Two neurons synapsing

Psychopharmacology Facts You Should Know

General Concepts

  1. Elderly individuals usually require lower doses of medications due to age-related changes in total body water, muscle to fat ratio, and kidney/liver function.
  2. Calculating the Child-Pugh Score to aid in adjusting the dose for individuals with liver problems.
  3. AST, ALT, and Alkaline Phosphatase are not reliable indicators of liver function as they do not reflect the synthetic or metabolic functions of the liver.
  4. Men with increased muscle mass may be at higher risk for developing extrapyramidal symptoms with high-potency antipsychotics (anecdotal evidence)
  5. Bright light therapy and bupropion (Wellbutrin) are used to manage Seasonal Affective Disorder (SAD)
  6. Avoid beta blockers for individuals with severe lung disease (e.g., COPD) or Asthma
  7. Oxazepam, Temazepam, and Lorazepam (“Outside The Liver”) do not undergo Phase 1 metabolism and should be used for individuals with liver impairment.
  8. Zolpidem (Ambien) and Zaleplon can cause a dissociative-like states such as sleep walking, binge eating, aggressive outbursts, and night driving.
  9. For Restless Leg Syndrome, use dopamine agonists (levodopa, ropinirole, pramipexole, rotigotine), benzodiazepines (clonazepam), gabapentin, pregabalin, anticonvulsants, and/or opioids. Replete iron if deficient!
  10. Excessive daytime sleepiness, fatigue, sleep paralysis, headaches, irritability, and cognitive problems are suggestive of a sleep disorder (order a sleep study!)
  11. Risk factors for Obstructive Sleep Apnea (OSA) include obesity, snoring, and large neck circumference
  12. Stimulants (Amphetamines, Methylphenidate), non-stimulants (atomoxetine, a norepinephrine reuptake inhibitor), and modafinil are used to treat Attention Deficit Hyperactivity Disorder, Narcolepsy, Anergic depression, and chronic fatigue
  13. Most common side effects of stimulants (Amphetamines, Methylphenidate) in children/adolescents are insomnia, anorexia, and tics
  14. Remelteon is useful for initial insomnia (i.e., getting to sleep) due to its short half-life.
  15. Benzodiazepine overdose is treated with flumazenil (but use caution as flumazenil may precipitate seizures in those with pre-existing seizure disorders)
  16. Naloxone (Narcan) is used for opioid overdose but it has a short half-life and may need to be repeatedly administered to prevent a return to opioid-induced coma/respiratory depression
  17. Anticholinergic agents (e.g., benztropine, atropine, diphenhydramine, doxepin, low-potency antipsychotics) can cause cognitive impairment, worsening dementia, and may precipitate delirium in the elderly.
  18. Electroconvulsive therapy (ECT) is used for medication-resistant Depression, Mania, Catatonia, Psychosis, Neuroleptic Malignant Syndrome, Parkinson Disease, and Peripartum Depression
  19. There are no absolute contraindications to electroconvulsive therapy (ECT) but use caution in patients with space-occupying brain lesions and elevated intracranial pressure due to risk of herniation (ECT alters cerebral hemodynamics)
  20. Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase. Acetaldehyde is metabolized to Acetyl CoA by acetaldehyde dehydrogenase
  21. Disulfiram inhibits acetaldehyde dehydrogenase causing accumulation of acetaldehyde which causes facial flushing, nausea, and vomiting (may occur with anything containing alcohol).
  22. Disulfiram is most effective for motivated patients with a good support system.
  23. Narcolepsy (sudden-onset REM sleep with loss of muscle tone/cataplexy) is diagnosed by Multiple Sleep Latency Test and treated with stimulants, modafinil/armodafinil, or sodium oxybate (for cataplexy)
  24. Steady state of orally administered medications is reached after four to five half-lives (Example: Li takes approximately 5 days to reach steady state after initiation or dose change)
  25. Individuals who chronically abuse alcohol should always receive high dose parenteral thiamine (500mg-1500mg/day) before they are administered glucose/dextrose
  26. Catatonia is managed by stopping antipsychotics and attempting an intravenous lorazepam challenge. Memantine and Zolpidem also have been used successfully in some cases.
  27. Malignant catatonia requires emergency Electroconvulsive Therapy (ECT)
  28. Side effects of Electroconvulsive Therapy (ECT) include musculoskeletal pain, amnesia surrounding the time of treatment, and headache
  29. Many psychiatric medications lower the seizure threshold. The highest risk appears to be clozapine, chlorpromazine, clomipramine, bupropion, lithium (toxicity), and abrupt withdrawal from benzodiazepines or anticonvulsants
  30. Therapeutic Index (TI) is an indicator of how much buffer room there is between the therapeutic and toxic thresholds and is determined using the formula TI = TD50/ED50 
  31. Propranolol (Inderal) is effective for social phobia (public speaking), akathisia, essential tremor, and lithium-induced tremors. 

