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When prescribing multiple long-term psychiatric medications, managing drug-drug interactions can pose a clinical challenge to prescribers.

"The real problem with drug-drug interactions are the ones you don't realize are happening," said Stephen Saklad, PharmD, BCPP, of the University of Texas at Austin, during a presentation at Psych Congress 2019. "If you know what you're doing and you're careful and you move slowly, you could actually use a drug interaction to manipulate pharmacology of the drugs that are on board and achieve a better, more well-tolerated result. If you're not that good, what you find out are a lot of bad adverse effects."

When prescribing long-term drugs for the management of psychiatric conditions -- major depression, generalized anxiety disorder, bipolar disorder, schizophrenia, or others -- providers must be aware of any potential interactions between specific drugs and overall classes of treatment prior to initiating polypharmacy.

According to Saklad, some of the most "clinically important" interactions to watch out for with psychiatric polypharmacy include increases and decreases in metabolic activity, changes in sodium, and the potential additive pharmacodynamic effects seen with combination treatments -- some of these include serotonin syndrome, increased bleeding risk, cardiac disturbances like QT prolongation, anticholinergic effects, and seizure risk.

Potential Interactions to Watch For

The specific risks when multiple psychiatric medications are prescribed depend on the classes of drugs that are combined, Manish Jha, MBBS, assistant professor of psychiatry and neuroscience at the Icahn School of Medicine at Mount Sinai in New York City, explained to 乌鸦传媒.

"The risk of serotonin syndrome is certainly there when prescribing multiple medications that act on the serotonin systems," he stated, noting that this can occur when adding one selective serotonin reuptake inhibitor (SSRI) antidepressant to another SSRI, or other serotonergic medication. The syndrome occurs with hyperstimulation of post-synaptic serotonin receptors -- most usually the 5-HT2A receptor.

Marsal Sanches, MD, PhD, associate professor of psychiatry at McGovern Medical School at UTHealth in Houston, agreed, telling 乌鸦传媒 that serotonin syndrome is "definitely a risk to be considered," especially when combining multiple antidepressants.

"It is a relatively rare condition but it can be life-threatening if not promptly addressed, and it may be of difficult identification and diagnosis," he added.

Although there aren't any typical lab findings with serotonin syndrome, it can physically present with symptoms including hyperthermia, tremors and hyperreflexia, myoclonus, and spontaneous or ocular clonus.

During his presentation, Saklad pointed out another syndrome that can occur with dopamine antagonists -- neuroleptic malignant syndrome -- which can often be confused with serotonin syndrome. While this condition also presents with symptoms of hyperthermia, it instead has symptoms of hyporeflexia and lead pipe-like rigidity. Nonetheless, both syndromes require a change in therapy to resolve the symptoms.

Another concerning adverse psychiatric drug-drug interaction includes cardiac disruptions, such as drug-induced arrhythmias like QT prolongation.

"Some medications carry a higher risk of QT prolongation than others and I usually try to avoid combining those with a higher risk of inducing increases in the QT interval," Sanches suggested. These most commonly include typical, first-generation antipsychotics, some of which include chlorpromazine, haloperidol (Haldol), thioridazine, and pimozide (Orap). Due to adverse side effects, more prescribers are opting for second-generation atypical antipsychotics instead.

Certain patient factors and comorbidities can also raise individuals' risk for experiencing QT prolongation, explained Saklad, such as being a woman, age greater than 65, renal failure, cirrhosis, pulmonary embolism, or thiamine deficiency. Various conditions -- including endocrine, cardiovascular electrolyte, inflammatory, and autoimmune disorders -- can also increase QT prolongation risk.

Other risks to look out for are drugs that can increase fall risk, especially in elderly patients, Jha highlighted, adding how this risk is particularly relevant when prescribing combination sedative medications. "Falls in the elderly are generally associated with higher risk of mortality," he underscored.

Strategies to Minimize Adverse Interactions

One of the most straightforward strategies for reducing adverse events from psychiatric drug interactions is minimizing polypharmacy and avoiding the use of multiple medications as much as possible, Jha suggested.

"The second thing that I do when prescribing medications to someone while they're on multiple medications is reduce drug interactions using a web-based tool," he said.

Saklad also sung the praises of using an app or web-based tool as a resource to quickly check which drugs pose an interaction threat with each other.

"It is also important for doctors to create the systematic habit of asking their patients about over-the-counter medicines and naturopathic treatments," Sanches suggested. "Many of those agents may produce significant drug interactions with psychiatric medications, and patients often forget to mention to their doctors that they are taking these treatments."

Royce Lee, MD, of the University of Chicago Medicine was in agreement, telling 乌鸦传媒 that it is "best practice at the end of each visit to scan the medication list of your patient and take note of potential drug interactions."

However, in order to do this, providers need to first be aware of general patterns of interactions, such as how certain classes interact and which metabolic pathways they activate.

"Immune modulating drugs: CYP3A4. Tricyclic antidepressants: CYP2D6. Anticonvulsants: CYP3A4. SSRIs: each one is different, and all potentially problematic. One doesn't really have the time to enter each drug into a database and compare with every other drug, so this kind of quick pattern recognition is important," Lee explained. "It is also important for the clinician to have a way of ball-parking the magnitude of significance of each drug interaction. For example, NSAIDS or ACE inhibitors and lithium: 100-200% increases in lithium level. It makes a difference in your decision-making if you are expecting a little bump versus [a] large increase."

He also brought up how it's "unfortunate" that most modern electronic medical records don't automatically flag these interactions. "They should, given the fact that is why they exist," he said. Jha agreed with this point, adding that even when some records do automatically flag potential drug interactions, it's not always reliable.

Another factor providers should watch out for is the misclassification of certain drugs.

"For example, Tegretol (carbamazepine) is related to tricyclic antidepressants, and thus can cause death when combined with a MAO (monoamine oxidase) inhibitor," Lee pointed out. "Another example, Flexeril (cyclobenzaprine) is classified as a muscle relaxer, but is actually a tricyclic antidepressant. Even more problematically, it, like other tricyclics, affects 2D6 metabolism. So many problems can be caused by an internist adding cyclobenzaprine to the drug combination of a patient with depression and chronic pain," he explained, adding that this most likely occurs because the mechanism of action is typically listed as "unknown" when looking the drug up.

"It is quite alarming that the drug marketing language affects how we think of these medications by class," he said.

One other way to reduce the risk of drug interactions is to avoid using medications to treat the side effects of other medications, said Sanches, saying this method of prescribing can "create a vicious circle."

Another strategy to avoid harmful psychiatric drug interaction includes taking into account racial and ethnic differences, or "pharmacogenomics" -- how genes predetermine a patient's response to certain drugs.

"Pharmacogenomics is here to stay," said Lee, "yet concise descriptions of which pharmacogenomics findings are directly relevant to clinical practice do not agree with each other, and even major publications [are] filled with misinformation."

"Understanding racial and ethnic differences in drug metabolism is very important," Lee noted, adding that this is particularly true when treating Asian patients, who are known to experience interactions even to drugs that are assumed to have few interactions, like citalopram (Celexa) and escitalopram (Lexapro). He also recommended HLA testing for all Asian patients prior to treatment with carbamazepine -- calling this a "must" for these patients.

However, he said, finding a reliable pharmacogenomic test can be tricky for providers, as the clinician must comb through the literature to separate the good from the bad.

Jha recommended that the best pharmacological treatment for psychiatric conditions ultimately must involve shared decision-making between the patient and provider to ensure the patient feels empowered and prepared to handle any potential adverse effects that may arise.

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