Bipolar Disorder PBSN-631 Lecture Notes PDF

PBSN-631: Pharmacology/ Medicinal Chemistry-IV Bipolar Disorder Spring 2025 Mon-10:15-12:30 Wed: 11:30 – 12:30  Objectives § Compare and contrast mania, hypomania, and depressive episodes in bipolar disorder § Identify symptoms o...

PBSN-631: Pharmacology/ Medicinal Chemistry-IV Bipolar Disorder Spring 2025 Mon-10:15-12:30 Wed: 11:30 – 12:30  Objectives § Compare and contrast mania, hypomania, and depressive episodes in bipolar disorder § Identify symptoms of lithium toxicity § Predict how certain medications, alterations in fluid status, and alterations in GFRs will affect lithium serum concentrations and the need for dose adjustments § Compare and contrast mechanisms of action, ADRs, PK parameters, and considerations for use of medications used in the treatment of bipolar disorder § Identify the mechanism and management of drug interactions between medications used in treatment of bipolar disorder Must watch animation: < 10 min=== https://www.osmosis.org/learn/Bipolar_disorder?query=Bipolar_and_related_disorders&language=en 2  Overview of Bipolar Disorder § Cyclic mood disorder characterized by episodes of mania and depression Mania: periods of abnormally elevated, intense energy, racing thoughts, and other extreme and exaggerated behaviors; person may partake in risky behaviors such as excessive spending, hypersexual behavior; may feel invincible; delusions/hallucinations may occur Depression: periods of persistent feelings of sadness, loss of interest, reduced energy levels, difficulty concentrating, etc. § Estimated to affect around 1-5% of the population Symptom onset typically occurs in late adolescence or early adulthood – average age of onset around 18-20 years old Equal incidence in males and females § 18th leading cause of disability in the US § Genetic risk factors – 40-70% lifetime risk in monozygotic twins § Environment risk factors: Prenatal factors include viral infection during pregnancy, maternal stress Postnatal factors include childhood trauma, stressful events 3  Diagnosis of Bipolar Disorder The DSM-5 provides criteria for diagnosis of an episode of mania, hypomania, and depression Mania: ≥7 days of abnormally & persistently elevated mood (expansive or irritable) and energy + at least 3-4 symptoms == The mood disturbance is sufficiently severe to cause marked impairment in functioning or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features (such as hallucinations or delusions) Hypomania: ≥4 days of abnormally and persistently elevated mood (expansive or irritable) and energy + at least 3-4 symptoms == The episode is not severe enough to cause marked impairment in functioning or to necessitate hospitalization; == NO psychotic features Depression: ≥14 days of depressed mood or loss of interested, + at least 4-5 symptoms 4  Diagnosis of Bipolar Disorder Symptoms of Mania/Hypomania Symptoms of Depression == Depressed, sad mood (adults); can be irritable mood == Inflated self-esteem (grandiosity) in children == Decreased interest and pleasure in normal activities == Decreased need for sleep == Decreased or increased appetite, weight loss or == Increased talking (pressure of speech) weight gain == Insomnia or hypersomnia == Racing thoughts (flight of ideas) == Psychomotor retardation or agitation == Distractibility (poor attention) == Decreased energy or fatigue == Feelings of excessive guilt or worthlessness == Increased goal-directed activity or == Impaired concentration or indecisiveness psychomotor agitation == Recurrent thoughts of death, suicidal thoughts or attempts Excessive involvement in risky activities 5  Classification of Bipolar Disorder Types of bipolar disorder based on DSM-5 Bipolar I disorder: Manic episode ± major depressive or hypomanic episode Bipolar II disorder: Major depressive episode + hypomanic episode Cyclothymic disorder: fluctuations between subsyndromal depressive and hypomanic episodes (2 years for adults and 1 year for children and adolescents) Other specified and unspecified bipolar and related disorders https://www.bipolarpsychologist.com.au/understanding-bipolar/ The period of time between episodes may be referred to as “euthymia” Rapid cycling is when a patient experiences 4 or more episodes within 12 months Mixed episodes are also possible – patient experiences symptoms of mania and depression during the same episode Acute treatment depends on what episode the patient is experiencing, however most patients should stay on a mood-stabilizing drug indefinitely 6  Pathophysiology of Bipolar Disorder No single hypothesis for the underlying pathophysiology of bipolar disorder Some suggest that the dysfunction relates to numerous neuronal circuits rather than specific neurotransmitters Many of the effective mood stabilizer medications reduce neuronal activity by various mechanisms: Blockade of voltage gated Na+ channels – reduction in action potential propagation Decrease neurotransmission – increase GABA or reduce glutamate VG Na+ channels are