road lane, as revealed by the increased number of exits, thereby increasing the risk of accidents.  A Taiwanese study that look at increased risk of hospitalization related to motor vehicle accidents among people taking zolpidem found that OR for involvement in an motor vehicular accident after taking one defined daily dose of zolpidem was 1.74 (95% CI 1.25-2.43). 
Recently, a prospective, population-based study done to evaluate the association between use of benzodiazepines and incident dementia found that during a 15-year follow-up, new use of benzodiazepines was associated with an increased risk of dementia (HR 1.60, 95% CI 1.08-2.38).  Results of a complementary nested case-control study showed that benzodiazepine ever use was associated with an increased risk of Alzheimer's disease (OR 1.51, 95% CI 1.36-1.69). The strength of association increased with exposure density and with the drug half-life (OR = 1.43, 95% CI 1.27-1.61) for short-acting drugs and OR = 1.70 (95% CI 1.46-1.98) for long-acting ones.  This study brings to question the use of benzodiazepines in elderly patients, even those without cognitive impairment.
Other side effects
The other side effects of Z-group medications include fatigue and nausea.  A multicenter, randomized placebo-controlled outpatient study compared the efficacy and safety of zaleplon (5 mg/10 mg) and zolpidem (5 mg). The most common treatment-emergent adverse effects were headache, pain, somnolence, and rhinitis. There was no significant difference between either zaleplon dose and placebo in the frequency of total or individual CNS adverse events. The frequency of total CNS adverse events was significantly greater with zolpidem 5 mg, than with placebo (25% vs. 14%, P < 0.05). The incidence of somnolence in particular was significantly greater (P < 0.05) with zolpidem 5 mg (10%) than with placebo (2%) or zaleplon 5 mg (4%).  In a recent meta-analysis comparing the adverse effects of benzodiazepines in elderly found that use of benzodiazepines in elderly is associated with 2.45 times more risk of side effects when compared with placebo.  The pooled OR was 3.07 (P < 0.0001), the absolute risk reduction of taking placebo over benzodiazepines was 14% and the number needed to harm was seven. The risk of paradoxical activation due to benzodiazepines in the elderly age group is similar to that in the general adult population. However, a population-based cohort study in Canada found a significant association between suicide attempts and benzodiazepine usage (OR = 6.2).  The authors considered disinhibition and paradoxical reactions inducing suicidal impulses as a potential explanation for the association though psychosocial causes and co-morbid psychiatric disorders possibly played a role as well. A case of zolpidem induced psychosis has also been reported as well. 
These findings indicate that not only benzodiazepines, but also the Z-group of sedative-hypnotics are implicated in the serious and potentially life-threatening adverse effects in the geriatric population. This should, therefore, be kept in mind while prescribing hypnotics in this vulnerable population. When indicated, they should be started at low doses and preferably given for short periods to minimize the risk of adverse effects. An increase in dose should be done with care and caution.
| Indian Research|| |
The average elderly Indian is very different from his/her Caucasian counterpart. Differences may be pharmacogenomic, or may be due to nutritional status, co-morbidities, and available health care facilities. However, Indian literature regarding the development of ADRs in this population is scarce. There are a little data, but it is restricted to descriptive studies of prescriptions in this group and case reports of side effects. Sahana et al.,  reviewed the prescriptions of 78 elderly psychiatry patients and found that benzodiazepines were prescribed in 73.1% of patients with lorazepam being most frequently prescribed. Risperidone was the most commonly prescribed antipsychotic agent. Eighty-three percent (65 out of 78) received polypharmacy for psychiatric illness and among them, 55.1% received two medications, 23.1% received three medication combinations, 5.1% received four or more medications. Grover et al.  reported the use of antipsychotics in 89.8% patients with psychotic disorders, 48.7% patients with organic mental disorders and 44.4% patients with bipolar disorder. Olanzapine was the most frequently used antipsychotic, followed by quetiapine. Benzodiazepines were prescribed to patients across diagnostic groups, with clonazepam being the most frequently prescribed. In a study from Mysore by Lucca et al.  that looked at ADRs in 517 patients with antipsychotics, a total of 289 ADRs were identified with an overall incidence rate of 41.97%. Central nervous system and peripheral nervous system were the most commonly affected system organ class (20.4%), and weight gain (10.3%) was the most commonly observed ADR. Olanzapine was most commonly implicated in reported ADRs (31.8%) followed by risperidone (20.4%). Thomas et al. described a patient developing cardiac failure following the use of clozapine for psychotic symptoms which were secondary to dementia.  A case series with zolpidem intoxication delirium has also been reported in elderly patients. 
| Implications|| |
Research literature clearly demonstrates that psychopharmacology in the elderly is fraught with risks. So, what does this mean for the clinician? Time and again, the need to balance the potential risks with the expected benefits has to be kept in mind by clinicians who deal with this age group. Key points to remember while prescribing psychotropics in this age group are summarized in [Table 2].
|Table 2: Points to remember while prescribing psychotropics in the geriatric population|
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It is important that the treatment is individualized as per patients' diagnosis, age, physical status and factors life co-morbid conditions, other medication, patients past response, nutritional status, and so on. In addition, a clinician should keep in mind that medication prescription should be accompanied by appropriate advice. For example, if a patient is prescribed benzodiazepines, it should be imperative for the clinician to advise the patient to avoid activities like driving and operating heavy machinery. In case, a patient is on antipsychotic medication, frequent assessment of metabolic parameters and electrocardiograms may warn the psychiatrist of impending metabolic syndrome or cardiovascular events. And finally, keeping oneself abreast of the current literature will help a clinician better formulate a treatment plan, anticipate potential problems, and avoid them; thereby facilitating the well-being of the patient.
| Conclusion|| |
Use of psychotropic medication in the elderly involves multiple considerations especially as this population is much more vulnerable to ADRs, given their bodily changes, risk of comorbidities, and polypharmacy. Antipsychotic medications increase the risk of death, cerebrovascular and cardiac events, thromboembolism, metabolic syndrome, and other side effects. Sedative-hypnotic medication can increase the risk of falls, fractures, accidents, cognitive impairment, and even dementia. Prescription of these drugs must, therefore, be done with care.
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Conflicts of interest
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[Table 1], [Table 2]
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