CME
Pharmacovigilance for psychiatrists: An introduction Ravi Philip Rajkumar, George Melvin1
Departments of Psychiatry, 1Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, India Patients with psychiatric disorders are often managed with pharmacotherapy. Because of the chronic and relapsing nature of some of these disorders, most practice guidelines recommend that medications should be continued for several months or years.[1‑3] As a result, patients are at risk of experiencing a variety of adverse drug reactions (ADRs). At times, these ADRs can be life‑threatening (such as neuroleptic malignant syndrome)[4] or disabling (such as drug‑induced tardive dyskinesia).[5] It is important for psychiatrists to be aware of the processes involved in identifying and reporting ADRs, especially those that are new or unrecognized. These processes form the basis for the medical discipline of pharmacovigilance. Pharmacovigilance has been defined by the World Health Organization (WHO) as the science and activities related to the detection, assessment, understanding, and prevention of adverse drug effects.[6] As such, pharmacovigilance is not a “specialist” activity: It is one that must be carried out by all those involved in caring for patients on medication, including doctors, nurses, and pharmacists.[7,8] The birth of pharmacovigilance has a close relationship to psychiatry. In the 1960s, thalidomide was widely used in several countries to treat insomnia during pregnancy – a common problem affecting many women. It was soon noticed by physicians that babies exposed to the drug in utero developed congenital malformations, and it was this tragedy – related to a drug that was marketed as a “safe sedative” – that was the beginning of the field of pharmacovigilance.[9] This relationship has continued to the present day. In a recent review of nine major ADRs reported in Europe from 1995 to 2008, two of them involved psychotropics – seizures with bupropion, and suicidality in children taking SSRI antidepressants.[10] While the latter was identified by a re‑analysis of data from the pharmaceutical industry, the former was identified through physician Address for correspondence: Dr. Ravi Philip Rajkumar, Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, India. E‑mail: [email protected]
How to cite this article: Rajkumar RP, Melvin G. Pharmacovigilance for psychiatrists: An introduction. Indian J Psychiatry 2014;56:176-81. 176
reports. In an analysis of ADRs reported to the FDA between 1998 and 2005, many of the frequently implicated drugs were psychotropics[11] – antipsychotics (clozapine, olanzapine, risperidone), antidepressants (duloxetine, sertraline, paroxetine, bupropion), mood stabilizers (carbamazepine, valproate, lamotrigine), and even anti‑ADHD medication (atomoxetine). Now, as then, clinicians have a key role in identifying and reporting new or serious adverse drug effects. Why is Pharmacovigilance Important in Psychiatry? Pharmacovigilance activities are an important part of medical practice in general. A meta‑analysis found that around 5% of hospitalizations in a general medical setting are due to adverse drug effects.[12] A study in a general hospital in France found that 3% of new admissions were due to ADRs, and 6.6% of patients developed a significant ADR during their hospital stay.[13] However, there are four reasons why this field is of special importance to psychiatrists. First, pharmacotherapy is the principal modality of management in several psychiatric disorders. Most drugs used in psychiatry are frequently associated with ADRs. Often, patients do not respond to initial drug therapy, and may require several trials of different medications.[14,15] Some patients may require a combination of various drugs – polypharmacy – which can increase the risk of adverse effects or drug interactions.[16] Second, most clinical trials of psychotropics are conducted in “ideal” conditions – patients are selected according to stringent criteria, and comorbid medical conditions are usually excluded. These trials also tend to be short‑term, lasting for a few weeks or months. By contrast, the patients we encounter in practice often have more complex Access this article online Quick Response Code Website: www.indianjpsychiatry.org
DOI: 10.4103/0019-5545.130502
Indian Journal of Psychiatry 56(2), Apr-Jun 2014
Rajkumar and Melvin: Pharmacovigilance for psychiatrists
presentations and comorbid medical illnesses, and they remain under our care for longer periods of time.[17] In this context, ADRs that were not noticed in the context of a trial become more apparent, and the burden of managing them falls on the psychiatrist. Third, there is a publication bias in clinical trials, particularly those in psychiatry.[18] Even in published trials, ADRs are not always reliably reported, and there is a concern that relevant data may be misrepresented in some cases.[19] Hence, the onus is on treating psychiatrists to identify such reactions and report them, particularly those related to newer drugs. Fourth, psychotropics directly affect brain functioning, and can produce undesirable changes in behavior. Sometimes, these changes can be life‑threatening, as in the case of suicidal behavior induced by antidepressants in children.[20] In other cases, long‑term changes in behavior can be seen, including the re‑appearance of symptoms – a phenomenon that has recently been documented with antidepressants, and has been termed “tardive dysphoria.”[21] For all these reasons, it is important that psychiatrists acquaint themselves with the concepts and methods of pharmacovigilance. The first step in this process is the identification of potential ADRs. Adverse Drug Reactions: Classification and Identification