responsible for propagation of the action potential down the axon 7  Approach to Treatment Most patients will be on at least one medication for maintenance therapy – medications used for maintenance therapy are called “mood stabilizers” An additional medication (acute therapy) may be added on during an episode of mania or depression After the episode is over, the additional medication may either be tapered off, OR added to the maintenance therapy Note: FDA indications of these medications Medications used in the treatment of bipolar disorder may not always represent the full clinical use; for example, carbamazepine ER is Classical “mood stabilizers” approved for acute treatment of mania but it Lithium is also used for maintenance treatment Valproate Lamotrigine Carbamazepine, oxcarbazepine Second generation antipsychotics – used during acute episodes but also often used as maintenance therapy Commonly used SGAPs: quetiapine, olanzapine, risperidone, ziprasidone, lurasidone, aripiprazole Antidepressants – typically only used during acute depressive episodes; increased risk of a switch to mania Benzodiazepines – typically only used during acute manic episodes to reduce agitation 8  9 Lithium (Eskalith, Lithobid) MOA: unknown, multiple mechanisms proposed Modulates multiple neurotransmitters Decreases dopamine, glutamate signaling Enhances GABA, serotonin signaling Affects intracellular signaling proteins Lithium is typically Alters brain structure administered as lithium carbonate, and dissociates Effective for acute mania, acute depression, and into lithium ions (Li+) for maintenance therapeutic action Associated with reduction in suicide (but caution in patients with active suicidal ideation due to overdose concerns) The many therapeutic actions and ADRs of lithium are related to its Higher lithium concentrations in drinking water are associated with a reduction in population suicide rates ionic properties  as a small charged molecule it can displace electrolytes such as Na+, K+ and even Ca2+  10 Lithium (Eskalith, Lithobid) ADRs ADRs including weight gain of >10kg in 20% of patients, GI effects (diarrhea, nausea), tremor, polydipsia and polyuria, EKG changes, thyroid hormone alterations (hypothyroidism > hyperthyroidism), hypercalcemia, sedation Mechanism for polyuria: lithium causes desensitization or downregulation of anti-diuretic hormone (also called vasopressin) receptors in the kidney, thus reducing water reabsorption and increasing urine output. This can lead to diabetes insipidus which is sometimes irreversible. PK considerations: Completely absorbed, highly distributed, not metabolized, excreted unchanged in urine; half life of 12-24 hrs Serum levels are highly influenced by alterations in kidney function Lithium has a narrow therapeutic window – important to monitor serum concentration = General recos for therapeutic serum levels are between 0.6 – 1.2 mEq/L, but this can be highly patient specific = May need higher concentrations during acute mania (up to 1.5) & lower concentrations in elderly patients = Acute toxicity can begin to occur with levels >1.5; symptoms of toxicity include vomiting, tremor, agitation, delirium, tachycardia, hypotension, seizures, coma  Lithium (Eskalith, Lithobid) Renal Elimination of Lithium Lithium is freely filtered by the glomerulus About 75% is usually reabsorbed Most (~60%) is reabsorbed in the proximal tubule Smaller amounts of lithium are reabsorbed throughout the rest of the tubule Diuretics alter renal elimination of lithium Thiazide diuretics cause a compensatory increase in lithium reabsorption in proximal tubule Osmotic diuretics decrease lithium reabsorption in the proximal tubule Other diuretics (loops, K+ sparing, have a variable or minor effect) https://pubmed.ncbi.nlm.nih.gov/8521679/ 11  12 Lithium (Eskalith, Lithobid) Lithium levels are highly dependent on kidney function and fluid status Fluid status Increase in fluid volume = decrease in serum lithium concentration Decrease in fluid volume = increase in serum lithium concentration Kidney function Alterations in glomerular filtration rate (GFR) Increase in GFR = decrease in serum lithium concentrations GFR increases by up to 50% in pregnancy Reduction in GFR = increase in serum lithium concentration Medications that reduce GFR include ACEI (Lisinopril, fosinopril, benazepril, etc.) – dilation of efferent arteriole ARBs (losartan, valsartan, etc.) – dilation of efferent arteriole NSAIDs (ibuprofen, diclofenac, naproxen, etc.) – constriction of afferent arteriole  Lithium (Eskalith, Lithobid) 13 Alteration in Kidney function Alterations in reabsorption of electrolytes Diuretic medications Thiazides (hydrochlorothiazide, chlorthalidone) = increase in serum lithium Loop diuretics (furosemide, torsemide) and K+ sparing (spironolactone) = variable, minor effects Osmotic diuretics (mannitol) = decrease in serum lithium Dietary sodium intake [Increase in sodium intake = decrease in serum lithium] [Lithium and sodium compete for reabsorption] Other