Preventing, Detecting, and Managing Side Effects of Medications



Preventing, Detecting, and Managing Side Effects of Medications


STANLEY KUTCHER

AINSLIE MCDOUGALL

ANDREA MURPHY





KEY POINTS



  • Treatment emergent adverse events (side effects) are a complicating factor in psychopharmacologic treatment and need to be properly managed and, if possible, avoided.


  • Side effects can be physiological, emotional, or behavioral.


  • Educating the patient and appropriate caregivers about common side effects and rare but serious side effects and what to do if they occur is an integral component of psychopharmacologic treatment.


  • The use of a side effects checklist applied at baseline and at subsequent visits can provide the clinician and patient with a good framework for identification and management of treatment-emergent adverse events.


  • A number of successful strategies to manage side effects can be employed, thus increasing the likelihood of treatment adherence and improved therapeutic outcomes.


  • Side effects of antidepressants include, among others, suicidality, activation, manic switch, and serotonin syndrome.



Introduction

Medications play a necessary but often insufficient role in the treatment of most child and adolescent mental disorders. Unlike psychological, social, or other types of interventions, medications are regulated by agencies responsible for the safety, efficacy, and quality of these products. These include the Food and Drug Administration (FDA) (USA), Health Canada (Canada), Medicines and Healthcare Products Regulatory Agency (MHRA) (UK), European Medicines Evaluation Agency (EMEA) (European Union), and the Therapeutic Goods Administration (Australia). Although the process for medication approval may vary from one agency to another, requiring clinical trials that demonstrate the safety and efficacy of the medications is compulsory. Many medications used in treating children and adolescents, including those with mental disorders, have initially received approval for use in adult populations prior to manufacturers seeking regulatory approval for indications relevant to pediatric patients. In many instances where approval in children or adolescents has not been sought, medications are used in an “off-label” fashion (see also Chapter 4). Off-label use of a drug has been described as prescribing a medication for uses that are not included in the product information.1 Some clinicians also consider the use of doses that are higher than recommended as off-label. As few as a quarter of marketed medications can be deemed to have met regulatory criteria for safety and efficacy in pediatric populations.2 This is not an uncommon phenomenon in populations in which research is sparse, for a variety of reasons including legal and ethical concerns. More recently, the number of medication studies conducted in child and adolescent mental disorders has increased and so too has the number of medications that have received regulatory approval.3,4


Of particular importance in the regulatory process is the determination of treatment-emergent adverse events (referred to in this chapter as “adverse events” or “side effects”) that have been systematically collected for those compounds registered. Adverse events can be defined as symptoms that onset during treatment and arise from that treatment.5 Although this has served to better inform clinicians about side effects of various medications, the research is limited in children and adolescents.6 The “off-label” use of many medications poses significant challenges for clinicians because information regarding their therapeutic value and side effects may be less readily available.2 Also, information related to side effects collected by regulatory agencies and in the public domain may be based on data from adults. As such, information about child and adolescent-specific adverse effects may be lacking and not listed in medication information provided to or by regulatory authorities.2

Many studies of medication use in various child and adolescent mental disorders are relatively short term with limited follow-up periods. Thus, although there may be reasonably good information about adverse events in the acute intervention phase, there may be fewer data about side effects that occur later in the course of treatment. The information captured during these trials can also be limited to a priori specific questionnaires or scales that do not incorporate all possible side effects. Some information on longer term adverse events may be available through postmarketing surveillance, but it is not clear how this is captured for medications used “off-label.” In Canada, for example, reporting of adverse reactions regardless of how the medications are used (i.e., “off label” or for approved indications) remains a voluntary process. The situation in most other countries is similar. Although viewed as a professional responsibility, the decision to report is at the discretion of the clinician, and for a variety of reasons (e.g., lack of time, unrecognized adverse reaction) reporting may be suboptimal. Other sources of information are observational studies—including case reports, case series, or case-control and cohort studies—published in journals, bulletins, web pages, or newsletters distributed by regulatory agencies. It is unlikely these can adequately capture the variety and frequency of adverse events. Nor is it likely that all practitioners will be informed about these adverse events using these methods of information distribution.