Lithium

  1. Lithium is toxic to the thyroid gland
  2. About 5-10% of patients on lithium develop hypothyroidism
  3. About 30% of patients on chronic lithium therapy have elevated Thyroid Stimulating Hormone (TSH)
  4. Prior to starting lithium, check TSH levels, then recheck after 6 months and then annually
  5. Lithium Toxicity requires emergency dialysis when there are signs of neurotoxicity (confusion, seizures, ataxia, slurred speech) and the Lithium level is greater than approximately 2.5
  6. Lithium is not protein bound and is easily dialyzed and only should be dosed immediately after dialysis
  7. Dialysis is not a contraindication for prescribing lithium. 
  8. Lithium can worsen skin conditions such as Acne and Psoriasis
  9. Lithium’s mechanism of action is incompletely understood but thought to interact with signal transduction pathways (e.g., IP3 pathway)
  10. Lithium dose should be reduced or discontinued in patients undergoing electroconvulsive therapy (ECT) as Lithium has been associated with prolonged seizures.
  11. Pregnant patients taking Lithium should have Echocardiography after 16-18 weeks of pregnancy to look for Epstein’s anomaly (dysfunctional tricuspid valve with displacement into the right ventricle)
  12. Lithium use during pregnancy (especially 1st trimester) increases risk of Epstein’s anomaly (i.e., congenital downward displacement of tricuspid valve into a dysfunctional right ventricle)
  13. The therapeutic range for lithium in the treatment of bipolar disorder is 0.6-1.2 (for acute mania target should be 1.0-1.5)
  14. The following may decrease lithium levels and lead to treatment failure: Theophylline, caffeine, osmotic diuretics, acetazolamide, and increased sodium intake (hypernatremia)
  15. The following may increase lithium levels and cause toxicity: Low sodium states (hyponatremia), Diuretics, NSAIDs (not aspirin), COX-2 inhibitors, Tetracycline, ACE inhibitors
  16. Lithium is also known to be a potential precipitant of serotonin syndrome in people concurrently on serotonergic medications such as antidepressants, buspirone, and certain opioids (meperidine, tramadol, oxycodone, fentanyl)
  17. Lithium co-treatment is also a risk factor for neuroleptic malignant syndrome in people on antipsychotics and other anti-dopaminergic medications.
  18. Lithium is associated with acquired nephrogenic diabetes insipidus in about 50% of patients on long term Lithium treatment
  19. Lithium treatment may cause abnormal findings on EKG such as T-wave flattening and/or T-wave inversion. 
  20. Lithium interferes with Atrial-Ventricular conduction and the pace making activity of the sinus node so use with caution in individuals with sick sinus syndrome
  21. Avoid using Lithium in individuals with Brugada syndrome, a condition caused by a genetic defect of cardiac sodium channels

