This document discusses drug interactions in psychiatry. It begins by defining drug interactions and explaining why they are important, noting the increased risk for psychiatric patients on multiple medications. It then describes how interactions can present and lists various risk factors. The document outlines the main types of interactions - pharmacokinetic involving absorption, distribution, metabolism and excretion, and pharmacodynamic involving receptor-level effects. Finally, it analyzes specific drug interaction case examples and consequences like serotonin syndrome or increased sedation.

1. DRUG INTERACTIONS
IN PSYCHIATRY
CO-ORDINATOR: DR. MITTHAT MIGLANI PRESENTER- DR. DEEPIKA BANSAL
REFERENCES-
Stahls Essential Psychopharmacology 4th Edition
Kaplan & Sadock’s Comprehensive Textbook Of Psychiatry 10th Edition
Journal Of Psychiatric Practice 2018 By Sheldon H. Preskorn
Exploring Drug Interactions In Psychiatry By Neil B. Sandson
Lippincott Pharmacology 6th Edition

2. INTRODUCTION
 Drug interaction refers to modification of response to one drug by another when
they are administered simultaneously or in quick succession. It can be beneficial
or harmful or it can have no significant effect.

3. WHY THESE ARE IMPORTANT?
 Drug-drug interactions are very common and are responsible for considerable patient morbidity
and mortality.
 A growing evidence base implicates drug-drug interactions as a major contributor to hospital
admissions, treatment failures, avoidable medical complications, and subsequent health care
costs
 A large percentage of the population is receiving psychiatric medications and the number has
been continuously increasing over the past 5 decades.
 These patients are more likely to be receiving complex medication regimens and thus are likely
to be on multiple medications which means that they are at increased risk for an adverse DDI.

4.  Knowledge of DDIs can help the doctor in better prescribing(adjustment of dose, combining or
switching drugs) leading to better patient outcomes.
 DDIs may occur but not be recognized even though they have significant health care consequences
for the patient.
 All drugs, including psychiatric medications, interact on the basis of their pharmacodynamics and
pharmacokinetics rather than their therapeutic use. Therefore, psychiatric medications may interact
with medications prescribed for nonpsychiatric reasons as well as with other psychiatric
medications.
 These consequences can range from a catastrophic outcome to more everyday clinical problems
involving a myriad of presentations.
 Many psychiatric illness have a chronic course due to which the medical treatment can often
continue for many months or years once started. For this reason, the potential for DDIs increases
over the lifespan of the individual, making them important to study and be aware of.

5. HOW DO DDIs PRESENT?
 A multitude of different types of serious adverse events (SAEs), such as sudden death,
seizures, cardiac rhythm disturbances, serotonin syndrome, malignant hypertension,
neuroleptic malignant syndrome, and delirium. These are fortunately infrequent to rare
events.
 Poor tolerability (ie, patient is “sensitive” to adverse drug effect).
 Lack of efficacy (ie, patient is “resistant” to the beneficial effect of the drug).
 Symptoms that mimic and lead to a misdiagnosis of a new disease because the DDI
produces the symptoms of that disease.
 The apparent worsening of the disease being treated.
 Withdrawal symptoms or drug-seeking behavior on the part of the patient.

6. RISK FACTORS
 Elderly, obese, females, malnourished, critically ill
 Multiple prescribers
 Polypharmacy- Multiple drugs
 Multiple pharmacological effects of a drug
 Multiple diseases – hepatic/renal disease
 Poor patient compliance
 Patients taking high dose of medications- common in psychiatric patients.
 Irresponsible dispensing by pharmacists
 Genetic make-up
 Drugs with narrow therapeutic index (lithium, digoxin)

7. TYPES OF DRUG-DRUG INTERACTIONS
 Drugs do not interact on the basis of their therapeutic class (eg, “psychiatric” vs. “cardiac”
medications) but instead on the basis of their pharmacodynamics (ie, their action on the body) and their
pharmacokinetics (ie, the actions of the body on them)
 PHARMACOKINETIC
 ABSORPTION
 DISTRIBUTION
 METABALISM
 EXCREATION
 PHARMACODYNAMIC
 AGONISTS
 ANTAGONISTS

8. DRUG INTERACTIONS- DRUG EFFECTS IN
THE BODY

10. INTERACTION AT ABSORPTION LEVEL
 Absorption of the object drug is altered ( faster/slower, complete/incomplete)
Mechanism
 Alteration in GI ph (Antacids & chlordiazepoxide)
 Alteration in gut motility (Metoclopramide & Levodopa, Anticholinergic &
Lithium)
 Alteration in GI microflora ( Antibiotics & Digoxin )

11. INTERACTION AT DISTRIBUTION LEVEL
 The major interaction at the level of distribution is PROTEIN-DRUG BINDING.
 Can occur when two or more highly protein-bound drugs compete for a limited number of binding sites on
plasma proteins
 This is more common for the mood-stabilizing AEDs, including phenytoin, valproic acid, diazepam, as
well as for antipsychotics including clozapine, risperidone, olanzapine, and ziprasidone.
 However, these medications are often present in such small quantities in the blood that their contribution
to displacement of other highly protein-bound drugs does not generally result in clinically relevant
displacement and subsequently significantly altered therapeutic actions. .