Stevens‑Johnson syndrome with carbamazepine. A higher index of suspicion is needed to identify such reactions. Recently, a third category – type C adverse reactions – has been added.[26] This term refers to an increased frequency of “spontaneous” disease that may be statistically related to the drug, but in which causality is difficult to prove. An example is the increased risk of gastrointestinal bleeding in patients taking SSRIs.[27] Every adverse event that occurs during drug treatment need not necessarily be an ADR, as is discussed in Table 1. In order to establish causality, various methods of causality assessment have been developed, the most common being Naranjo’s algorithm[28] and the WHO Table 1: Common terms used in describing drug‑related events[22] Term
Definition
Example
Adverse drug reaction Adverse drug event Adverse event
An adverse outcome that occurs at therapeutic doses of a drug, and which is causally linked to it An adverse event that is linked to use of a drug at non‑therapeutic doses, or in an indirect way An event that occurs during use of a drug, but is not related to it
Parkinsonism in a patient taking 15 mg/day of haloperidol Lithium toxicity in a patient taking an overdose with suicidal intent Enteric fever in a patient taking fluoxetine for depression
Table 2: Examples of ADR severity in psychiatry Type
Example
An adverse drug reaction (ADR) can be defined as any adverse patient outcome that occurs at therapeutic doses of a drug, and which can be causally linked to use of the given drug.[22] The terms used in describing ADRs differ somewhat from the similar‑sounding terms used in drug trials. To avoid confusion, the definitions used in the field of pharmacovigilance are listed in [Table 1].
Mild
Olanzapine‑induced sedation Amitryptiline‑induced dry mouth Fluoxetine‑induced nausea Lithium‑induced diabetes insipidus Antipsychotic‑induced parkinsonism Valproate‑induced weight gain Haloperidol‑induced neuroleptic malignant syndrome SSRI‑induced suicidality in children and adolescents Carbamazepine‑induced Stevens‑Johnson syndrome
The severity of ADRs can be categorized as mild, moderate, or severe based on the modified Hartweig and Seigel scale.[23] Table 2 gives examples of ADRs based on severity.
ADR – Adverse drug reaction; SSRI – Selective serotonin reuptake inhibitor
When an ADR results in a serious outcome, such as death, disability, threats to life, hospitalization, or birth defects, then it is known as a serious ADR.[24] Examples of serious ADRs [Table 3].
Nature of the serious ADR
Example
Death
Fatal cardiac arrhythmia in an out‑patient with schizophrenia who is receiving pimozide Admission of a patient who develops diabetes mellitus due to the use of olanzapine Tardive dyskinesia in a patient receiving depot fluphenazine injections in a follow‑up clinic for psychotic disorders Neuroleptic malignant syndrome in a patient given parenteral haloperidol for sedation in the emergency department Spina bifida in a baby whose mother was exposed to valproate (given for bipolar disorder) in the first trimester
ADRs are commonly divided into two broad categories: Type A and type B.[25] Type A reactions are those that are predictable on the basis of the drug’s mechanism of action, such as extrapyramidal side effects with antipsychotics. They tend to be common and are easier to recognize. Type B reactions, on the other hand, are unpredictable and rare, can be fatal, and are related to idiosyncratic mechanisms such as immune reactions. Examples of type B reactions are clozapine‑induced myocarditis and Indian Journal of Psychiatry 56(2), Apr-Jun 2014
Moderate
Severe
Table 3: Examples of serious adverse drug reactions in psychiatry
Hospitalization Disability Threat to life Birth defect
ADR – Adverse drug reaction
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causality assessment scale.[29] These scales use different parameters for assessment, which include: • Temporal relationship: Did the suspected ADR occur after starting the drug? Did it occur within a reasonable time frame (days or weeks for an acute event; can be longer for a chronic event) • Abnormal laboratory tests: Is there documented evidence of organ dysfunction, as indicated by investigations (such as ECG changes or abnormal liver enzymes)? • Absence of other causes: Is there no other cause, or no other concurrent drug, that can explain the ADR? (for example, if a patient taking both valproate and isoniazid develops hepatitis, either drug could be responsible). • Response to de‑challenge: Does the ADR, including the abnormal lab values, resolve after discontinuation of the drug? • Response to re‑challenge: Does the ADR, including the abnormal lab values, re‑appear when the drug is started again? (Note that this may not be ethically possible in some cases, particularly in a life‑threatening event). The following [Table 4], based on the World Health Organization criteria, can help a practicing psychiatrist in identifying the likelihood that a specific adverse event is due to a particular drug. In cases where re‑challenge is not feasible, only a “likely” or “possible” level of certainty can be achieved. But even in such cases, reporting an ADR can have positive long‑term benefits. What is the Psychiatric Clinician’s Role in Pharmacovigilance? There are various methods by which ADRs can be identified on a large scale. All of these depend on “signal generation” – a credible report (the “signal”) of a specific, new adverse effect associated with a given drug.[26] Not all “signals” will be confirmed on further evaluation, as some of them may represent “false positives” due to confounding factors. The process by which further reports confirm the original signal is known as “signal strengthening.”[30] As a signal grows stronger – that is, as more and more reports of the same ADR accumulate – then it can be systematically assessed, described in the literature, and guide clinical practice.
