A comprehensive review introduction



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Adverse drug events (ADEs) or adverse drug reactions (ADRs) are a burden to everyone involved; to the patient, to the families, to the clinicians and to the entire healthcare system.

According to the American Society of Hospital Pharmacists (ASHP), ASHP defines a significant ADR as any unexpected, unintended, undesired, or excessive response to a drug that (62):

1. Requires discontinuing the drug (therapeutic or diagnostic)

2. Requires changing the drug therapy

3. Requires modifying the dose (except for minor dosage adjustments)

4. Necessitates admission to a hospital

5. Prolongs stay in a health care facility

6. Necessitates supportive treatment

7. Significantly complicates diagnosis

8. Negatively affects prognosis

9. Results in temporary or permanent harm, disability, or death

Adverse drug events include manifestations of side effects and toxic effects. From the patient’s perspective as well as its impacts upon the health system, adverse events (ADEs) are discussed in greater depth in the following section.


It is not unusual for patients on psychotropic medications to experience serious adverse effects. In fact, their notorious serious adverse effect profiles are known to undermine patient compliance. These untoward reactions may manifest in any of the following signs and symptoms:

  • Allergic reaction

  • Change in level of alertness

  • Change in eating patterns

  • GIT disturbances

  • Cardiac disturbances

  • Fainting or dizziness

  • Abnormal gait

  • Jaundice
  • Unusual bruising

Additionally, the mentally ill patient may not always be able to verbalize the side effects they’re experiencing, making them all the more vulnerable. It is the clinicians’ and guardians’ responsibility to observe their patients closely and watch out for the early signs of these side effects before they worsen and cause fatalities. Moreover, an awareness of the medications with black box warning is important. A black box warning is an FDA notice to the public and appears on the package inserts of drugs that have serious adverse effects.

Below is a list of drugs with a “black box warning” on their labels: (63)






















Table 7: Commonly prescribed psychotropic drugs with black box warnings

Clinicians and the healthcare system

Adverse drug events do not only affect the patient and families. They affect the hospital and the entire healthcare system. They cost a lot of money. It is estimated that close to 770,000 people suffer from ADEs of one kind or another in a year and the cost of legal fees to each

hospital can be as high as $5.6 million[64, 65] yearly. This figure is exclusive of the litigation and malpractice costs and does not include the cost of admissions.


One of the common most and basic ADE is the patient injury associated with it. The consequence in these cases may range from a simple allergic reaction to sudden death. Studies have shown that up to 9.7% of ADE’s lead to a permanent form of disability. In the US, institutionalized patients who experienced ADE’s during their confinement are covered by the hospital. The prolonged hospital stays is a costly sequel to ADEs, with thousands of dollars consumed in the process, from hospitalization costs to insurance employment benefits. The length of hospital stay also depends on the type of adverse event that caused the hospitalization. A U.S. study found that patients who experience serious ADEs such as arrhythmias, seizures, bleeding disorders, and CNS suppression could be confined up to 20 days in the hospital. On the other hand, patients who experienced milder ADEs can be confined for up to 13 days. When these numbers are compared to those who encountered no ADEs at all during their hospital stay, the average length of admission was only 5 days [66]. Outpatients are most likely covered by their insurance companies in the event of ADEs.


Most adverse drug events are preventable. This is why patients need to be vigilant while on therapy and clinicians and other healthcare professionals be thorough in their work and proceed with caution. One cause of ADEs is attributed to errors that occurred during a pharmacy visit. This could be anywhere from wrong prescription, wrong transcription and medication dispensing. Clinicians do make mistakes too. They may prescribe the wrong dose or miss an allergic history, etc. A study on typical errors that lead to ADEs reported that missed doses accounted for 7% of the errors whereas wrong technique and illegibility errors accounted for 6% of ADEs. Duplicate therapy accounted for another 5%, which was almost similar to the ADEs caused by drug–drug interactions. Additionally, equipment issues, lack of proper monitoring and preparation errors each accounted for about 1 % of the total adverse events that occurred (67, 68, 69).