Antidepressants

  1. In Elderly patients with depression or anxiety, use Selective Serotonin Reuptake Inhibitors due to minimal side effects and AVOID tricyclic antidepressants due to anticholinergic, cardiac, and cognitive side effects
  2. The treatment for Obsessive Compulsive Disorder typically requires higher doses of Selective Serotonin Reuptake Inhibitors (SSRIs) or Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) than would be required for depression.
  3. Clomipramine is the most serotonergic of the Tricyclic Antidepressants (TCAs) and therefore is a good choice for SSRI-refractory Obsessive Compulsive Disorder.
  4. All SSRIs except Paroxetine and Fluvoxamine are very safe to use during pregnancy.
  5. SSRIs and the reported risk of persistent pulmonary hypertension of the newborn during 2nd and 3rd trimesters is controversial.
  6. Safest SSRIs during pregnancy: Sertraline, Fluoxetine, Citalopram
  7. Safest SSRIs during breast feeding due to minimal secretion in breastmilk: Paroxetine, Sertraline, Fluoxetine, Citalopram
  8. Paroxetine is not a the best first choice as an antidepressant and anxiolytic during pregnancy due to a small risk of congenital defects
  9. Paroxetine should be dosed once daily at bedtime due to anticholinergic and antihistamine properties (usually sedating)
  10. Paroxetine does not have an active metabolite and has a relatively short half life and therefore often causes withdrawal syndrome when abruptly stopped.
  11. Paroxetine has anticholinergic properties and a potent inhibitor of CYP2D6
  12. Fluoxetine and Sertraline are generally considered more “activating” SSRI antidepressants (but not always).
  13. Sertraline (Zoloft) is a weight neutral SSRI
  14. SSRIs have shown effectiveness in premenstrual dysphoria and irritability.
  15. SSRIs and SNRIs have shown effective for vasomotor symptoms “hot flashes” in perimenopause.
  16. Bupropion is a good choice for patient’s who smoke or have low libido.
  17. Bupropion is a good choice for SSRI-induced sexual side effects.
  18. Bupropion is a good choice for seasonal affective disorder.
  19. Bupropion should be used with caution in patient’s with a history of seizure disorders and/or eating disorders as it may lower the seizure threshold
  20. Bupropion is the least likely of the studied antidepressants to induce mania or cause rapid cycling in depressed patients with bipolar disorder
  21. Tricyclic Antidepressants (TCAs), SNRIs, and Monoamine Oxidase Inhibitors (MAOIs) are most likely to induce mania in depressed patients with bipolar disorder
  22. TCAs cause slowing of cardiac conduction leading to a widening of the QRS complex and fatal heart blocks.
  23. Antidepressants with noradrenergic properties (e.g. Duloxetine, Venlafaxine, Desvenlafaxine, Levomilnacipran, Stimulants) may be the best choice for patients with depression and neuropathic pain
  24. Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) are usually dosed in the morning (except Paroxetine)
  25. For patients with Tricyclic Antidepressant (TCA) overdose, the treatment of choice is NaHCO3 (sodium bicarbonate)
  26. Monoamine Oxidase Inhibitors (MAOIs) carry a risk for hypertensive crises when used in combination with tyramine rich foods (aged cheese, red wine, deli meats, sausage, sauerkraut) as well as other catecholaminergic drugs (ephedrine, pseudoephedrine, amphetamines, and other monoamine antidepressants).
  27. An antidepressant discontinuation syndrome occurs most frequently with Paroxetine, Sertraline, Escitalopram, Duloxetine, and Venlafaxine when abruptly stopped.
  28. Fluoxetine is rarely associated with a discontinuation syndrome due to its very long half-life (fluoxetine is often used to treat SSRI discontinuation syndrome).
  29. Trazodone carries a risk of priapism “traza-BONE”
  30. Trazodone has minimal anticholinergic activity and is a good choice for elderly patients (but there is a risk for falls due to alpha 1 antagonism and associated orthostatic hypotension)
  31. Bipolar depression: Best choices are lithium, Quetiapine, Olanzapine/Fluoxetine combination, Lurasidone, Lamotrigine, or Electroconvulsive Therapy (ECT)
  32. Before increasing the dose of antidepressants, ensure that the antidepressant treatment has been administered for a sufficient duration and at a sufficient dose. Allow at least four (4) weeks before making a conclusion about a patient’s response.
  33. No treatment should continue unmodified if there has been no symptomatic improvement after two (2) weeks.
  34. Serotonin Syndrome can be caused by combinations of any of the following: TCAs, MAOIs, SSRIs, SNRIs, Triptans, Linezolid, Methylene blue, meperidine, tramadol, dextromethorphan, fentanyl, St johns wort, MDMA

