Ten Drug Combinations That Show the Risks of Psychiatric Polypharmacy


Using multiple drugs to treat a single condition is growing, said Paul Zarkowski, MD, a clinical assistant professor at Harborview Medical Center and psychiatrist in Seattle, Washington, at Psych Congress 2018. But how much do we know about how well they work?

Using multiple drugs to treat a single condition is growing, said Paul Zarkowski, MD, a clinical assistant professor at Harborview Medical Center and psychiatrist in Seattle, Washington, at Psych Congress 2018. But how much do we know about how well they work?

In a presentation called “Doing More by Prescribing Less: Top Ten Drug Interactions That Limit Efficacy,” Zarkowski talked about why he is picking this topic to research.

“We’ve only got a few neurotransmitters, [like] serotonin, we’ve got lots of receptors, but we only have a few neurotransmitters to manipulate,” he said. “And if you start adding more and more meds, what happens is, you start blocking the actions of the other meds.”

Zarkowski said between 1996 and 2006, the average person went from 1 psychiatric medicine per indication to 2, according to one study. That goes for antidepressants, antipsychotics, and anti-anxiety medications, he noted.

There is not a lot of data about these drug combinations, Zarkowski said. Most trials are limited to 1 drug at a time.

“Whenever it comes time to study 2 at once, there’s crickets in the room,” he said, noting the hurdles such a study would pose in getting review board approval. However, there are uncertain gains for quality of care and clinical outcomes when these drugs are paired up, he said.

So Zarkowski decided to create his own list, using 3 criteria:

  • Pairings where there were opposing clinical indications and side effects, suggesting an interaction that would limit efficacy, or as he called it, “one to make you wound up, and one to make you relax.”
  • That the drugs antagonize each other at a very specific receptor critical for efficacy.
  • Evidence from clinical studies with simultaneous administration of medications confirming decreased efficacy. He called this extremely rare from human data, but said there is evidence from rats and mice.

Zarkowski pulled the data from an electronic chart review from the Genoa Healthcare Database, which provides pharmacy services to behavioral health and addiction treatment communities, including the 10 community mental health organizations that released data about 12,488 patients.

The resulting top 10 list he came up with includes both approved and off-label uses.

Fluoxetine and cyproheptadine

Fluoxetine is indicated for the treatment of major depressive disorder (MDD) but it causes sexual dysfunction in about 36% of patients. Cyproheptadine is sometimes prescribed as an off-label use for anorgasmia caused by some selective serotonin reuptake inhibitors, but may cause depression to relapse.

A clinician could reduce the dose of fluoxetine or switch to an antidepressant with fewer sexual side effects, Zarkowski said. Another possibility is to add trazodone to an existing selective serotonin reuptake inhibitor.

Amitriptyline and naltrexone

Amitriptyline is indicated for depression and is sometimes used off-label for pain. Naltrexone is indicated for alcohol and opioid use disorder. In rat studies, naltrexone blocked the effect of amitriptyline. Naltrexone does not block every pain medication, however. And in one human case study, naltrexone caused depression to relapse.

Amphetamine-dextroamphetamine and haloperidol

Amphetamine-dextroamphetamine, an attention-deficit hyperactivity disorder (ADHD) medication, creates a drug-induced psychosis in 8% to 46% of regular users, depending on the dose, method, and duration. Haloperidol is used to counteract the psychosis. The interaction comes into play in internal “clock speed,” where amphetamine-dextroamphetamine speeds up processing, but haloperidol slows it down—unless the patient taking haloperidol has an affinity for the amphetamine-dextroamphetamine euphoria.

Donepezil and oxybutynin

Donepezil, a reversible acetylcholinesterase inhibitor, is indicated for Alzheimer disease, but 7% of patients will develop urinary incontinence. Oxybutynin is indicated for bladder muscle dysfunction, but it is associated with a decline in greater decline in mini-mental state examination scores over 2 years. Zarkowski said there are other medication choices that have fewer cognitive effects.

Amphetamine-dextroamphetamine and alprazolam

Amphetamine-dextroamphetamine can create anxiety in 8% of patients. Alprazolam is indicated for anxiety, but can cause sleepiness, memory impairment, and cognitive disorder. These 2 drugs have opposite effects on performance and also leads to a lessening in discriminative ability by people taking amphetamine. Studies from Europe have shown that the combination leads to more driving accidents.

Atomoxetine and propranolol

Atomoxetine, an ADHD drug, can increase heart rate and blood pressure. Propranolol, a hypertension drug, can impair learning performance.

Ropinirole and olanzapine

Ropinirole is indicated for restless leg syndrome (RLS), but can cause psychosis an 8% of Parkinson disease patients, or even in people taking it purely for RLS. There are case reports of olanzapine, used for schizophrenia, causing RLS. The drugs have opposite effects on the dopamine receptor.

Mirtazapine and clonidine

Clonidine is used off-label treatment for ADHD, but there are reports of MDD in up to about 2.3% of people taking it. Mirtazapine is an antidepressant, but causes sedation about half of the time. Mirtazapine blocks the alpha-2a receptor, but the clonidine stimulates it.

Clozapine and sertraline

Clozapine is indicated for schizophrenia, but it is linked to the emergence or worsening of obsessions, because it stimulates the receptor involved in OCD. Sertraline is indicated for obsessive compulsive disorder.

Venlafaxine and prazosin

Venlafaxine is indicated for MDD, which carries the risk of adverse side effect of nightmares (7% vs 2% on placebo). Prazosin is used off-label for nightmares and posttraumatic stress disorder (PTSD). Venlafaxine is not recommended for people with PTSD.

Clinician takeaways

Zarkowski said there are 3 things to keep in mind:

  • More extensive medication regimens are associated with inferior results.
  • For geriatric patients, anticholinergic medications are often prescribed for numerous indications, but they limit the efficacy of acetylcholinesterase inhibitors. Not all anticholinergic drugs are the same.
  • Stimulants are commonly prescribed to increase focus and improve attention, but concurrent prescription of benzodiazepines are associated with an increased risk of automobile collisions and other accidents.
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