Some “signals” come from pharmaceutical company data, or from the pooled analysis of data from hospitals or academic centers. However, the most cost‑effective form of signal generation is through a “spontaneous reporting database,” through which clinicians can submit reports of suspected ADRs to a central authority. Though this method has its limitations – particularly reporting biases – it is used throughout the world, and was recently implemented in India. As the number of reports of a particular ADR increase, the “signal” in this database grows stronger, and can then be analyzed statistically. This process of analysis is known as data mining.[7,30] The question always arises as to whether clinicians should publish new ADRs as case reports, or report it to a “spontaneous ADR database.” The answer to this question depends on the nature of the reaction being reported. Most journals have a publication bias toward rare, life‑threatening or disabling adverse events. Hence, reports of a less “dramatic” ADR – such as sexual dysfunction with a new antidepressant – may go unpublished. On the other hand, reporting to a spontaneous database will allow a “signal” to be generated over time, even for relatively minor adverse effects. Hence, it is always better to report ADRs to local or national databases. Publication of case reports is an academic activity that can supplement pharmacovigilance, but cannot replace it. Pharmacovigilance Studies of Psychotropics In the past decade, there have been several published studies that examine different aspects of pharmacovigilance related to psychotropics. These include: • General drug‑based studies: Some studies have focused exclusively on all ADRs reported with the use of a particular drug. Examples include UK‑based studies of mirtazapine[31] and olanzapine.[32] The latter led to the identification of drug‑induced diabetes mellitus as a significant ADR. • Serious ADR drug‑based studies: Other researchers have mainly focused on serious ADRs occurring with a particular drug, or group of drugs, that is widely used. Such studies are helpful in informing clinical practice. Examples include a French‑based study of bupropion, which found that allergic reactions and seizures were both common serious ADRs.[33]
Table 4: Estimating the likelihood that an event or laboratory abnormality is due to a drug Absence of other causes
Temporal relationship
Pharmacological mechanism
+ + + + ‑ + ‑ +/− Adverse event, with additional data pending Adverse event with insufficient or contradictory information
+ +/− +/− +/−
Response to de‑challenge
Response to re‑challenge
+ + +/− +/−
+ ‑ ‑ ‑
Likelihood Certain Likely Possible Unlikely Unclassified Unclassifiable
Key: + – Present; +/− – May or may not be present; − – absent
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• Specific ADR drug‑based studies: Some studies have “followed a signal” by studying the association between a particular drug group and a rare ADR. Examples include studies of pituitary tumors with antipsychotics (which found a positive association),[34] ischemic colitis with antipsychotics (a rare but positive association was found)[35] and gastrointestinal bleeding with SSRIs (where a risk of up to 1% was found).[27] • Specific adverse event studies: A French study studied the relationship between falls and the use of any psychotropic medication, and found a specific association not only with benzodiazepines, but with antidepressants.[36] • Studies in special populations: A study from England examined the profile of ADRs seen in children and adolescents taking antipsychotics, and found it to be similar to that of adults – weight gain, extrapyramidal symptoms, and raised prolactin were all common.[37] Recently, pharmacovigilance studies of psychotropics in India have also been published. A study of out‑patients in Kolkata found that 17% of patients studied had “possible” ADRs.[38] Antipsychotics were the most commonly implicated drugs, and common ADRs included tremors, weight gain, and constipation. A study of olanzapine in Pondicherry[39] found that weight gain, tremors, elevated plasma glucose, and somnolence were all probable adverse effects. There is a definite need for more research to examine the burden of adverse reactions to psychotropics in the Indian setting. The Pharmacovigilance Programme in India In India, attempts were made to initiate pharmacovigilance activities in 1986, 1997, and 2005. These efforts were short‑lived. However, in 2010, the Pharmacovigilance Program (PvPI) of India was started by an initiative of the Central Drugs Standard Control Organization (CDSCO) under the Ministry of Health and Family Welfare, Government of India.[40] The Indian Pharmacopoeia Commission, Ghaziabad is presently entrusted with the responsibility of spearheading the program as the National Coordinating Centre (NCC). The PvPI is based on the WHO recommendations. Its aim is to foster the reporting of ADRs by health workers in India, and thereby generate data on ADRs in the Indian context and share it with the WHO’s Uppasala Monitoring Centre (UMC) in Sweden. The PvPI is in the process of establishing ADR monitoring centers (AMC) in medical colleges. At present there are 22 AMCs as per the CDSCO website. The PvPI’s vision is to have an AMC in every medical college, and thereby make our country a center of excellence in the field of pharmacovigilance in the Asia Pacific region by 2015. The reports which are collected at the AMC are sent to the NCC, Ghaziabad with the help of a special software package Indian Journal of Psychiatry 56(2), Apr-Jun 2014
