|Year : 2012 | Volume
| Issue : 3 | Page : 237-242
A retrospective study of the metabolic adverse effects of antipsychotics, antidepressants, and mood stabilizers in the psychiatry outpatient clinic of a tertiary care hospital in south India
Kingshuk Lahon1, Harsha M Shetty1, Amith Paramel2, Gyaneshwar Sharma3
1 Department of Pharmacology, Psychiatry, Mahatma Gandhi Medical College and Research Institute (MGMCRI), Pondicherry, India
2 Senior Pharmacovigilance Physician, Quintiles, Bangalore, India
3 Core Trainee in Psychiatry, SHO in Psychotherapy, Therapeutic Community and Unity House, London, United Kingdom
|Date of Web Publication||8-Aug-2012|
Department of Pharmacology, Mahatma Gandhi Medical College and Research Institute (MGMCRI),Pondicherry - 607 402
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Persons with severe mental illness are at relatively greater risk of developing obesity, type 2 diabetes mellitus, hypertension, and dyslipidemia as compared to the normal population. Psychotropic medication such as antipsychotics, antidepressants, and mood stabilizers may further increase the risk in these patients. Hence, we wanted to study the prevalence and pattern of metabolic adverse effects of antipsychotics, antidepressants, and mood stabilizers. Materials and Methods: We conducted a 1-year retrospective study of case records in the outpatient clinic of the psychiatric unit of our hospital and assessed the causality, severity, and preventability of the documented metabolic adverse events. We calculated prevalence rates by descriptive methods and used standard scales for assessing the causality, severity, and preventability of the adverse drug reactions (ADR). Results: Out of 222 patients who received antipsychotics, antidepressants, or mood stabilizers, 20 patients developed metabolic ADRs (9.01%), which included weight gain, hyperglycemia, dyslipidemia, and galactorrhea. These ADRs were possible to probable, mild to moderately severe, and probably preventable as per the respective scales. Conclusions: The prevalence of metabolic ADR was low but the pattern was similar to that found in previous studies from the West. Weight gain was the most common metabolic ADR, and olanzapine was the psychotropic drug most commonly responsible for causing metabolic ADRs. Awareness and timely intervention on the part of treating physicians can help in prevention (by lifestyle modification) and management of such ADRs (by change of drug and/or using specific treatment for the metabolic derangement, e.g., oral hypoglycemic drugs for diabetes mellitus) and thus help decrease the morbidity and mortality among psychiatric patients.
Keywords: Adverse drug reactions, antidepressants, antipsychotics, metabolic, mood stabilizers
|How to cite this article:|
Lahon K, Shetty HM, Paramel A, Sharma G. A retrospective study of the metabolic adverse effects of antipsychotics, antidepressants, and mood stabilizers in the psychiatry outpatient clinic of a tertiary care hospital in south India. Int J Nutr Pharmacol Neurol Dis 2012;2:237-42
|How to cite this URL:|
Lahon K, Shetty HM, Paramel A, Sharma G. A retrospective study of the metabolic adverse effects of antipsychotics, antidepressants, and mood stabilizers in the psychiatry outpatient clinic of a tertiary care hospital in south India. Int J Nutr Pharmacol Neurol Dis [serial online] 2012 [cited 2020 Jan 29];2:237-42. Available from: http://www.ijnpnd.com/text.asp?2012/2/3/237/99477
| Introduction|| |
Persons with severe mental illness, particularly schizophrenia, suffer from increased morbidity and mortality compared with the general population. They are at greater risk of developing obesity, type 2 diabetes mellitus, hypertension, and dyslipidemia as compared to the normal population. Psychotropic medication may further increase the risk of developing such metabolic derangements in these patients; in other words, these metabolic derangements can be considered as adverse drug reactions as per the accepted definition, i.e., an adverse drug reaction is any noxious change which is suspected to be due to a drug, occurs at doses normally used in man, requires treatment or decrease in dose, or indicates the need for caution in the future use of the same drug'.
More than 450 million people worldwide suffer from mental disorders. According to WHO's Global Burden of Disease, 2001, 33% of the years lived with disability are due to neuropsychiatric disorders Four of the six leading causes of years lived with disability are neuropsychiatric disorders (depression, alcohol-use disorders, schizophrenia, and bipolar disorder). More than 150 million persons suffer from depression at any point in time. Nearly one million commit suicide every year. About 25 million suffer from schizophrenia and more than 90 million suffer from an alcohol- or drug-use disorder. In India, epidemiological studies report prevalence rates for psychiatric disorders of 9.5-370 per 1000 population. However, the prevalence of mental disorders reported in epidemiological surveys in India can be considered underestimations rather than accurate reflections of the true prevalence in the population.
