Pharmacodynamic interactions are caused by additive or competing effects of multiple drugs. The most serious of these involve medications that increase a patient’s risk of serotonin syndrome or neuroleptic malignant syndrome (NMS); both are medical emergencies that require immediate hospitalization.
Although any medication with serotonergic activity can induce serotonin syndrome, combinations of serotonergic drugs in particular are associated with increased risk.10 Serotonin syndrome is characterized by hyperthermia, altered muscle tone, altered mental status, and autonomic instability; rhabdomyolysis and disseminated intravascular coagulation are potential lethal complications.10 A high index of suspicion can help clinicians rapidly detect serotonin syndrome, discontinue offending agents, and initiate supportive treatments.
NMS is a life-threatening complication of antipsychotics characterized by fever, delirium, muscle rigidity, autonomic instability, and abnormal laboratory findings that include elevated white blood count and increased creatinine kinase from muscle injury. In early stages, NMS may be mistaken for extrapyramidal symptoms. Although NMS can occur with any antipsychotic as monotherapy, additive antidopaminergic effects increase the risk. Patients with a compromised CNS as a result of mental retardation, traumatic brain injury, or metabolic abnormalities also are at increased risk of developing NMS.11
Other pharmacodynamic interactions involve medications that may have additive effects on prolonging QTc intervals. For example, TCAs are pro-arrhythmic and have quinidine-like effects, which can cause cardiac conduction abnormalities and prolonged PR and QTc intervals.12 Employ routine ECG monitoring when prescribing multiple medications known to cause QTc prolongation, such as TCAs (Table 3).13,14 The Arizona Center for Education and Research on Therapeutics (www.azcert.org) provides a searchable list of QT-prolonging drugs (see Related Resources).
Medications also can interact with food, disease states, and herbal supplements. Alcohol interacts with many CNS-active medications, including many psychotropics. Patients taking benzodiazepines may experience oversedation and respiratory depression from alcohol’s additive sedating effects.5 Advise patients to limit their alcohol intake while taking CNS-depressing psychotropics such as benzodiazepines, antipsychotics, and some antidepressants. Monoamine oxidase inhibitors (MAOIs) and tyramine-containing food—such as cheese, beer, preserved meat, and soy sauce—can lead to a dangerous hypertensive crisis that requires immediate medical intervention to prevent life-threatening complications.5 Hypertensive crisis may be more significant in patients who have pre-existing hypertension. Finally, herbal supplements also can interact with medications. Patients who take St. John’s wort for depressive symptoms might not realize that it can reduce the efficacy of other drugs or increase their risk of serotonin syndrome.9
Table 2
Cytochrome P450 substrates, inhibitors, and inducers
| 3A4 | 2D6 | 2C9 | 2C19 | 1A2 | |
|---|---|---|---|---|---|
| Substrates | Carbamazepine Citalopram Fluoxetine Haloperidol Mirtazapine Oxcarbazepine Quetiapine Sertraline Ziprasidone | Aripiprazole Citalopram Duloxetine Fluoxetine Haloperidol Mirtazapine Paroxetine Risperidone Sertraline Venlafaxine TCAs | Amitriptyline Carbamazepine Sertraline Valproic acid | Citalopram Clomipramine Sertraline Valproic acid | Carbamazepine Clozapine Olanzapine |
| Inhibitors | Amiodarone Aprepitant Azole antifungals Carbamazepine Cimetidine Diltiazem Erythromycin Fluoxetine (norfloxetine) Grapefruit juice Imatinib Paroxetine Ritonavir Sertraline Verapamil | Amiodarone Bupropion Cimetidine Duloxetine Fluoxetine Methadone Paroxetine Ritonavir Sertraline | Amiodarone Fluconazole Isoniazid Sertraline Trimethoprim-sulfamethoxazole Valproic acid | Cimetidine Fluoxetine Ketoconazole Omeprazole Sertraline Valproic acid | Amiodarone Cimetidine Fluoroquinolones |
| Inducers | Carbamazepine Phenobarbital Phenytoin Rifampin St. John’s wort | Rifampin | Phenobarbital Rifampin | Carbamazepine Rifampin | Nafcillin Phenobarbital Rifampin Smoking |
| TCAs: tricyclic antidepressants Source: References 5,7,9 | |||||
Table 3
Psychotropics associated with QT prolongation
| Class | Agents |
|---|---|
| Antidepressants | Mirtazapine, SNRIs (desvenlafaxine, venlafaxine), SSRIs (citalopram, fluoxetine, paroxetine, sertraline), TCAs (amitriptyline, clomipramine, desipramine, doxepin, imipramine, protriptyline, trimipramine), trazodone |
| Typical antipsychotics | Chlorpromazine, fluphenazine, haloperidol, perphenazine, thioridazine, trifluoperazine |
| Atypical antipsychotics | Aripiprazole, asenapine, clozapine, iloperidone, paliperidone, quetiapine, risperidone, ziprasidone |
| Mood stabilizers | Lithium |
| Miscellaneous agents | Amantadine, atomoxetine, chloral hydrate, diphenhydramine, galantamine |
| Stimulants | Amphetamine/dextroamphetamine products, methylphenidate/dexmethylphenidate |
| SNRIs: serotonin-norepinephrine reuptake inhibitors; SSRIs: selective serotonin reuptake inhibitors; TCAs: tricyclic antidepressants Source: Adapted from references 13,14 | |
“Black-box” warnings issued by the FDA are included in the package insert to highlight a medication’s risks of dangerous and potentially lethal adverse effects. Table 4 highlights current black-box warnings for various psychotropics.5,14-16
Antidepressants and suicide. All medications with antidepressant indications carry a black-box warning for risk of suicidal ideation and behavior in children, adolescents, and young adults during the early months of medication therapy. This includes not only SSRIs and serotonin-norepinephrine reuptake inhibitors, but also anticonvulsants and atypical antipsychotics indicated for treating mood disorders. Monitor young patients carefully and advise family members to alert clinicians of any signs of suicidality or unusual behavior.
Lamotrigine and aseptic meningitis. Aseptic meningitis—inflammation of the meninges that is not caused by bacteria—is a rare but serious adverse effect of lamotrigine. Symptoms include headache, fever, stiff neck, nausea and vomiting, delirium, rash, and sensitivity to light.5 Forty cases of aseptic meningitis in children and adults were reported over 15 years, representing <.01% of all lamotrigine prescriptions.5 Most of these patients required hospitalization, but symptoms resolved after lamotrigine was discontinued. Prompt identification and management of aseptic meningitis are necessary to prevent permanent brain damage and death. Other complications of aseptic meningitis include long-term neurologic sequelae such as cognitive impairment, seizure disorders, and behavioral disturbances.