named Vigiflow, which is a web‑based report management tool. Through this software, data may also be sent to the WHO ADR monitoring center in Uppsala, Sweden. On receiving reports, the NCC performs causality analyses and checks for signal generation. The NCC then sends the information to the CDSCO, which takes regulatory actions as recommended by the expert panel of the NCC. Under the PvPI, any health worker can report a suspected ADR to the ADR monitoring center of their hospital. How should an ADR be Reported? As mentioned above, any psychiatrist – whether in Government or private practice – can report adverse effects. A standard form is available for reporting ADRs, which can be downloaded from the CDSCO website. All information collected will be kept strictly confidential, including the reporter’s identity. There is no medico‑legal liability associated with making an ADR report. This form can be accessed at: http://cdsco.nic.in/pharmacovigilance.htm Information should be as complete as possible so as to gather adequate data for causality analysis, and should include patient details, details of diagnosis and treatment, comorbid medical conditions or substance use, and other drugs that the patient was taking at the time. This is important in psychiatry because patients often receive multiple medications. However, even an incomplete report is better than none at all. It is not necessary to perform a “re‑challenge” or to be “certain” [Table 3] about the cause of an ADR when reporting. Even if a clinician finds that the event is only “probable” or “possible,” the event should be reported, as this can help in signal generation. There is a tendency to report only serious ADRs. But in psychiatry, where the long‑term consequences of drug treatment are still being unraveled, any unusual events – including behavioral changes – should be reported. Similarly, if a patient with comorbid medical and psychiatric illness experiences a worsening of medical illness during psychotropic treatment, this could represent an ADR. The Benefits of Pharmacovigilance in a Psychiatric Setting The positive effects of pharmacovigilance in psychiatry can be broadly divided into four categories: Benefits to the patient, benefits to clinicians, benefits to the pharmaceutical industry, and benefits to regulatory authorities. 1. Benefits to the patient: Most adverse drug events, even if not life‑threatening, can be distressing and troublesome to patients. Reporting these events could help in building trust between patients and physicians. The practice of regular reporting can also lead to earlier 179
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identification of problems, which can improve patient compliance and quality of life. 2. Benefits to the physician: The practice of pharmacovigilance can help psychiatrists to identify and manage potential ADRs. In several cases, physicians may be responsible for bringing a particular ADR to light, and can gain credit for this. This is particularly the case for events such as behavioral toxicity (drug‑induced mania, drug‑induced suicidality) that are best recognized by practitioners who are in close contact with their patients. 3. Benefits to the pharmaceutical industry: The role of the pharmaceutical industry in psychiatry has come under fire recently, with reports of serious ADRs being under‑reported and suppressed during trials.[41] If the principal investigators in such trials develop a “culture of pharmacovigilance,” then such ADRs can be identified at the earliest possible stage, and necessary action taken before the drug is marketed. The CDSCO has made the reporting of adverse reactions by the pharmaceutical industry mandatory.[40] This is known as “periodic safety update reporting” (PSUR). 4. Benefits to regulatory authorities: As mentioned above, most published trials of psychotropic medication are short‑term trials. Regulatory authorities may grant approval on the basis of this data, but long‑term adverse effects may emerge much later. Early “signal detection” of such events could help authorities in withdrawing the drug responsible, or limiting its use. Conclusion Pharmacovigilance is an essential activity for all practicing physicians. In the field of psychiatry, where long‑term drug therapy is the norm, clinicians are ideally placed to identify and report ADRs to regulatory authorities. With the setting up of the Pharmacovigilance Program in India, it is important for all psychiatrists to familiarize themselves with the key principles of this science, and to apply them for the welfare of our patients and the healthcare community. Acknowledgments The authors wish to thank Prof. Steven A. Dkhar, Professor, Department of Pharmacology, JIPMER, for his general support.
