Bipolar Disorder and Lithium Treatment

• Bipolar disorder is characterized by cyclic mood changes, including episodes of mania and depression
• Objectives include being able to compare and contrast mania, hypomania and depression, identify lithium toxicity symptoms and manage lithium levels with medication and kidney alterations

Overview of Bipolar Disorder

• A cyclic mood disorder with episodes of mania and depression
• Mania involves abnormally elevated mood, intense energy, racing thoughts, and risky behaviors
• Depression involves persistent feelings of sadness, loss of interest, and reduced energy
• Affects around 1-5% of the population
• Symptom onset typically occurs in late adolescence or early adulthood around ages 18-20
• Equally affects males and females
• Is the 18th leading cause of disability in the US
• Genetic risk factors have a 40-70% lifetime risk in monozygotic twins
• Environmental risk factors include prenatal viral infections, maternal stress, postnatal childhood trauma, and stressful events

Diagnosis of Bipolar Disorder

• The DSM-5 provides criteria for diagnosis of mania, hypomania, and depression episodes
• Mania is characterized by ≥7 days of abnormally and persistently elevated mood and energy, plus at least 3-4 symptoms
• Mania mood disturbance is severe and results in functional impairment, hospitalization, or psychotic features
• Hypomania is characterized by ≥4 days of abnormally and persistently elevated mood and energy, plus at least 3-4 symptoms
• A hypomania episode is not severe enough to cause marked impairment or hospitalization, and there are no psychotic features
• Depression is characterized by ≥14 days of depressed mood, loss of interest, plus at least 4-5 symptoms

Symptoms of Mania/Hypomania

• Inflated self-esteem (grandiosity)
• Decreased need for sleep
• Increased talking (pressure of speech)
• Racing thoughts (flight of ideas)
• Distractibility (poor attention)
• Increased goal-directed activity or psychomotor agitation and/or excessive involvement in risky activities

Symptoms of Depression

• Depressed/sad mood in adults, irritability in children
• Decreased interest and pleasure in normal activities
• Decreased or increased appetite, weight loss or weight gain
• Insomnia or hypersomnia
• Psychomotor retardation or agitation
• Decreased energy or fatigue
• Feelings of excessive guilt or worthlessness
• Impaired concentration or indecisiveness
• Recurrent thoughts of death, suicidal thoughts or attempts

Classification of Bipolar Disorders

• Types are based on the 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
• Episodes occur over 2 years for adults and 1 year for children and adolescents
• Other specified and unspecified bipolar and related disorders are also classified
• "Euthymia" refers to the period of time between episodes
• Rapid cycling means four or more episodes occur within 12 months
• Mixed episodes are also possible, where patients experience symptoms of both mania and depression during the same episode
• Acute treatment depends on the episode patients are experiencing but most should stay on a mood-stabilizing drug indefinitely

Pathophysiology of Bipolar Disorder

• There is no single hypothesis for the underlying pathophysiology
• Some suggest dysfunction relates to numerous neuronal circuits rather than specific neurotransmitters
• Many mood stabilizer medications reduce neuronal activity by various mechanisms
• These mechanisms include blocking voltage-gated Na+ channels to reduce action potential propagation, and reducing neurotransmission by increasing GABA or reducing glutamate

Approach to Treatment

• Most patients will be on at least one medication for maintenance therapy called "mood stabilizers"
• An additional medication (acute therapy) can be added during an episode of mania or depression
• After the episode, the additional medication may be tapered off or added to the maintenance therapy
• Medications include mood stabilizers, second-generation antipsychotics, antidepressants, and benzodiazepines
• "Classical" mood stabilizers include Lithium, Valproate, Lamotrigine, Carbamazepine, and oxcarbazepine
• Second-generation antipsychotics are used during acute episodes and often as maintenance therapy
• SGAPs include quetiapine, olanzapine, risperidone, ziprasidone, lurasidone, and aripiprazole
• Antidepressants are typically only used during acute depressive episodes, and increase the risk of a switch to mania
• Benzodiazepines are typically only used during acute manic episodes to reduce agitation

Lithium

• Lithium (Eskalith, Lithobid) MOA is unknown but involves multiple mechanisms
• Modulates multiple neurotransmitters and decreases dopamine/glutamate signaling and enhances GABA/serotonin signaling
• Affects intracellular signaling proteins and alters brain structure
• Effective for acute mania/depression and maintenance
• Associated with a reduction in suicide, but caution should be taken in patients with active suicidal ideation due to overdose concerns
• Higher lithium concentrations in drinking water are associated with reduced population suicide rates
• Typically administered as lithium carbonate, dissociating into lithium ions (Li+)
• Many therapeutic actions and ADRs of lithium are related to its ionic properties displacing electrolytes

Lithium (Eskalith, Lithobid) cont.