Anticonvulsant Mood Stabilizers

  1. Carbamazepine/oxcarbazepine are CYP450 inducers and have many drug interactions. Remember oral contraceptives need to be increased in patients on carbamazepine or oxcarbazepine.
  2. Conversely, many oral contraceptives alter the pharmacokinetics of anticonvulsants such as lamotrigine and valproic acid. Be careful!
  3. Amenorrhea, Galactorrhea, Sexual dysfunction, and Headaches in a patient on antipsychotics suggests elevated prolactin. Reduce dose or stop medication for symptomatic prolactin elevations.
  4. Avoid Valproic acid in pregnancy due to risk of neural tube defects and decreased IQ
  5. Before initiating lithium and valproic acid treatment, order a pregnancy test
  6. Folate during pregnancy may diminish risk of Neural Tube Defects (NTDs) but there is very little evidence to support this.
  7. Ultrasound at 18-20 weeks will detect Neural Tube Defects (NTDs).
  8. Carbamazepine rarely causes acute aplastic anemia (fever, chills, bleeding gums, fatigue, pallor), agranulocytosis, and Steven Johnsons Syndrome.
  9. Avoid Carbamazepine and Clozapine combination due to additive bone marrow suppression.
  10. Carbamazepine increases risk of Steven Johnson Syndrome (SJS) in patients of Asian descent with HLA-B1502 allele.
  11. Consider genetic testing prior to administering carbamazepine to patients of Asian descent.
  12. Lamotrigine dosed 25mg daily for two weeks then 25mg twice daily for two weeks then 50mg twice daily for two weeks to reduce the risk of developing a benign rash or, rarely, SJ/TEN
  13. Therapeutic range (blood levels) for valproic acid is 45-125ug/mL. (Serum levels >125ug are likely to cause side effects). Loading dose for acute mania is typically 25mg/kg/day.
  14. Prothrombin time, fibrinogen levels, and serum transaminases are frequently elevated with valproic acid
  15. Monitor White blood cell count and platelet count when prescribing valproic acid and carbamazepine (due to risk of thrombocytopenia/leukopenia)

Antipsychotics

  1. Clozapine ANC schedule: Baseline, weekly for 6 months, then biweekly for 6 months then monthly after 12 months
  2. Neuroleptic Malignant Syndrome (NMS): Patient starts typical or atypical antipsychotic then a few days or weeks later develops delirium, fever, muscle rigidity, and extremely elevated CPK
  3. NMS can be caused by antipsychotics, phenothiazine antiemetics (promethazine, prochlorperazine), metoclopramide, or abrupt discontinuation of L-dopa or other dopamine agonists. 
  4. NMS Treatment: Stop antipsychotic, administer intravenous fluids (IVF), use cooling blankets, try dantrolene and/or bromocriptine
  5. Antipsychotics increase risk of extrapyramidal symptoms (EPS). Typical antipsychotics are associated with higher risk compared to atypical antipsychotics.
  6. EPS includes Acute Dystonia, Pseudoparkinsonism, Akathisia, and Tardive Dyskinesia.
  7. Acute dystonia (painful muscle spasms and contractions) can be lethal if laryngeal muscles involved.
  8. Treatment of acute dystonia: Intramuscular benztropine (Cogentin) or diphenhydramine (benadryl)
  9. Tardive dyskinesia: Repetitive, involuntary movements of the limbs, torso, and fingers. Grimacing, tongue movements, lip smacking, lip puckering, pursing of lips, excessive eye blinking
  10. Treatment of Tardive Dyskinesia: Decrease dose or stop the offending agent. Try one of the new treatments available. If this is not possible, try clozapine.
  11. Akathisia: Restlessness, can’t sit still, feel like they always need to be moving, rocking back and forth in chair. Treatment with propranolol or clonazepam
  12. Clozapine and Olanzapine are the most likely to cause metabolic syndrome (insulin resistance, glucose abnormalities, dyslipidemia), worsen diabetes, or even precipitate diabetic ketoacidosis. 
  13. Haloperidol can be used for Tourette’s and Hiccups
  14. Parkinson’s disease Psychosis: Use pimavanserin (a new 5HT2A antagonist with no dopamine antagonist properties). If not available, use clozapine or quetiapine at lowest dose possible (less D2 blockade). Avoid typical antipsychotics. 
  15. High doses of haloperidol, fluphenazine, or flupenthixol may be hazardous when used with lithium as irreversible toxic encephalopathy has been reported.
  16. All antipsychotics have risk of prolonging QT interval and causing torsades
  17. All antipsychotics lower seizure threshold to varying degrees
  18. Risperidone and Aripiprazole used to treat behavioral outbursts and aggression in children with autism
  19. Clozapine, despite its significant anticholinergic activity, paradoxically causes hypersalivation in some patients; Best treatment for antipsychotic induced hypersalivation is glycopyrrolate
  20. Clozapine associated with myocarditis, pericarditis, cardiomyopathy, agranulocytosis, and aplastic anemia
  21. Tachycardia and orthostatic hypotension are the most common cardiac side effects of Clozapine

Bipolar Disorder Treatment Tables

Pharmacotherapy For Bipolar ManiaMonotherapyCombination Therapy Options
First-LineLithiumLithium + Atypical Antipsychotic
Lithium + Benzodiazepine
Valproic AcidValproic Acid + Atypical Antipsychotic
Atypical Antipsychotic: Olanzapine, Quetiapine, Risperidone, Aripiprazole, Ziprasidone, Asenapine, Paliperidone
Second-LineCarbamazepine Lithium + Valproic Acid