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Source of Support: Nil, Conflict of Interest: None declared
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Pharmacovigilance for psychiatrists: An introduction Ravi Philip Rajkumar, George Melvin1
Departments of Psychiatry, 1Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, India Patients with psychiatric disorders are often managed with pharmacotherapy. Because of the chronic and relapsing nature of some of these disorders, most practice guidelines recommend that medications should be continued for several months or years.[1‑3] As a result, patients are at risk of experiencing a variety of adverse drug reactions (ADRs). At times, these ADRs can be life‑threatening (such as neuroleptic malignant syndrome)[4] or disabling (such as drug‑induced tardive dyskinesia).[5] It is important for psychiatrists to be aware of the processes involved in identifying and reporting ADRs, especially those that are new or unrecognized. These processes form the basis for the medical discipline of pharmacovigilance. Pharmacovigilance has been defined by the World Health Organization (WHO) as the science and activities related to the detection, assessment, understanding, and prevention of adverse drug effects.[6] As such, pharmacovigilance is not a “specialist” activity: It is one that must be carried out by all those involved in caring for patients on medication, including doctors, nurses, and pharmacists.[7,8] The birth of pharmacovigilance has a close relationship to psychiatry. In the 1960s, thalidomide was widely used in several countries to treat insomnia during pregnancy – a common problem affecting many women. It was soon noticed by physicians that babies exposed to the drug in utero developed congenital malformations, and it was this tragedy – related to a drug that was marketed as a “safe sedative” – that was the beginning of the field of pharmacovigilance.[9] This relationship has continued to the present day. In a recent review of nine major ADRs reported in Europe from 1995 to 2008, two of them involved psychotropics – seizures with bupropion, and suicidality in children taking SSRI antidepressants.[10] While the latter was identified by a re‑analysis of data from the pharmaceutical industry, the former was identified through physician Address for correspondence: Dr. Ravi Philip Rajkumar, Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, India. E‑mail: [email protected]
How to cite this article: Rajkumar RP, Melvin G. Pharmacovigilance for psychiatrists: An introduction. Indian J Psychiatry 2014;56:176-81. 176
reports. In an analysis of ADRs reported to the FDA between 1998 and 2005, many of the frequently implicated drugs were psychotropics[11] – antipsychotics (clozapine, olanzapine, risperidone), antidepressants (duloxetine, sertraline, paroxetine, bupropion), mood stabilizers (carbamazepine, valproate, lamotrigine), and even anti‑ADHD medication (atomoxetine). Now, as then, clinicians have a key role in identifying and reporting new or serious adverse drug effects. Why is Pharmacovigilance Important in Psychiatry? Pharmacovigilance activities are an important part of medical practice in general. A meta‑analysis found that around 5% of hospitalizations in a general medical setting are due to adverse drug effects.[12] A study in a general hospital in France found that 3% of new admissions were due to ADRs, and 6.6% of patients developed a significant ADR during their hospital stay.[13] However, there are four reasons why this field is of special importance to psychiatrists. First, pharmacotherapy is the principal modality of management in several psychiatric disorders. Most drugs used in psychiatry are frequently associated with ADRs. Often, patients do not respond to initial drug therapy, and may require several trials of different medications.[14,15] Some patients may require a combination of various drugs – polypharmacy – which can increase the risk of adverse effects or drug interactions.[16] Second, most clinical trials of psychotropics are conducted in “ideal” conditions – patients are selected according to stringent criteria, and comorbid medical conditions are usually excluded. These trials also tend to be short‑term, lasting for a few weeks or months. By contrast, the patients we encounter in practice often have more complex Access this article online Quick Response Code Website: www.indianjpsychiatry.org
DOI: 10.4103/0019-5545.130502
Indian Journal of Psychiatry 56(2), Apr-Jun 2014
Rajkumar and Melvin: Pharmacovigilance for psychiatrists
presentations and comorbid medical illnesses, and they remain under our care for longer periods of time.[17] In this context, ADRs that were not noticed in the context of a trial become more apparent, and the burden of managing them falls on the psychiatrist. Third, there is a publication bias in clinical trials, particularly those in psychiatry.[18] Even in published trials, ADRs are not always reliably reported, and there is a concern that relevant data may be misrepresented in some cases.[19] Hence, the onus is on treating psychiatrists to identify such reactions and report them, particularly those related to newer drugs. Fourth, psychotropics directly affect brain functioning, and can produce undesirable changes in behavior. Sometimes, these changes can be life‑threatening, as in the case of suicidal behavior induced by antidepressants in children.[20] In other cases, long‑term changes in behavior can be seen, including the re‑appearance of symptoms – a phenomenon that has recently been documented with antidepressants, and has been termed “tardive dysphoria.”[21] For all these reasons, it is important that psychiatrists acquaint themselves with the concepts and methods of pharmacovigilance. The first step in this process is the identification of potential ADRs. Adverse Drug Reactions: Classification and Identification