drug interactions Risk of serotonin syndrome when combined with drugs that increase serotonergic signaling (such as SSRIs)  Practice question Fills in the blanks with the correct answer choice: ACEIs such as lisinopril can _______ the glomerular filtration rate. Therefore, patients on lithium may require a/an _______ in their lithium dose to maintain therapeutic concentrations. A. Increase, increase B. Increase, decrease C. Decrease, decrease D. Decrease, increase 14  Valproate / Divalproex (Depakote) MOA Prolongs inactivation of VG Na+ channels Enhances GABA Blocks T-type calcium channels Effective in acute mania, acute depression, and maintenance PK considerations: Metabolized by CYP2C19 and 2C9 followed by glucuronidation, Inhibitor of 2C9 and glucuronidation ADRs: Weight gain, nausea, vomiting, alopecia, rash, elevation of hepatic enzymes (occurs during initiation in up to 40% of patients) Serious ADRs: hepatotoxicity, teratogenicity (spina bifida), pancreatitis 15  Lamotrigine (Lamictal) MOA: Prolongs inactivation of VG Na+ channels Effective in maintenance therapy and acute treatment of depressive episodes PK considerations Metabolized by glucuronidation Important drug interactions affect the dose Start at a higher dose for inducers of glucuronidation (carbamazepine) Start at a lower dose for inhibitors of glucuronidation (valproic acid) ADRs: May cause rash (~10% of patients), this can be minimized by starting a low dose and slow upward titration – important to give “starter kit” Rash is more common in children Rash thought to be due to the aromatic ring structure Dizziness, headache, somnolence, nausea 16  Carbamazepine (Tegretol), oxcarbazepine (Trileptal) MOA: prolongs the inactivation of VG Na+ channels Effective in treatment of mania and in maintenance treatment; however, less effective than other agents; carbamazepine has been studied more than oxcarbazepine PK considerations Carbamazepine: metabolized by 3A4; strong inducer of CYP (especially 3A4) and glucuronidation; undergoes autoinduction Oxcarbazepine: metabolized by hydrolase enzymes; weak CYP inducer ** ADRs: Carbamazepine has higher incidence of overall ADRs compared to oxcarbazepine related to epoxide metabolite [Exception is hypervolemic hyponatremia which is more common with oxcarbazepine] == Hypersensitivity Reactions – related to aromatic rings, higher risk in carriers of the HLA-B*1502 allele (??) == Common ADRs: nausea, headache, fatigue, blurred vision, mild leukopenia that usually resolves, 17 elevated liver enzymes  Second Generation Antipsychotics MOA: weak antagonism (or partial agonism) at D2 and antagonism at 5HT2A receptors Commonly used SGAPs: quetiapine, olanzapine, risperidone, ziprasidone, lurasidone, aripiprazole Overall, SGAPs are effective in acute treatment of mania and in maintenance therapy (especially for prevention of mania); quetiapine and lurasidone are also effective in acute treatment of depressive episodes Onset of effects in treatment of mania are more rapid (within days) compared to the classical mood stabilizers Note: FGAPs (such as haloperidol and chlorpromazine) may also be used in acute episodes but are less preferred long-term due to ADRs ADRs and PK: refer back to schizophrenia slides 18  Special considerations in pregnancy Risk and benefits should be carefully weighed These medications cross the placental barrier In many cases the benefits of continuing medication outweigh the risks of birth defects Highest Risk Moderate risk Lowest Risk Valproate Lithium Lamotrigine Rate of major congenital Rate of major congenital Appears to be low risk, but abnormalities is 5-11%; risk abnormalities is around 2-3%; risk cannot be ruled out for neural tube defects such risk for Epstein's’ anomaly = as spina bifida, cognitive heart defect of the tricuspid impairment, and other valve abnormalities Carbamazepine/oxcarbazepine Antipsychotics Rate of major congenital Overall, appears to be low abnormalities is around 2-5%; risk, but risk cannot be ruled risk for neural tube defects and out facial abnormalities 19  Summary Bipolar disorder is a cyclic mood disorder characterized by episodes of mania and depression Types of bipolar disorder include Bipolar I, Bipolar II, cyclothymic disorder, and other Maintenance therapy is essential for prevention of manic and depressive episodes Combination therapy is commonly required During acute episodes, additional therapies may be added on The main medications used in bipolar disorder include lithium, certain anticonvulsants (valproate, lamotrigine, carbamazepine, oxcarbazepine), and second-generation antipsychotics 20 References Katzung’s Basic and Clinical Pharmacology, 15th edition. Chapter 29: Antipsychotic Agents & Lithium Goodman & Gilman‘s The Pharmacological Basis of Therapeutics, 13th edition. Chapter 16: Pharmacotherapy of Psychosis and Mania Foye’s Principles of Medicinal Chemistry, 8th edition. Chapter 11: Drugs Used to Treat Mental, Behavioral, and Cognitive Disorders Other references listed on slides. 21