Pharmacotherapy of depressive and adjustment disorders and the psychoses, including schizophrenia and bipolar disorder, has changed greatly over the last few years. Tricyclic antidepressants and monoamine oxidase (MAO) inhibitors are being gradually replaced by selective serotonin reuptake inhibitors (SSRIs) and novel antidepressants such as mirtazapine, duloxetine, venlafaxine, milnacipran, etc. First-generation antipsychotics such as haloperidol and chlorpromazine are giving way to second-generation drugs such as clozapine, olanzapine, risperidone, ziprasidone, quetiapine, and aripiprazole. Valproic acid and carbamazepine are used frequently nowadays in the pharmacotherapy of bipolar disorder and mania, even though the gold standard is still lithium carbonate.
Second-generation antipsychotics, antidepressants, and mood stabilizers have been implicated in the development of metabolic adverse effects like weight gain, hyperglycemia, and dyslipidemia, often leading to metabolic syndrome.,,
The American Diabetic Association has recognized the danger posed by the metabolic effects of antipsychotic drugs in their guidelines. But practical problems still exist in implementing the guidelines as the study by Amiel et al. shows. Moreover, potential diabetes risk is currently not taken into consideration in the clinical guidelines for treating depression. A brief recommendation for managing the weight gain, hyperglycemia, and dyslipidemia that occurs during treatment with psychotropic drugs is provided by the Indian Psychiatric Society but a comprehensive algorithm for the management of psychotropic drug-induced metabolic effects is lacking. Indians are more susceptible to the metabolic effects of psychotropic drugs, and seeing the paucity of Indian studies on this aspect, we present this study to raise awareness about this problem. We studied the metabolic adverse effects of antipsychotics, antidepressants, and mood stabilizers with a view of providing information that would help in preventing these adverse reactions in the future (if possible), and thus decrease the morbidity associated with these drugs.
Our objective was to study the prevalence and pattern of metabolic adverse effects of antipsychotics, antidepressants, and mood stabilizers in a tertiary care hospital in South India.
| Materials and Methods|| |
We conducted a 1-year (1st January 2006 to 31st December 2006) retrospective study of case records from the outpatient clinic of the psychiatric unit of our hospital. As it was a non-interventional study, the institutional research committee granted a waiver on the assurance that subject confidentiality would be maintained. All patients (old and new) who attended the psychiatry outpatient clinic during the study period and were diagnosed with a psychiatric disorder and received treatment with an antidepressant, antipsychotic, or mood stabilizer were included. We excluded patients who were being treated for their psychiatric disorders by continuing only those medications which were prescribed outside our hospital without any new prescription from our psychiatric unit. We collected the data, using a data collection sheet (proforma) and recorded any weight gain, hyperglycemia, and/or lipid profile abnormalities that were documented by the treating physicians in the case records during the follow-up visits. Besides physicians' notes, hyperglycemia and dyslipidemia were also assessed by the results of laboratory test. Prevalence rates were calculated by simple descriptive methods. We then assessed the causality, severity, and preventability of the documented metabolic adverse drug reactions (ADRs) by Naranjo scale, modified Siegel and Hartwig scale, and modified Schumock and Thornton scale, respectively.,, A problem that can occur during causality assessment is that there may be other concomitant medications, and drug interactions may be responsible for causing the ADR. The Naranjo scale has no provision for measuring drug interactions. To overcome this limitation, we used another scale called the drug interaction probability scale (DIPS) wherever there was a possibility of drug interaction-induced ADRs; the DIPS is based on the same set of questions as the Naranjo scale for drug combinations.
| Results|| |
Out of 222 patients, who were administered antipsychotics, antidepressants, or mood stabilizers, 20 patients developed metabolic ADRs (9.01%). The patients were either from Pondicherry or from Cuddalore district of Tamil Nadu in South India. Among them, 11 patients were diagnosed with schizophrenia, including 5 with post-schizophrenic depression. Seven of the twenty had depressive disorders and two were diagnosed with bipolar affective disorder. The distribution of the pattern of ADR, along with the associated drug(s), is shown in [Table 1]. Causality assessment scales like Naranjo's and DIPS objectively attempt to find the association between an adverse event and the likelihood that it is due to a drug(s), thus classifying ADRs as doubtful, possible, probable or definite. The results of the causality assessment are shown in [Table 2] and [Table 3].
|Table 2: Assessment of causality of the metabolic ADRs with individual drugs (Naranjo scale)|
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|Table 3: Assessment of causality of the metabolic ADRs with drug combinations (DIPS)|
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The prescribing pattern of antipsychotics, antidepressants, and mood stabilizers in our hospital during the study period reflects the following trends: among patients prescribed antipsychotics, 94.5% received second-generation antipsychotics, i.e., olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole; among the patients prescribed antidepressants, 96.36% received the newer antidepressants, i.e., duloxetine, escitalopram, sertraline, and mirtazapine; and among patients prescribed mood stabilizers, 90.9% received valproic acid (excluding those patients who received antipsychotics as mood stabilizers).