The figure below shows the commonly encountered medication errors and the frequency with which they occur in general (70).


Studies have proven a centralized and computerized monitoring system to be an effective method of preventing ADEs. The data entered into the computers was able to notify all healthcare workers involved of any allergic reaction, drug-drug interaction, and drug-food interaction. The system enabled pharmacists to check for any errors that could occur because of excessive or inappropriate doses. Moreover, allergic reactions to drugs were identified earlier through this process, preventing the reaction to escalate to a serious event. Physicians were then notified and able to modify their prescriptions. Computerized physician order entry (CPOE) was also shown to reduce the errors caused by illegible orders, inappropriate doses, and improper routes and frequency of administration. Essentially, ADEs have greater chances of being caught in time because of the sophisticated technological advances in healthcare computer systems. In fact, almost all hospitals in the country have invested in state of the art monitoring systems to protect their patients and themselves, preferring that than risk facing the consequences of ADEs (66).

Drug-Drug Interactions (DDIs)

Drug-drug interactions are preventable in many cases. This is especially true for those that are mediated by the cytochrome P-450 enzyme family. Correct and sufficient knowledge of a drug’s pharmacokinetic and pharmacodynamics profiles will enable clinicians to educate their patients and families on their use.

Drug interactions result from the concomitant administration of multiple drugs, alcohol, substance and food. In this section, most of the section will focus on drug-drug interactions of psychotropic drugs with other drugs. As mentioned previously, coadministration practices such as polypharmacy, and multiple comorbid conditions predispose individuals to drug-drug interactions.

Drug-drug interactions exhibit varying degrees of the severity of their consequences. DDIs may make drugs less effective, cause unexpected side effects, or increase/decrease the action of another drug. Some drug interactions can even lead to fatal consequences. There are cases too where drug interactions cause nothing more than inconvenient side effects.

One of the reasons why drug interactions are particularly common with psychotropic drugs is because they are usually prescribed over a long period of time. Mentally ill patients may need to use other drugs for other conditions during this period such as antibiotics, pain and hypertensive drugs. Doctors, nurses and pharmacists who see such patients should be made aware of their psychotropic medication regimens and prescribe, administer, and dispense accordingly.

As mentioned above, there are two mechanisms upon which drug-drug interactions occur. Firstly, they may occur via pharmacodynamics interactions i.e. the physiological effect of the drug may either be enhanced or weakened or secondly, it may occur through the alteration of the pharmacokinetics of the drug i.e. its availability, absorption, bioavailability, distribution, metabolism, and excretion may be changed.

Pharmacokinetic interactions

DDIs that affect the pharmacokinetics of drugs are due to the cytochrome P450 group of microsomal enzymes in the liver. The cytochrome P450 enzyme family is responsible for the metabolism of the majority of drugs, eleven of which have been identified as major players. Not all individuals exhibit the same degree of CYP isozyme activity; genetic variations divide the human population into three types of metabolizers.

  • Poor metabolizers: They have dysfunctional or inactive CYP isozymes and are more prone to suffer from drug toxicity as a result of reduced drug metabolism and elimination processes. Since some drugs are formulated as prodrugs, poor metabolizers may respond poorly or not at all to such treatments.

  • Extensive metabolizers: They are considered to have normal CYP isozyme activity, the majority of individuals fall under this category.

  • Ultra rapid metabolizers: They have overactive CYP isozymes. Drugs are rapidly metabolized by these enzymes; leading to sub-therapeutic plasma levels of the drug. These individuals may receive little or no therapeutic benefit. When prodrugs are administered, toxicity is a very real possibility -with very high levels of active metabolites circulating in such a short period of time.

In drug-drug interactions involving the CYP isozymes, drugs either induce or inhibit their activity, resulting in a change in the substrate metabolism and subsequent clearance of the drug. Two of the most common isozymes involved in these interactions are the CYP2D6 and CYP3A4.