Stevens‑Johnson syndrome with carbamazepine. A higher index of suspicion is needed to identify such reactions. Recently, a third category – type C adverse reactions – has been added.[26] This term refers to an increased frequency of “spontaneous” disease that may be statistically related to the drug, but in which causality is difficult to prove. An example is the increased risk of gastrointestinal bleeding in patients taking SSRIs.[27] Every adverse event that occurs during drug treatment need not necessarily be an ADR, as is discussed in Table 1. In order to establish causality, various methods of causality assessment have been developed, the most common being Naranjo’s algorithm[28] and the WHO Table 1: Common terms used in describing drug‑related events[22] Term
Definition
Example
Adverse drug reaction Adverse drug event Adverse event
An adverse outcome that occurs at therapeutic doses of a drug, and which is causally linked to it An adverse event that is linked to use of a drug at non‑therapeutic doses, or in an indirect way An event that occurs during use of a drug, but is not related to it
Parkinsonism in a patient taking 15 mg/day of haloperidol Lithium toxicity in a patient taking an overdose with suicidal intent Enteric fever in a patient taking fluoxetine for depression
Table 2: Examples of ADR severity in psychiatry Type
Example
An adverse drug reaction (ADR) can be defined as any adverse patient outcome that occurs at therapeutic doses of a drug, and which can be causally linked to use of the given drug.[22] The terms used in describing ADRs differ somewhat from the similar‑sounding terms used in drug trials. To avoid confusion, the definitions used in the field of pharmacovigilance are listed in [Table 1].
Mild
Olanzapine‑induced sedation Amitryptiline‑induced dry mouth Fluoxetine‑induced nausea Lithium‑induced diabetes insipidus Antipsychotic‑induced parkinsonism Valproate‑induced weight gain Haloperidol‑induced neuroleptic malignant syndrome SSRI‑induced suicidality in children and adolescents Carbamazepine‑induced Stevens‑Johnson syndrome
The severity of ADRs can be categorized as mild, moderate, or severe based on the modified Hartweig and Seigel scale.[23] Table 2 gives examples of ADRs based on severity.
ADR – Adverse drug reaction; SSRI – Selective serotonin reuptake inhibitor
When an ADR results in a serious outcome, such as death, disability, threats to life, hospitalization, or birth defects, then it is known as a serious ADR.[24] Examples of serious ADRs [Table 3].
Nature of the serious ADR
Example
Death
Fatal cardiac arrhythmia in an out‑patient with schizophrenia who is receiving pimozide Admission of a patient who develops diabetes mellitus due to the use of olanzapine Tardive dyskinesia in a patient receiving depot fluphenazine injections in a follow‑up clinic for psychotic disorders Neuroleptic malignant syndrome in a patient given parenteral haloperidol for sedation in the emergency department Spina bifida in a baby whose mother was exposed to valproate (given for bipolar disorder) in the first trimester
ADRs are commonly divided into two broad categories: Type A and type B.[25] Type A reactions are those that are predictable on the basis of the drug’s mechanism of action, such as extrapyramidal side effects with antipsychotics. They tend to be common and are easier to recognize. Type B reactions, on the other hand, are unpredictable and rare, can be fatal, and are related to idiosyncratic mechanisms such as immune reactions. Examples of type B reactions are clozapine‑induced myocarditis and Indian Journal of Psychiatry 56(2), Apr-Jun 2014
Moderate
Severe
Table 3: Examples of serious adverse drug reactions in psychiatry
Hospitalization Disability Threat to life Birth defect
ADR – Adverse drug reaction
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causality assessment scale.[29] These scales use different parameters for assessment, which include: • Temporal relationship: Did the suspected ADR occur after starting the drug? Did it occur within a reasonable time frame (days or weeks for an acute event; can be longer for a chronic event) • Abnormal laboratory tests: Is there documented evidence of organ dysfunction, as indicated by investigations (such as ECG changes or abnormal liver enzymes)? • Absence of other causes: Is there no other cause, or no other concurrent drug, that can explain the ADR? (for example, if a patient taking both valproate and isoniazid develops hepatitis, either drug could be responsible). • Response to de‑challenge: Does the ADR, including the abnormal lab values, resolve after discontinuation of the drug? • Response to re‑challenge: Does the ADR, including the abnormal lab values, re‑appear when the drug is started again? (Note that this may not be ethically possible in some cases, particularly in a life‑threatening event). The following [Table 4], based on the World Health Organization criteria, can help a practicing psychiatrist in identifying the likelihood that a specific adverse event is due to a particular drug. In cases where re‑challenge is not feasible, only a “likely” or “possible” level of certainty can be achieved. But even in such cases, reporting an ADR can have positive long‑term benefits. What is the Psychiatric Clinician’s Role in Pharmacovigilance? There are various methods by which ADRs can be identified on a large scale. All of these depend on “signal generation” – a credible report (the “signal”) of a specific, new adverse effect associated with a given drug.[26] Not all “signals” will be confirmed on further evaluation, as some of them may represent “false positives” due to confounding factors. The process by which further reports confirm the original signal is known as “signal strengthening.”[30] As a signal grows stronger – that is, as more and more reports of the same ADR accumulate – then it can be systematically assessed, described in the literature, and guide clinical practice.