Among the twenty patients who developed metabolic abnormalities, 14 (70%) were females and 6 (30%) were males. Four patients (20%) were aged less than 20 years, thirteen (65%) were in the 21-40 years age-group, one (5%) was in the age-group of 41-60 years, and two (10%) were above 60 years.
Among the patients who developed weight gain, there were ten female and four male patients. Four of them were aged less than 20 years, nine were between 21-40 years, and one was above 60 years. Nine of these patients were diagnosed with schizophrenia, three with depressive disorder, and two with bipolar affective disorder. In all patients who developed weight gain, the prescribed daily doses of drugs were as follows: olanzapine 2.5-15 mg, risperidone 6 mg, haloperidol 1 mg, quetiapine 50-100 mg, ziprasidone 40-120 mg, aripiprazole 10-15 mg, divalproex/valproate 500-2000 mg, and mirtazapine 7.5-15 mg. The duration of treatment ranged from 39 to 300 days, and the mean duration of treatment was 110.7 days.
There was no record of baseline weight, but once the patient presented with weight gain, monitoring was done on subsequent follow-up visits. Hence, the degree of weight gain (highest recorded value minus the baseline value) could not be calculated.
One male (33.33%) and two female (66.66%) patients developed hyperglycemia. Of these patients, one (33.33%) was in the 21-40 year age group , one (33.33%) in the 41-60 year age-group, and one (33.33%) above 60 years. Two patients were diagnosed with schizophrenia and one with severe depressive disorder with psychotic features. The prescribed daily doses of drugs were as follows: olanzapine 2.5-15 mg, duloxetine 20-40 mg, and mirtazapine 7.5-15 mg. The duration of treatment was 45 days for one patient (olanzapine × 45 days), 14 days for another patient (olanzapine ×14 days and duloxetine × 12 days), and 90 days for the third patient (olanzapine × 90 days and mirtazapine × 22 days). Hyperglycemia with olanzapine developed at daily dose levels of 5 mg in one patient and at a dose of 15 mg in the other two. Blood sugar levels were 147 mg/dL (postprandial) in one patient and 228 mg/dL (random) in another. No quantitative record of the level was available for the other patient. The patient with random blood sugar level of 228 mg/dL initially developed symptoms of polydipsia (increased thirst) and polyuria (increased frequency of urination) and had to be treated with the oral hypoglycemic pioglitazone in addition to decrease in the dose of olanzapine.
None of the patients who developed hyperglycemia were known diabetics.
Two patients, one male (50%) and one female (50%), both in the 21-40 years age-group, developed dyslipidemia. Both were diagnosed with depressive disorder; one had comorbid alcohol dependence (on treatment with acamprosate and lorazepam) and the other had epilepsy (on treatment with phenytoin/carbamazepine). In one patient, mirtazapine in a dose of 7.5 mg was prescribed for 10 days, following which the patient developed hypercholesterolemia and an abnormal lipid profile. In the other, duloxetine followed by mirtazapine were the drugs that caused abnormalities of the lipid profile. Data on dose and duration of treatment were not available for this patient. Lipid profile reports were not available.
In both cases, mirtazapine was stopped when the ADR developed.
Galactorrhea was observed in one patient, a 28-year-old female diagnosed with recurrent depressive episode and treated with escitalopram and clonazepam. She was concurrently administered risperidone and sodium valproate to stabilize her mood. Risperidone was suspected to be the cause of the galactorrhea and it was stopped.
Data on dose and duration of treatment were not available for this patient. Prolactin level estimation was not done.
For weight gain, hyperglycemia, and dyslipidemia, the patients were advised lifestyle modification, such as dietary restriction and regular exercise.
Modified Hartwig and Siegel Severity assessment scale classifies ADRs as Mild (Levels 1 and 2), Moderate (Levels 3 and 4) and Severe (Levels 5 through 7) based on the impact of management of the ADR. All ADRs could be categorized as 'mild' in severity except for hyperglycemia, which was categorized as 'moderate' (level 3) severity. Modified Schumock and Thornton scale classifies ADRs as definitely, probably or not preventable according to the response to a set of questions about medication safety. All ADRs were classifiable as 'probably preventable,' except for galactorrhea ('not preventable').
| Discussion|| |
Our objective was to study the prevalence and pattern of metabolic ADRs of antidepressants, antipsychotics, and mood stabilizers. Known types of metabolic ADRs were observed in the study, but prevalence was low. As per the study of Nasrallah et al., the prevalence of such metabolic adverse effects ranges from as low as 2% up to a high of 36%. Weight gain was the most common metabolic ADR observed in our study. Overall, olanzapine was the drug that was most commonly associated with metabolic ADRs: olanzapine alone in six cases and in combination with other drugs (mirtazapine and/or divalproex) in seven cases.