These issues notwithstanding,7,8 substantial data pertaining to adverse events in young people are available. Although it is beyond the scope of this chapter to list all those that have been identified, resources are available to the practicing clinician in which this information can be found. These include both textbook and online sources and are listed in the resources section at end of this chapter. The purpose here is to provide a framework by which to understand and address treatment-emergent adverse events pertaining to the treatment of depression in young people.

The evidence for pharmacologic treatment of depression in children and adolescents is growing but still limited (see Chapter 6). At this time it is reasonable to consider the use of selective serotonin reuptake inhibitors (SSRIs)—especially fluoxetine—as first-line pharmacotherapy.9, 10, 11 Every treatment decision is based on a benefit/risk evaluation, where the benefit should outweigh the risk.5 Many medications used for the treatment of depression in adults have either not undergone sufficient
evaluation in children and adolescents, have not shown to be significantly more effective than placebo, or have a side-effect profile that makes their risk generally unacceptable in young people. Table 14.1 summarizes this information. Accordingly, this chapter primarily focuses on side effects associated with antidepressants that have the best available evidence for efficacy in this population.








TABLE 14.1 USE AND AVOIDANCE OF ANTIDEPRESSANTS FOR CHILDREN AND ADOLESCENTSa

























USEb AVOIDANCE
Evidence Available
to Support Use		 Not Extensively Studied
or Negative Evidence		 Ineffective Substantial Risk of Side Effects
Fluoxetine
Citalopramc
Sertralinec,d		 Mirtazapine
Fluvoxamine
Escitalopram
Reversible inhibitor of
  monoamine oxidase-type A
  (RIMAs)
Bupropion
Paroxetine		 Imipramine
Desipramine
Amitriptyline
Venlafaxine		 All tricyclic antidepressants
All monoamine oxidase
  inhibitors (MAOIs)
Venlafaxine
aTable contents based on meta-analyses and systematic reviews of efficacy and safety included in this chapter.
bOnly fluoxetine has received regulatory approval in the United States and some other countries for the treatment
of pediatric depression (see also Chapter 6).
cConsidered second line to fluoxetine.
dData favor adolescents.


WHAT ARE TREATMENT-EMERGENT ADVERSE EVENTS?

Adverse events can be defined as any effect (physical, emotional, or behavioral) that is unwanted, caused by the medication, and has a negative or deleterious effect on the well-being or functioning of the individual. It is essential that the identified adverse effect is caused by the medicine. All therapeutic interventions may elicit adverse effects—even placebo! Therefore, it may be difficult to determine in the individual patient if the adverse event is caused by the medication or not.5 This complexity is demonstrated in Table 14.2. As a result, tables that list side-effect prevalence rates (i.e., 12% reporting headaches) are not very useful for clinicians. What would be more useful is an indication of how much more frequently specific side effects occur compared with placebo. Unfortunately, such data are not easily available.








TABLE 14.2 COMBINED TREATMENT-EMERGENT ADVERSE EVENTS INCIDENCEa FOR PATIENTS TREATED WITH PROZAC VERSUS PLACEBO FOR DEPRESSION, OBSESSIVE-COMPULSIVE DISORDER, AND BULIMIA COMBINED
























































Adverse Event Prozac (N = 2,444) Placebo (N = 1,331)
BODY AS A WHOLE
Headache
21
20
Astheniab 12  6
Flu syndrome  5  4
Fever  2  1
CARDIOVASCULAR SYSTEM
Vasodilation
 3
 1
Palpitation  2  1
DIGESTIVE SYSTEM
Nauseab
23
10
Diarrhea 12  8
Anorexiab 11  3
Dry mouth 10  7
Dyspepsia  8  5
aPercentage of patients reporting event.
bDifference of $5%.
Adapted from reference 12.