Some “signals” come from pharmaceutical company data, or from the pooled analysis of data from hospitals or academic centers. However, the most cost‑effective form of signal generation is through a “spontaneous reporting database,” through which clinicians can submit reports of suspected ADRs to a central authority. Though this method has its limitations – particularly reporting biases – it is used throughout the world, and was recently implemented in India. As the number of reports of a particular ADR increase, the “signal” in this database grows stronger, and can then be analyzed statistically. This process of analysis is known as data mining.[7,30] The question always arises as to whether clinicians should publish new ADRs as case reports, or report it to a “spontaneous ADR database.” The answer to this question depends on the nature of the reaction being reported. Most journals have a publication bias toward rare, life‑threatening or disabling adverse events. Hence, reports of a less “dramatic” ADR – such as sexual dysfunction with a new antidepressant – may go unpublished. On the other hand, reporting to a spontaneous database will allow a “signal” to be generated over time, even for relatively minor adverse effects. Hence, it is always better to report ADRs to local or national databases. Publication of case reports is an academic activity that can supplement pharmacovigilance, but cannot replace it. Pharmacovigilance Studies of Psychotropics In the past decade, there have been several published studies that examine different aspects of pharmacovigilance related to psychotropics. These include: • General drug‑based studies: Some studies have focused exclusively on all ADRs reported with the use of a particular drug. Examples include UK‑based studies of mirtazapine[31] and olanzapine.[32] The latter led to the identification of drug‑induced diabetes mellitus as a significant ADR. • Serious ADR drug‑based studies: Other researchers have mainly focused on serious ADRs occurring with a particular drug, or group of drugs, that is widely used. Such studies are helpful in informing clinical practice. Examples include a French‑based study of bupropion, which found that allergic reactions and seizures were both common serious ADRs.[33]
Table 4: Estimating the likelihood that an event or laboratory abnormality is due to a drug Absence of other causes
Temporal relationship
Pharmacological mechanism
+ + + + ‑ + ‑ +/− Adverse event, with additional data pending Adverse event with insufficient or contradictory information
+ +/− +/− +/−
Response to de‑challenge
Response to re‑challenge
+ + +/− +/−
+ ‑ ‑ ‑
Likelihood Certain Likely Possible Unlikely Unclassified Unclassifiable
Key: + – Present; +/− – May or may not be present; − – absent
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• Specific ADR drug‑based studies: Some studies have “followed a signal” by studying the association between a particular drug group and a rare ADR. Examples include studies of pituitary tumors with antipsychotics (which found a positive association),[34] ischemic colitis with antipsychotics (a rare but positive association was found)[35] and gastrointestinal bleeding with SSRIs (where a risk of up to 1% was found).[27] • Specific adverse event studies: A French study studied the relationship between falls and the use of any psychotropic medication, and found a specific association not only with benzodiazepines, but with antidepressants.[36] • Studies in special populations: A study from England examined the profile of ADRs seen in children and adolescents taking antipsychotics, and found it to be similar to that of adults – weight gain, extrapyramidal symptoms, and raised prolactin were all common.[37] Recently, pharmacovigilance studies of psychotropics in India have also been published. A study of out‑patients in Kolkata found that 17% of patients studied had “possible” ADRs.[38] Antipsychotics were the most commonly implicated drugs, and common ADRs included tremors, weight gain, and constipation. A study of olanzapine in Pondicherry[39] found that weight gain, tremors, elevated plasma glucose, and somnolence were all probable adverse effects. There is a definite need for more research to examine the burden of adverse reactions to psychotropics in the Indian setting. The Pharmacovigilance Programme in India In India, attempts were made to initiate pharmacovigilance activities in 1986, 1997, and 2005. These efforts were short‑lived. However, in 2010, the Pharmacovigilance Program (PvPI) of India was started by an initiative of the Central Drugs Standard Control Organization (CDSCO) under the Ministry of Health and Family Welfare, Government of India.[40] The Indian Pharmacopoeia Commission, Ghaziabad is presently entrusted with the responsibility of spearheading the program as the National Coordinating Centre (NCC). The PvPI is based on the WHO recommendations. Its aim is to foster the reporting of ADRs by health workers in India, and thereby generate data on ADRs in the Indian context and share it with the WHO’s Uppasala Monitoring Centre (UMC) in Sweden. The PvPI is in the process of establishing ADR monitoring centers (AMC) in medical colleges. At present there are 22 AMCs as per the CDSCO website. The PvPI’s vision is to have an AMC in every medical college, and thereby make our country a center of excellence in the field of pharmacovigilance in the Asia Pacific region by 2015. The reports which are collected at the AMC are sent to the NCC, Ghaziabad with the help of a special software package Indian Journal of Psychiatry 56(2), Apr-Jun 2014