• ADRs include weight gain, GI effects, tremor, polydipsia/polyuria, EKG changes, thyroid hormone alterations like hyper or hypothyroidism, hypercalcemia, and sedation Causes desensitization or downregulation of anti-diuretic hormone which can cause diabetes insipidus
• Completely absorbed, highly distributed, not metabolized, and excreted unchanged in urine
• Half life of 12-24 hrs
• Serum levels are highly influenced by alterations in kidney function
• Narrow therapeutic window which requires monitoring of serum concentration
• Therapeutic serum levels are between 0.6 – 1.2 mEq/L, but this can be highly patient-specific
• Higher concentrations may be needed during acute mania, lower concentrations may be needed in elderly patients
• Acute toxicity can occur with levels >1.5, symptoms include vomiting, tremor, agitation, delirium, tachycardia, hypotension, seizures, and coma
• Renal Elimination of Lithium
• Freely filtered by the glomerulus
• About 75% is usually reabsorbed, mostly in the proximal tubule
• Smaller amounts are reabsorbed throughout the rest of the tubule
• Diuretics alter renal elimination
• Thiazide diuretics cause a compensatory increase in lithium reabsorption in the proximal tubule
• Osmotic diuretics decrease lithium reabsorption in the proximal tubule
• Adjust lithium dose when using ACEIs and ARBs because they can decrease GFR

Fluids and Lithium

• Lithium levels are highly dependent on kidney function and fluid status
• Increase in fluid volume = decreases in serum lithium concentration
• Decrease in fluid volume = increase in serum lithium concentration
• Increase in GFR = decreases in serum lithium concentrations
• GFR increases by up to 50% in pregnancy
• Medications that reduce GFR include ACEIs, ARBs, and NSAIDs
• Alteration in Kidney function includes diuretic medications: Thiazides increase serum lithium Loop diuretics and K+ sparing have variable minor effects Osmotic diuretics decrease serum lithium
• Increase sodium intake, decreases lithium and sodium compete for reabsorption Increased serotonin signaling with serotonin drugs, such as SSRIs, increases the risk of Serotonin Syndrome

Valproate/Divalproex (Depakote)

• MOA: Prolongs inactivation of VG NA+ channels, enhances GABA, and 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), hepatotoxicity, teratogenicity (spina bifida), pancreatitis

Lamotrigine (Lamictal)

• Lamotrigine's MOA prolongs the inactivation of VG Na+ channels
• Effective in maintenance therapy and acute treatment of depressive episodes
• Metabolized by glucuronidation
• Important drug interactions that affect the dose should be considered
• Start at a higher dose for inducers of glucuronidation, such as carbamazepine
• Start at a lower dose for inhibitors of glucuronidation, such as valproic acid
• There may be rashes; this can be minimized by starting with low doses and slow upward titration -- important to give a “starter kit” because Rash is more common in children

Carbamazepine/Oxcarbazepine

• Carbamazepine and oxcarbazepine MOA: prolongs the inactivation of VG Na+ channels
• Effective in the treatment of mania and in maintenance treatment
• Carbamazepine is metabolized by 3A4 and is a strong inducer of CYP (3A4) and glucuronidation
• Oxcarbazepine metabolized by hydrolase enzymes; weak CYP inducer
• Carbamazepine has a higher incidence of ADRs compared to oxcarbazepine related to the epoxide metabolite
• Hypersensitivity Reactions are related to aromatic rings, higher risk for carriers of the HLA-B*1502 allele
• Common ADRs: nausea, headache, fatigue, blurred vision, mild leukopenia that usually resolves and elevated liver enzymes

Second Generation Antipsychotics

• Weak antagonism (or partial agonism) at D2 and antagonism at 5HT2A receptors
• Commonly used SGAPs: quetiapine, olanzapine, risperidone, ziprasidone, lurasidone, and aripiprazole
• Effective in acute treatment of mania and especially in maintenance therapy
• Quetiapine and lurasidone are also effective in acute treatment of depressive episodes
• Onset of effects in treatment of mania are frequently more rapid (within days) compared to the classical mood stabilizers
• FGAPs may also be used in acute episodes but are less preferred long-term due to ADRs
• Refer back to schizophrenia slides for ADRs and PK

Special considerations in pregnancy

• Risks and benefits should be carefully weighed, especially in pregnancy
• Lithium, valproate, lamotrigine, carbamazepine and antipsychotics cross the placental barrier
• benefits of continuing medication outweigh the risks of birth defects
• Valproate is the highest risk, with major congenital abnormalities and neural tube defects
• Lithium is moderate risk, major congenital abnormalities and risk for Epstein's anomaly
• Lamotrigine is low risk, but risk cannot be ruled out
• Carbamazepine/oxcarbazepine are a risk for neural tube defects and facial abnormalities
• Antipsychotics are overall low risk but risk cannot be ruled out

This quiz covers the diagnosis and management of bipolar disorder, focusing on lithium treatment. It addresses symptoms, adverse effects, drug interactions, and monitoring requirements related to lithium therapy. The quiz also explores the mechanisms of action of lithium and its impact on thyroid function in bipolar disorder.