Drug-Drug Interactions in Psychiatry

Polypharmacy refers to the use of multiple medications, or drugs, in one individual. Medications, whether for blood pressure or depression, do not work in a vacuum. When we swallow, inhale, or inject medications, they make their way through our bodies in complex ways.
Most medications are transported in blood attached to proteins. Others are transported unattached in a “free form.” As medications make their way to their targets, they come in contact with all types of tissues, cells, and fluids before being metabolized, or digested, and eliminated from the body.
Taking multiple medications, whether prescription or over the counter (OTC), increases the probability that they will interact with each other and alter their ability to work. We call these “drug-drug interactions.” Some drug-drug interactions are beneficial, but most are not. 

How Drugs Move Through The Body

After swallowing a drug, it travels to the stomach and intestines. Within the intestines, there are proteins called enzymes. Enzymes are like a bunch of Pac-Man swimming around gobbling up drugs. When these Pac-Man gobble up the drugs they “spit out” the digested debris. We call the digested debris “metabolites.” Not all of the drug that was swallowed is metabolized or “gobbled up” in the small intestine. Most of the drug is absorbed through the wall of our intestine and finds its way into the blood stream. From there, the drug moves to the liver where more enzymes (or “Pac-Man”) metabolize the drug. Again, not all the drug is gobbled up. From the liver, the remaining drug moves through the heart and lungs and then is pumped out to the rest of the body where it will act on whatever target it acts on.

While all of this is happening, the drug and its digested debris (i.e. metabolites) are passing through the kidney or back to the intestines where they are eliminated or excreted in feces (poop) or urine (pee). Keep in mind that some of the “digested debris” will actually still be active. For example, Fluoxetine (Prozac), a serotonin reuptake inhibitor, is a powerful antidepressant. Fluoxetine is digested by enzymes to a compound called Norfluoxetine. Norfluoxetine is also a serotonin reuptake inhibitor. You can see how this can get a bit complicated. When you swallow fluoxetine, not only are you getting the drug itself, but you are getting it’s metabolite, too! Interestingly, norfluoxetine stays in the human body a very long time (up to two weeks!). This explains why stopping Fluoxetine abruptly rarely causes withdrawal. 

So, in summary, drugs are swallowed and slowly find their way through the body. Along the way, these Pac-Man, called enzymes, are gobbling up the drugs and spitting them out. And sometimes the “spit” is still active drug! So let’s take a closer look at these enzymes…

Enzymes in our body breakdown drugs

After taking a drug, the body will work hard to eliminate it. But most drugs must be digested into smaller products before they can be eliminated. They also need to be changed into a form that is soluble in water so they can be eliminated in the urine.

Most drugs are digested in the liver, intestines, and other organs by enzymes (Pac-Men) that “chew” them up and transform them into more water-soluble products so they can be eliminated in urine or feces. If a drug isn’t soluble in water, it will be difficult to eliminate in urine because urine is primarily water. It is important to note that some drugs like lithium and gabapentin (Neurontin) are not chewed up at all. They are eliminated in the urine without being metabolized in the body at all! 

Our liver and intestines are full of Pac-Man called “CYP450 enzymes.” Don’t worry about the names. All you need to know is that there are many different types of CYP450 enzymes, and they all metabolize different things. One drug may be metabolized but just one enzyme whereas others may be metabolized by eight different enzymes! These “Pac-Man” Enzymes have names such as “CYP3A4” or “CYP3A5”. There are many! CYP2D6, CYP2B6, CYP2C8, CYP2C9, CYP1A2, CYP2C19, CYP2A6, CYP2E1…you get the point. The majority of medications used to treat medical conditions are metabolized by two enzymes: CYP3A4 and CYP2D6. Some of us have a lot of these enzymes and some of us don’t. Genetics determines how much we have. This is why two different people will have two different responses to the same medication. If Dave and Sallie both take Prozac, but Dave doesn’t have much of the enzyme that metabolizes Prozac, then Dave is going to have much higher levels of Prozac than Sallie. This may mean more side effects for Dave. It could also mean Sallie needs a higher dose than Dave to achieve the same response.

Lost yet?

The whole point is that we can do genetic tests to look at how many enzymes we have. To make things even more confusing, Dave and Sallie can have the same number of enzymes, but Dave’s enzymes are lazy and don’t work as well as Sallie’s. You can see how there can be a lot of variability!

Medications can “interact” in a variety of ways

Here are the most common types of drug-drug interactions (this is not a comprehensive list):
  1. Displacement from transport proteins: Some medications might displace or remove another medication from its transport protein.
  2. Altering the activity of metabolic enzymes: Some medications alter the activity of metabolic enzymes that metabolize other medications. If the enzyme’s activity is increased, then the medication metabolized by that enzyme may be metabolized too quickly and therefore decrease blood levels of the medication (which might decrease the medication’s effectiveness). If the enzyme’s activity is decreased, then the medication metabolized by that enzyme may be metabolized too slowly and therefore increase blood levels of the medication (which might cause toxicity).
  3. Competing for receptors: Some medications might compete with other medications at their receptors and alter their effects.
  4. Altering the function of organs like the kidneys, intestines, and liver: Some medications can change the kidney’s/intestine’s/liver’s ability to eliminate drugs from the body.