12. INTERACTIONS AT METABOLISM LEVEL
ENZYME INDUCTION
• Increased rate of metabolism of
object drug
• Decrease drug efficacy
• EXAMPLES-
• All antiepileptics except
valproate
• Rifampicin
• Greisofulvin
• Isoniazid
• Meat
• Alcohol(Chronic)
• Smoking
ENZYME INHIBITION
• Decreased rate of metabolism of
object drug
• Drug accumulation
• Increased risk of ADRs
• Toxicity
• EXAMPLES-
• Valproate
• SSRI
• Ketoconazole
• Alcohol(Acute)
• Cimetidine

13. DIFFERENT METABOLIC PATHWAYS

14. CYTOCHROME P 450
 CYP 450 is a very large family of hemoproteins that act as enzymes to cause oxidative
metabolism.
 CYPs are the metabolic factories in the liver and the mucosal surface of the intestinal tract.
 They can be regarded as the “body’s waste management system for drugs, toxins, and
cellular waste products” as well as “cellular highways for drugs.”

15. 5 core enzymes—CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4—are responsible for approximately
90% CYP450 activity.

16. CYP 450
 SUBSTRATE- Any drug metabolized by cyp 450 enzyme
 INHIBITOR- Any drug that inhibits the metabolism of cyp 450 substrate
 INDUCER- Any drug that increases the metabolism of cyp450
 4 classes of CYP metabolizer
 1.Poor
 2.Intermediate
 3.normal(extensive)
 4.Ultrarapid .

19. CASE DISCUSSION
 A 72-year-old female with type II diabetes mellitus and atrial fibrillation
was receiving warfarin (Coumadin) 5 mg/day (INR=2.9) and amitriptyline
50 mg hs for neuropathic pain. Fluoxetine (Prozac) 20 mg/day was added
to her regimen for major depression. Over the following 10 days, she
experienced increasing dizziness, dry mouth and inability to void. She
eventually required transportation to the emergency department (ED),
where a bladder catheterization yielded two liters of dark urine. Her INR
was found to be 17.3.

20.  Warfarin's metabolism CYP 2C9
Fluoxetine is a strong 2D6 inhibitor and a moderate inhibitor of 2C9, 2C19 and 3A4
Metabolism of warfarin inhibited
Increase in the warfarin blood level.
 This drastically increased the anticoagulant effect of warfarin.
This is an example of an inhibitor added to two substrates,

21.  Amitriptyline metabolism by CYP 2D6, 3A4 and 2C19
 Fluoxetine INHIBITOR of CYP 2D6, 3A4 and 2C19
 Metabolism of Amitriptyline inhibited
 Increase in levels of Amitriptyline
 The resultant increase in anticholinergic tone led to the inability to void and subsequent
bladder wall distension. These combined effects of a hypo coagulable state and
anticholinergic-induced urinary retention led to spontaneous bleeding within the patient's
distended bladder

22. INTERACTIONS AT ELIMINATION LEVEL
 Rare
 Medications administered in acute care such as nonsteroidal anti-inflammatory drugs
(NSAIDs), angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II receptor
blockers (ARBs) should be used cautiously, if at all, in patients already receiving lithium.
 NSAIDs, except aspirin and sulindac
 Decreased renal excretion of lithium
 Increased lithium level
 Dizziness, blurry vision, tremor, nausea, vomiting, confusion, etc.

23. PHARMACODYNAMIC DRUG INTERACTIONS
 These interactions derive from modification of the action of one drug at the target site by
another drug, independent of a change in its concentration.
 This may result in an enhanced response (synergism), an attenuated response (antagonism)
or an abnormal response.

24. ACETYLCHOLINE
 Muscarinic acetylcholine receptor antagonism
 Mitigates and can even fully reverse the EPS caused by excessive D2 blockade
BIOGENIC AMINE (EFFECTS ON D, NE, AND 5-HT)
 Catechol-O-methyltransferase/ MAO inhibition
 Potentiates the effects of other drugs by increasing the synaptic concentration of D, NE, and
5-HT
 Could theoretically increase the likelihood and severity of hypertensive crisis and serotonin
syndrome
 Antagonizes the effects of drugs that block specific D, NE, and 5-HT receptors.