Carbamazepine (Tegretol), phenobarbital (Donnatal), phenytoin (Dilantin), rifampicin (Rifadin) and St John’s Wort are all inducers of the CYP3A4 enzyme. An example of a DDI mediated by the induction of CYP3A4 is the reduced metabolism and efficacy of haloperidol when coadministered with carbamazepine (Tegretol). The latter is an inducer of the same CYP isozyme. Another example is the reported severe myotoxic effects (e.g. rhabdomyolysis) associated with the use of the antidepressant, nefazodone (Serzone), with simvastatin (Zocor), a cholesterol lowering drug [71]. These toxic effects are the direct result of the nefazodone-induced inhibition of the CYP3A4 isozyme pathway, wherein simvastatin is also a substrate.

Alcohol is also a substrate and an inducer of the CYP2E1 isozyme (see table below). When alcohol is given in combination with venlafaxine (Effexor), a substrate of the CYP2E1 isozyme, it induces its metabolism, resulting in faster clearance and diminished antidepressant effects.

The absorption of amphetamines is decreased when given with gastrointestinal acidifying agents and reduced when given with alkalinizing agents. Monoamine oxidase inhibitors slow down the metabolism of amphetamine which results in deleterious effects. Hypertensive crisis and hyperpyrexia may ensue, fatal consequences of the drug-drug interaction. Amphetamines also interact with haloperidol (Haldol), lithium carbonate (Eskalith), ethosuxamide (Emeside), meperidine (Demerol), phenobarbital (Donnatal), norepinephrine, phenytoin (Dilantin) and a number of other drugs.

Another mode of DDI is through enzyme inhibition via competitive enzyme binding. Enzyme inhibition is directly proportional to the plasma levels of the drug. Amiodarone (Cordarone), cimetidine (Tagamet), fluoxetine (Prozac) are enzyme inhibitors. The table below has the detailed list of enzymes and their competing substrates.

CYP enzymes





Amitriptyline, clozapine, duloxetine, fluvoxamine

Phenobarbital, inhaled smoke, insulin

Paroxetine, fluvoxamine



Disulfiram, alcohol



Alprazolam, amitriptyline, Aripiprazole, benzodiazepines, clozapine, citalopram, caffeine, propranolol

Barbiturates, carbamazepine, phenytoin, phenobarbital, St john’s Wort.

Cimetidine, chloramphenicol, diltiazem.


Amitriptyline, fluoxetine,


Fluoxetine, fluvoxamine


Diazepam, citalopram, amitriptyline





Aripiprazole Atomoxetine

Dexamethasone, rifampicin




Table 8: Psychotropic drugs and their competing substrates

Similarly, the plasma concentration of lithium is increased when coadministered with diuretics that promote sodium loss, leading to toxicity. Calcium channel blockers and methyldopa (Aldomet) can also increase the toxicity of lithium carbonate (Eskalith) and should not be given in combination. Tinnitus, diarrhea, nausea, vomiting and even ataxia occur with concomitant use of lithium and calcium channel blockers. Likewise, simultaneous use of lithium with antihypertensives such as ACE inhibitors (e.g. captopril (Capoten)) and angiotensin-2 receptor antagonists (e.g. losartan (Cozaar)), and NSAIDS also lead to dangerously high plasma lithium levels. Metronidazole (Flagyl), when combined with lithium, decreases the renal clearance of lithium, also resulting in increased plasma levels of the drug. These two drugs should be very carefully monitored if ever administered concomitantly.

A well known interaction mediated by the CYP2D6 isozyme is the one between tamoxifen (Nolvadex) and antidepressants. The following table summarizes the severity of the interaction among different antidepressants with tamoxifen (Nolvadex) and the clinical advice associated with their concomitant use (72).


Severity of effect on CYP2D6

Clinical advice on the safety of coadministration

Venlafaxine (Effexor)


Safest to concomitantly administer with tamoxifen

Mirtazapine (Remeron)

No studies


Citalopram (Celexa)

Nefazodone (Serzone)


Secondary choice if venlafaxine or mirtazapine are not available

Duloxetine (Cymbalta)

Sertraline (Zoloft)


Weigh benefits against risks

Paroxetine (Paxil)

Fluoxetine (Prozac)


Avoid concomitant administration

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