Common Drug-Drug Interactions

Below are the most common drug-drug interactions to be aware of when taking psychotropic medications (i.e., medications used to treat mental disorders). 

Valproic acid (VPA, Depakote) + Lamotrigine (Lamictal)

  • Valproic acid (VPA) increases lamotrigine levels by decreasing lamotrigine metabolism
  • Increased lamotrigine levels increase the risk of developing a severe rash
  • Increased lamotrigine levels increase the risk of Steven-Johnson’s Syndrome (SJS/TEN)
  • When taking both valproic acid (Depakote) and lamotrigine (Lamictal), the general recommendation is to decrease the dose of lamotrigine by 50%

Carbamazepine (CBZ) is an inducer of CYP3A4

  • CBZ induces its own metabolism by increasing the activity of the CYP3A4 enzyme
  • CBZ also induces the metabolism of other medications that are metabolized by CYP3A4 such as oral contraceptives, clozapine, alprazolam, buspirone, and clonazepam

Lithium levels are INCREASED when combined with the following

  • Non-Steroid Anti-inflammatory Drugs (NSAIDs), except aspirin
  • Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors)
  • Thiazide diuretics such as hydrochlorothiazide
  • Low sodium diets

Lithium levels are DECREASED when combined with the following

  • Caffeine
  • Theophylline
  • High sodium diets

Grapefruit Juice

  • Grapefruit juice is a potent inhibitor of CYP3A4 and P-glycoprotein (another protein that helps eliminate drugs)
  • Therefore, grapefruit juice increases blood levels of many medications metabolized by CYP3A4

Smoking Tobacco cigarettes

  • The hydrocarbons in the smoke of tobacco cigarettes, but not nicotine, increase the activity of CYP1A2 enzymes
  • Smoking cigarettes decreases blood levels of medications metabolized by CYP1A2 such as Olanzapine, Clozapine, and Caffeine

Tyramine + Monoamine Oxidase Inhibitors (MAOIs)

  • Tyramine (TIE-ruh-meen) is an amino acid that occurs naturally in the body and aids in regulating blood pressure. Elevated tyramine levels can lead to dangerously elevated blood pressures.
  • Tyramine is also found in certain foods such as banana peel, beer, fava beans, aged cheese, sauerkraut, sausage, soy sauce, and concentrated yeast extract.
  • An enzyme called monoamine oxidase (MAO) breaks down excess tyramine in the body. Monoamine oxidase inhibitors (MAOIs) are used to treat depression.
  • If taking a monoamine oxidase inhibitor, it is important to avoid certain foods high in tyramine.

Monoamine Oxidase Inhibitors (MAOIs)

  • Monoamine oxidase (MAO) is an enzyme that breaks down monoamines such as serotonin, dopamine and norepinephrine. Therefore, monoamine oxidase inhibitors (MAOIs), such as selegiline and phenelzine, are used to treat depression.
  • Combining MAOIs with Selective Serotonin Reuptake Inhibitors (SSRIs), Tricyclic Antidepressants (TCAs), Pseudoephedrine, and Stimulants increases the risk of serotonin toxicity and dangerously high blood pressures

Fluoxetine, Paroxetine, and Bupropion are potent inhibitors of CYP2D6 

  • Drugs like fluoxetine, paroxetine, and bupropion inhibit CYP2D6 enzymes and increase blood levels of other medications metabolized by CYP2D6.
  • Fluoxetine, paroxetine, and bupropion decrease the effectiveness of Tamoxifen and Codeine because Tamoxifen and Codeine require CYP2D6 activity to be effective. 

Antimicrobial-Psychotropic Drug Interactions

  • Antimalarials increase levels of phenothiazines such as chlorpromazine (Thorazine)
  • Azoles increase levels of alprazolam, midazolam, and buspirone
  • Clarithromycin and Erythromycin increase levels of alprazolam, midazolam, carbamazepine, clozapine, and buspirone
  • Quinolones increase levels of clozapine and benzodiazepines (but decreases the effects of benzodiazepines)
  • Isoniazid increases levels of haloperidol and carbamazepine. Isoniazid + disulfiram can cause problems with motor coordination (called ataxia)
  • Isoniazid and Linezolid are weak inhibitors of monoamine oxidase (MAO) and therefore increases the risk of serotonin syndrome and hypertensive emergencies if used with serotonergic drugs (like SSRIs, SNRIs, and TCAs)

Erythromycin, Clarithromycin, and Ketoconazole + Tricyclic Antidepressants or antipsychotics

  • Combining Erythromycin, Clarithromycin, or Ketoconazole with Tricyclic Antidepressants or antipsychotics increases the risk of QT prolongation and cardiac (ventricular) arrythmias

Drug-Drug Interaction Tables

Neuropsychiatric Side Effects of Antimicrobial Medications 


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