Side effects can be classified in many ways, for example (1) organ system involved (cardiovascular, digestive, locomotor, etc.); (2) impact on the individual (from nuisance [minor discomfort, such as morning drowsiness] to severe [necessitating discontinuation of treatment, or causing the onset of a debilitating illness, or a fatal result, such as an anaphylactic reaction]); (3) biochemical effects (such as anticholinergic or antihistaminic); and (4) domain in which symptoms manifest themselves (physical, emotional, or behavioral). Frequently, more than one classification is used concurrently (i.e., a minor behavioral event). Regardless of the schemata used, side effects should be described according to their frequency, severity, and duration, with adequate detail of onset and outcome. Side effects can also arise as a result of the cessation or withdrawal of treatment and are described similarly.

Adverse events arise from pharmacokinetic (what the body does to the drug, including absorption, distribution, metabolism, and elimination) or from pharmacodynamic (what the drug does to the body) interactions.



PHARMACOKINETIC INTERACTIONS

For kinetic interactions, it is important to establish whether manipulations such as adding, stopping, or dosage adjustments of concomitant medications—including prescription, nonprescription, natural health products, and illicit substances—can cause new side effects or potentate preexisting effects. These interactions often result from changes in absorption, metabolism, or elimination and less so for distribution interactions (e.g., protein binding) with concurrent use of several medications. For absorption interactions, medications may affect physiologic parameters, such as the gastric pH (e.g., antacids) or motility and transit time (e.g., laxatives).

There is a lack of documentation regarding clinically relevant interactions with the SSRIs that result from altering gastric pH. Some medications used to treat dyspepsia symptoms, including histamine-2 receptor antagonists (e.g., cimetidine) and proton pump inhibitors (e.g., omeprazole), may interact with some antidepressants, but this typically occurs by inhibiting the hepatic metabolism of the psychotropic. In excretion interactions, where the kidneys are primarily responsible for the elimination of a medication, it is often necessary to consider how other medications affect renal blood flow (e.g., nonsteroid anti-inflammatories and lithium), fluid and electrolyte homeostasis (e.g., diuretics and lithium), and whether the medication itself has been associated with causing nephrotoxicity (e.g., lithium). With concomitant lithium therapy it is essential to examine how the combination of medications may affect lithium’s clearance.

When medications are combined, unanticipated changes in the serum level of drugs (e.g., decreases or increases) and adverse events can result from interactions involving the hepatic cytochrome P450 (CYP450) system in which medications are substrates (i.e., metabolized by) and competing for the same enzyme, or in cases where one medication influences (i.e., induces or inhibits) the metabolism of another. Some medications (e.g., carbamazepine, St. John’s wort, modafinil) activate the CYP450 system (also called induction), resulting in an increased metabolism of other drugs metabolized by the same enzyme, typically resulting in reduced serum concentrations and a potential loss of effectiveness. A well-known example of this is carbamazepine, which has the ability to induce its own as well as the metabolism of other drugs (e.g., bupropion).13 Another example of the same process that is common in young people is cigarette smoking.14 St. John’s wort, a natural health product, is an inducer of the CYP450 system, particularly CYP3A415 (see Table 12.2).

Definitive guidelines for dosage adjustments of medications are not readily available for many CYP450 interactions. It can also be difficult to judge the clinical relevance of some interactions; although many are theoretically possible, data are often nonexistent, and frequently such interactions occur without significant clinical impact.

The commonsense approach when little or no data regarding interactions are available is to recognize the potential for interaction and increase vigilance in terms of frequency of monitoring at the initiation of use, with dosage change, and when other medications are added. Involving parents and other health care providers in monitoring can also facilitate collecting information on whether or not the effects of an interaction are clinically significant. Similarly, individual differences in the efficiency of drug metabolism may create different levels of drug metabolites that may have different effects on specific body organs (e.g., carbamazepine and its major metabolite). Some studies have noted individual differences in metabolic rates between Asian versus white patients;16,17 others are inconclusive.18


PHARMACODYNAMIC INTERACTIONS

Pharmacodynamic interactions usually result from the use of two or more medications that act as either agonists or antagonists at the same receptor group. The consequence can be potentiation of a side effect or emergence of new adverse effects. Examples include the following:



  • Taking together two drowsiness-inducing medicines may cause excessive sedation (e.g., fluoxetine plus an antihistamine, lorazepam and mirtazapine).