named Vigiflow, which is a web‑based report management tool. Through this software, data may also be sent to the WHO ADR monitoring center in Uppsala, Sweden. On receiving reports, the NCC performs causality analyses and checks for signal generation. The NCC then sends the information to the CDSCO, which takes regulatory actions as recommended by the expert panel of the NCC. Under the PvPI, any health worker can report a suspected ADR to the ADR monitoring center of their hospital. How should an ADR be Reported? As mentioned above, any psychiatrist – whether in Government or private practice – can report adverse effects. A standard form is available for reporting ADRs, which can be downloaded from the CDSCO website. All information collected will be kept strictly confidential, including the reporter’s identity. There is no medico‑legal liability associated with making an ADR report. This form can be accessed at: http://cdsco.nic.in/pharmacovigilance.htm Information should be as complete as possible so as to gather adequate data for causality analysis, and should include patient details, details of diagnosis and treatment, comorbid medical conditions or substance use, and other drugs that the patient was taking at the time. This is important in psychiatry because patients often receive multiple medications. However, even an incomplete report is better than none at all. It is not necessary to perform a “re‑challenge” or to be “certain” [Table 3] about the cause of an ADR when reporting. Even if a clinician finds that the event is only “probable” or “possible,” the event should be reported, as this can help in signal generation. There is a tendency to report only serious ADRs. But in psychiatry, where the long‑term consequences of drug treatment are still being unraveled, any unusual events – including behavioral changes – should be reported. Similarly, if a patient with comorbid medical and psychiatric illness experiences a worsening of medical illness during psychotropic treatment, this could represent an ADR. The Benefits of Pharmacovigilance in a Psychiatric Setting The positive effects of pharmacovigilance in psychiatry can be broadly divided into four categories: Benefits to the patient, benefits to clinicians, benefits to the pharmaceutical industry, and benefits to regulatory authorities. 1. Benefits to the patient: Most adverse drug events, even if not life‑threatening, can be distressing and troublesome to patients. Reporting these events could help in building trust between patients and physicians. The practice of regular reporting can also lead to earlier 179
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identification of problems, which can improve patient compliance and quality of life. 2. Benefits to the physician: The practice of pharmacovigilance can help psychiatrists to identify and manage potential ADRs. In several cases, physicians may be responsible for bringing a particular ADR to light, and can gain credit for this. This is particularly the case for events such as behavioral toxicity (drug‑induced mania, drug‑induced suicidality) that are best recognized by practitioners who are in close contact with their patients. 3. Benefits to the pharmaceutical industry: The role of the pharmaceutical industry in psychiatry has come under fire recently, with reports of serious ADRs being under‑reported and suppressed during trials.[41] If the principal investigators in such trials develop a “culture of pharmacovigilance,” then such ADRs can be identified at the earliest possible stage, and necessary action taken before the drug is marketed. The CDSCO has made the reporting of adverse reactions by the pharmaceutical industry mandatory.[40] This is known as “periodic safety update reporting” (PSUR). 4. Benefits to regulatory authorities: As mentioned above, most published trials of psychotropic medication are short‑term trials. Regulatory authorities may grant approval on the basis of this data, but long‑term adverse effects may emerge much later. Early “signal detection” of such events could help authorities in withdrawing the drug responsible, or limiting its use. Conclusion Pharmacovigilance is an essential activity for all practicing physicians. In the field of psychiatry, where long‑term drug therapy is the norm, clinicians are ideally placed to identify and report ADRs to regulatory authorities. With the setting up of the Pharmacovigilance Program in India, it is important for all psychiatrists to familiarize themselves with the key principles of this science, and to apply them for the welfare of our patients and the healthcare community. Acknowledgments The authors wish to thank Prof. Steven A. Dkhar, Professor, Department of Pharmacology, JIPMER, for his general support.
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Source of Support: Nil, Conflict of Interest: None declared
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