Weight gain was observed more often in females (71.4%) than in males (28.6%), and the maximum was seen in the age-group of <40 years (95%). This is consistent with findings of other studies. The most common drug associated with weight gain was olanzapine either alone or in combination with other drugs (mirtazapine and/or divalproex). This observation is also similar to the results of other studies., Risperidone, ziprasidone, quetiapine, and aripiprazole are known causes of antipsychotic-induced weight gain. The association of mirtazapine and valproate with weight gain is also supported by previous studies., Our causality assessment may have been confounded by comorbidities; for example, two patients had mild pedal edema (the edema may have been the cause of the weight gain), and another two patients were on treatment with carbamazepine for seizure disorder (carbamazepine has been known to cause weight gain).
The most common drug associated with hyperglycemia was also olanzapine (similar to observations in other studies),, either alone or in combination with mirtazapine or duloxetine. While mirtazapine has been previously associated with hyperglycemia, a recent meta-analysis did not find any association between hyperglycemia and duloxetine. The administration of mirtazapine in addition to olanzapine in the same patient may have increased the risk of hyperglycemia. This patient was concomitantly suffering from menorrhagia, which was under investigation but the cause had not yet been diagnosed; in this case, we have to consider the possibility of polycystic ovary syndrome (PCOS), which may have caused the hyperglycemia since insulin resistance and menstrual irregularities are both seen in PCOS.
The most common drug associated with dyslipidemia was mirtazapine. Mirtazapine is a drug that is known to cause dyslipidemia.
The lone case of galactorrhea was attributed to risperidone as it has been previously reported to be associated with galactorrhea.
As per causality, severity and preventability assessments, we observed possible to probable, mild to moderately severe and probably preventable ADRs with psychotropic drugs.
Increased appetite, carbohydrate craving, reduced insulin sensitivity, and abnormalities in lipid metabolism and hyperprolactinemia are believed to be the mechanisms behind the development of these metabolic effects by the action of the drugs on 5-HT2, H1, and dopamine D2 receptors.,,,, It is known that increased intake of carbohydrates may result in insulin resistance and metabolic syndrome.
A strength of this study is that we have reported the doses and duration of treatment with psychotropic drugs in patients developing metabolic ADRs; this information may help future researchers in finding a dose-response relationship between metabolic effects and causative drugs, other than for olanzapine for which the association is already established. Our study adds to the existing database on metabolic ADRs seen with psychotropic agents; barring the studies of Gautam, et al., Mattoo et al., Saddichha et al., Sahoo et al., and Jacob et al.,,,, there has been little research on this topic.
A major limitation of this study is that we did not have the baseline weights, blood sugar levels, and serum lipid profiles before the administration of the psychotropic drugs. This data would have reinforced the strength of causality association of the ADRs with the respective drugs. The lack of baseline values of weight did not allow quantification of the weight gain; however, once weight gain was observed in a patient, progressive increase in weight was documented on the follow-up visits. The lack of baseline values of blood sugar and serum lipids decreased the scores on the ADR causality scale, a negative history of diabetes or dyslipidemia notwithstanding, as the patients may have been suffering from undiagnosed diabetes or lipid abnormalities. Another limitation is that data regarding dose and duration of treatment was not available, as also information regarding the duration of psychiatric illness and treatment history prior to receiving treatment in our hospital. These limitations were due to the retrospective nature of the study.
| Conclusion|| |
The metabolic ADRs observed in our study were similar to those in Western studies, but the prevalence was relatively low. Weight gain was the most common metabolic ADR observed, and olanzapine the psychotropic drug most commonly associated with metabolic effects. This study reinforces the need to monitor psychiatric patients regularly for weight gain, glucose dysregulation, and lipid abnormalities. Baseline monitoring of weight, blood sugar, and lipid profile is necessary before initiating treatment with the second-generation antipsychotics, newer antidepressants such as duloxetine and mirtazapine, and mood stabilizers such as valproic acid.
Advice on lifestyle modifications (diet and exercise), as well as switching of psychotropic medication to one which causes less or no metabolic effects, are important treatment measures. Awareness and timely intervention on the part of treating physician can help in the prevention and management of such ADRs and decrease the morbidity and mortality among psychiatric patients.
Indians are said to be relatively more susceptible to metabolic adverse effects of psychotropic drugs but we do not have sufficient data from which to frame proper guidelines and treatment protocols in the Indian population. There is a need for adequately powered, prospective, collaborative research by psychiatrists, endocrinologists, and physicians to highlight and tackle this problem.
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[Table 1], [Table 2], [Table 3]