Pharmacotherapy For Bipolar MaintenanceMonotherapyCombination Therapy
First-LineLithiumLamotrigine + Quetiapine
Valproic AcidValproic Acid + Quetiapine
Atypical Antipsychotic: Quetiapine, OlanzapineValproic Acid + Bupropion
Olanzapine + Fluoxetine
Second-LineCarbamazepine Lithium + Valproic Acid
Lithium + Olanzapine
Lithium + Carbamazepine
Valproic Acid + Olanzapine

Pharmacotherapy For Bipolar DepressionMonotherapyCombination Therapy
First-LineLithiumLithium + Bupropion
Lithium + Valproic Acid
Lamotrigine Lamotrigine + Lithium
Lamotrigine + Quetiapine
Atypical Antipsychotic: Quetiapine, LurasidoneValproic Acid + Bupropion
Olanzapine + Fluoxetine
Second-LineValproic AcidLithium + Valproic Acid
Carbamazepine

Important Drug-Drug Interactions

→ Valproic acid (VPA) + Lamotrigine:

Valproic acid (VPA) increases lamotrigine levels which increases the risk of rash and Steven-Johnson’s Syndrome (SJS/TEN)

Decrease the dose of lamotrigine by 50% when used in combination with VPA

→ Carbamazepine (CBZ) is an inducer of CYP3A4 and therefore induces its own metabolism

CBZ induces the metabolism of numerous other medications including oral contraceptives, clozapine, alprazolam, buspirone, and clonazepam

→ Lithium Levels Increased by: NSAIDs (not aspirin), ACE Inhibitors, Thiazide diuretics, low sodium diet

→ Lithium Levels Decreased by: Caffeine, theophylline, high sodium diet

→ Grapefruit juice is a potent inhibitor of CYP3A4 and P-glycoprotein

Grapefruit juice increases blood levels of medications metabolized by CYP3A4 (e.g., Warfarin)

→ Hydrocarbons from cigarette smoke induce activity of CYP1A2

Smoking decreases blood levels of medications metabolized by CYP1A2 (e.g., Olanzapine, Clozapine, Caffeine)

→ Tyramine containing foods + MAOIs, SSRIs, TCAs, Pseudoephedrine, stimulants may precipitate a hypertensive crisis

Tyramine-rich foods include banana peel, beer, fava beans, aged cheese, sauerkraut, sausage, soy sauce, concentrated yeast extract

→ Fluoxetine, Paroxetine, and Bupropion are potent inhibitors of CYP2D6 and can raise blood levels of medications metabolized by CYP2D6.

→ Tamoxifen and Codeine are prodrugs requiring metabolism by CYP2D6. Efficacy of these drugs may be decreased when used with inhibitors of CYP2D6.

St Johns Wort, 5-HTP and Ginseng are used over the counter (OTC) for depression and they both have many drug interactions

St John’s Wort, 5-HTP, and L-Tryptophan may cause Serotonin Syndrome

→ Antiretroviral medications used to treat HIV/AIDS (e.g. Protease inhibitors) have numerous interactions with some psychotropic medications

References

  1. Cooper, J. R., Bloom, F. E., & Roth, R. H. (2003). The biochemical basis of neuropharmacology (8th ed.). New York, NY, US: Oxford University Press.
  2. Iversen, L. L., Iversen, S. D., Bloom, F. E., & Roth, R. H. (2009). Introduction to neuropsychopharmacology. Oxford: Oxford University Press.
  3. Puzantian, T., & Carlat, D. J. (2016). Medication fact book: for psychiatric practice. Newburyport, MA: Carlat Publishing, LLC.
  4. J. Ferrando, J. L. Levenson, & J. A. Owen (Eds.), Clinical manual of psychopharmacology in the medically ill(pp. 3-38). Arlington, VA, US: American Psychiatric Publishing, Inc.
  5. Schatzberg, A. F., & DeBattista, C. (2015). Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing.
  6. Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
  7. Stahl, S. M. (2014). Stahl’s essential psychopharmacology: Prescriber’s guide (5th ed.). New York, NY, US: Cambridge University Press.
  8. Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY, US: Cambridge University Press.
  9. Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Lippincotts illustrated reviews: pharmacology. Philadelphia, PA: Wolters Kluwer.
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