25. DOPAMINE
 Dopamine agonism (general)/ Dopamine reuptake inhibition
 Can ameliorate Parkinson disease
 Can cause dyskinesia, hyperactivity, hyperkinesia, and psychosis
 Dopamine antagonism (D2)
 Can cause EPS, including Parkinsonism
 Can aggravate Parkinson disease
HISTAMINE
 Receptor antagonism (H1)
 The sedation caused by central H1 antagonism can be amplified by Drugs that
promote GABA in the brain Ethanol, opiates, orexin antagonists

26. MELATONIN
 Receptor agonism (melatonin 1 and 2)
 Regulation of sleep-wake cycle
 May have sedative effects that may be amplified by sedative-hypnotics, including
ethanol
OPIOID
 Receptor agonism
 The decreased CNS arousal, particularly respiratory depression, caused by
opioids can be amplified by: Drugs that promote GABA in the brain
benzodiazepines, barbiturates; Drugs that block central H1 receptors, Ethanol

27. CONSEQUENCES OF
PHARMACODYNAMIC INTERACTIONS
 Hypertensive crisis
 MAO Inhibitor + SNRI/TCA
 Serotonin syndrome
 MAO inhibitor+ SSRI/SNRI
 Linezolid+ SSRI/SNRI
 QTc Prolongation
 Thioridazine+ quinidine/ fluoroquinolones
 Increased risk of bleeding
 SSRI/SNRI+ Aspirin/ NSAIDS/ Warfarin
 Increased sedation
 BZD+ Zolpidem/ Trazodone/ Alcohol

28. SIGNIFICANT DRUG
INTERACTIONS IN PSYCHIATRY

29. ANTIPSYCHOTICS
CLOZAPINE
 Carbamazepine(INDUCER) Decreased level of clozapine
 Possible loss of therapeutic efficacy
 Synergistic risk of blood dyscrasias (agranulocytosis from clozapine and aplastic anaemia from carbamazepine)
 Fluoxetine(INHIBITOR) Increased level of clozapine(50%)
 Fluvoxamine(INHIBITOR) Increased level of clozapine(3-4 FOLD)
 Increased sedation, anticholinergic symptoms, seizure risk

30. ARIPIPRAZOLE
 All other antipsychotic agents
 Significant displacement of other antipsychotics from the dopamineD2 receptor during
antipsychotic crossover titrations involving aripiprazole
 Aripiprazole binds more avidly to D2receptor
 Possible clinical decompensation during antipsychotic cross overtitration
HALOPERIDOL & OLANZAPINE
 Fluvoxamine(INHIBITOR) Increased level of haloperidol & olanzapine
 Increased EPS and other side effects
 Carbamazepine & phenytoin(INDUCERS) decrease levels of haloperidol,
olanzapine, quetiapine and risperidone

31. ANTIDEPRESSANTS
FLUOXETINE/ FLUVOXAMINE
 Potent enzyme INHIBITOR
 Increase levels of-
 Most typical antipsychotics
 TCA
 Risperidone, Clozapine
 Carbamazepine
 Duloxetine

32. MAO INHIBITORS
 All other anti-depressants Decreased metabolism of serotonin and
norepinephrine (and sometimes dopamine) by MAOIs, combined with serotonin,
norepinephrine, and dopamine reuptake inhibition by other antidepressants
 Central serotonin syndrome and/or hypertensive crisis
 Potentially fatal

35. SMOKING
 Induction of CYP450 1A2 by tobacco smoking
 TYPICAL ANTIPSYCHOTICS, CLOZAPINE, OLANZAPINE, TCA, FLUVOXAMINE
 Reduction of therapeutic efficacy

36. CAFFEINE
 Induction of CYP450 1A2 by caffeine
 CLOZAPINE, FLUVOXAMINE
 Reduction of therapeutic efficacy

37. HOW TO AVOID DDI?

41. CONCLUSION
 The array of available psychopharmacologic agents has expanded tremendously over the
last few decades. Thus, it is a formidable challenge to remain familiar with the evolving
evidence base.
 The growing range of treatment options has made treating patients more complex.
 DDI is an important domain of psychopharmacology which is critical to best practice,
and it should precede the quest for efficacy.
 To paraphrase Hippocrates, it is incumbent on clinicians to “First, do no harm”.
 All mental health practitioners should follow this dictum especially where drug-drug
interactions are concerned.

42. “
”
It is easy to get a thousand prescriptions, but
hard to get one single remedy
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