  • Taking medications with anticholinergic side effects concurrently can cause severe anticholinergic reactions, such as urinary retention, constipation, blurred vision, tachycardia, or confusion (e.g., imipramine and benztropine, chlorpromazine and benztropine).



“START LOW, GO SLOW, BUT GO”

Many side effects are dose related, and every medication has a toxic dose. It is important to recognize that because of individual differences, side effects can arise at different doses for different people. Receptor sensitivities can also vary from one person to another. Thus it is difficult to determine a priori what possible side effects (if any) an individual may experience as a result of taking a specific medication at any specific dose. A common approach when starting medications and titrating to the therapeutic dose is to “start low, go slow, but go;” this allows clinicians and patients to determine the individual tolerability of the medication.

As mentioned previously, side effects can also occur with placebo treatment. In many cases, double-blind, placebo-controlled trials (randomized controlled trials [RCTs]) demonstrate no statistically significant differences among reported rates of side effects between drug and placebo. It is not clear if this is owing to different methods of reporting (spontaneous or structured) or to physiologic, emotional, or behavioral changes induced by the placebo. Thus, for any individual, it may be difficult to determine if complaints following the onset of medication are the consequence of the medication itself. This is particularly true of mild to moderate symptoms. It does not seem to be as common with severe or life-threatening adverse events (personal experience of authors).


TYPES OF SIDE EFFECTS


PHYSICAL

Physical side effects include any manifestation pertaining to physical health, such as headaches, palpitations, orthostatic hypotension, dizziness, tremors, restlessness, drowsiness, dystonia, abdominal pain, diarrhea, skin rashes, anorgasmia, erectile dysfunction, and so on. Changes in laboratory parameters owing to medication but without physical symptoms are a subcategory of the physical side effects. Examples of this are increased thyroid-stimulating hormone (TSH) with lithium, elevated prolactin (PRL) levels with antipsychotic medications, increased heart rate, or prolongation of the QT interval with tricyclic antidepressants (TCAs). In some cases, changes in laboratory values may predict the onset of physical symptoms such as hypothyroidism with increased TSH, and galactorrhea with increased PRL. In many cases, these laboratory-identified changes are asymptomatic and of no clinical significance; in others, they can have substantial consequences in the long run (e.g., metabolic syndrome if olanzapine is added to an SSRI in the treatment of psychotic depression). In young people, it is not well known what long-term consequences (if any) of subclinical changes in these measures may herald. A final issue, especially in children, is that some medications (such as psychostimulants) may affect growth negatively (i.e., height and weight). This occurs over time and may not be noticed unless growth and weight are plotted over the course of treatment.

The SSRI antidepressants are, as a group, unlikely to cause clinically significant endocrine, metabolic, or cardiovascular side effects or significant changes in laboratory parameters. As a result, laboratory monitoring of SSRI treatment is not necessary; the exception is routine pregnancy testing in sexually active young women.


EMOTIONAL/BEHAVIORAL

Any medication that affects the central nervous system has the potential to induce emotional or behavioral adverse effects (e.g., mood changes such as depression or manic symptoms, anxiety or agitation, lethargy, hyperactivity). Some medications may cause unwanted effects on cognition, such as problems with attention or concentration, and difficulties with memory. All of these symptoms may be induced by antidepressant medicines, although they are relatively uncommon and usually mild.


PREVENTION OF SIDE EFFECTS

The first step in prevention is a good working knowledge of several issues pertaining to the pharmacokinetics and pharmacodynamics of specific medications, which include the following:


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Oct 17, 2016 | Posted by in PSYCHOLOGY | Comments Off on Preventing, Detecting, and Managing Side Effects of Medications

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