week 7 Lithium and Bipolar Disorder Lecture Notes

A collection of flashcards covering key vocabulary, concepts, and mechanisms related to lithium and its role in treating bipolar disorder.

Bipolar I Disorder

A severe mood disorder defined by the occurrence of at least one full manic episode, which may be preceded or followed by hypomanic or major depressive episodes. The manic episodes are often intense and can lead to significant functional impairment, hospitalization, or psychotic features.

Bipolar II Disorder

A type of bipolar disorder characterized by the experience of at least one major depressive episode and at least one hypomanic episode, but explicitly without the occurrence of a full manic episode. The depressive episodes are often the most problematic aspect of this disorder, while hypomania may even be perceived as productive.

Cyclothymic Disorder

A chronic mood disorder characterized by numerous periods of hypomanic symptoms and numerous periods of depressive symptoms, neither of which meet the full diagnostic criteria for a hypomanic or major depressive episode. These mood fluctuations typically persist for at least two years in adults (one year in children/adolescents) and occur for at least half the time, with no more than two consecutive months free of symptoms.

Neurobiology of Bipolar Disorder

The understanding that bipolar disorder involves complex dysregulation and imbalances within the brain's intricate neurotransmitter systems, including glutamate, GABA, dopamine, serotonin, and norepinephrine. These imbalances critically affect mood, energy regulation, thought processes, and behavior, often involving structural and functional changes in brain regions responsible for emotion regulation and executive function.

Lithium Carbonate

The most widely recognized and primary salt form of lithium used in psychiatric treatment for mood stabilization, particularly efficacious for managing bipolar disorder. It is typically administered as oral tablets or capsules and is foundational in preventing both manic and depressive episodes, requiring careful monitoring due to its narrow therapeutic index.

Lithium Citrate

An approved liquid form of lithium that has been in use since the 1970s, recognized for its role in stabilizing mood in patients, particularly those who have difficulty swallowing tablets or who require more flexible dosing. It provides an alternative administration route while maintaining similar efficacy and safety profiles to lithium carbonate, necessitating the same rigorous monitoring.

Lithium Orotate

A less common, nutraceutical form of lithium, theorized to cross the blood-brain barrier more readily than other forms, which has led to claims of efficacy at lower doses. However, its use raises notable concerns regarding potential organ toxicity (especially renal toxicity) due to its unknown long-term safety profile and lack of rigorous clinical trials at higher doses when compared to FDA-approved lithium salts. Its efficacy in psychiatric conditions is not well-established.

Neuronal Damage

The injury or death of brain cells, which can result from unchecked overactivity, excitotoxicity, and oxidative stress prevalent during mood episodes in bipolar disorder. This environmental stress can eventually lead to cellular inflammation, mitochondrial dysfunction, altered neuroplasticity, and neurodegeneration, contributing to cognitive deficits and disease progression.

Glycogen Synthase Kinase 3 beta (GSK-3ß)

A ubiquitous enzyme found to be overactive during manic and depressive episodes in bipolar disorder, playing a critical role in cellular signaling pathways related to mood, neuroplasticity, and cell survival. Lithium acts as a potent inhibitor of GSK-3ß, which is widely believed to contribute significantly to its mood-stabilizing and neuroprotective effects by promoting cellular health, resilience, and inhibiting programmed cell death.

Inositol Monophosphatase (IMPase)

A key enzyme involved in the inositol signaling pathway, which is crucial for brain cell communication and function; IMPase is specifically responsible for converting myo-inositol monophosphates to free inositol, a precursor to important secondary messenger molecules. Lithium's inhibition of IMPase leads to a reduction in intracellular inositol levels, thus dampening overactive neuronal signaling and representing a significant component of its proposed mechanism of action in mood stabilization.

Lithium Toxicity

A serious medical condition arising from excessive levels of lithium in the bloodstream, manifesting with a range of dose-dependent symptoms that can become life-threatening. Toxicity is typically considered when plasma lithium levels exceed 1.2 ext{ mEq/L}. Symptoms include, but are not limited to, fine tremor progressing to coarse tremor, confusion, drowsiness, muscle weakness, ataxia, severe gastrointestinal distress (nausea, vomiting, diarrhea), blurred vision, slurred speech, dysarthria, and in severe cases, seizures, cardiac arrhythmias, renal failure, coma, and even death, requiring immediate medical intervention.

Side Effects of Lithium

Common adverse reactions to lithium therapy, which often occur within the therapeutic range but can be managed. These include fine tremor (especially of the hands), cognitive dulling (slowing of thought processes, difficulty concentrating), gastrointestinal issues (nausea, diarrhea, stomach upset), dermatological reactions (acne flare-ups, psoriasis exacerbation), polyuria (increased urination), polydipsia (increased thirst), and potential impairments in renal and thyroid functions (e.g., hypothyroidism).

Narrow Therapeutic Range

A critical pharmacological characteristic of lithium, referring to the narrow margin between its effective therapeutic plasma concentration and doses that can cause toxicity. The general therapeutic range is typically 0.6 ext{ mEq/L} - 1.0 ext{ mEq/L}. Optimal dosing is based on clinical responses in conjunction with plasma lithium levels. Maintenance levels are now often considered lower than previously thought, with ranges like 0.5-0.8 ext{ mEq/L} being favored over 0.7-1.0 ext{ mEq/L} to minimize side effects. Lower maintenance doses, the use of controlled-release (CR) or extended-release (ER) formulations, and dosing at night are strategies employed to reduce the impact on kidney function.

Patient Education for Lithium

Comprehensive advice provided to patients initiating lithium therapy, emphasizing critical aspects such as maintaining adequate hydration (especially during exercise or illness to prevent dehydration and subsequent lithium accumulation), consistently taking medication as prescribed, recognizing early signs of side effects or toxicity (e.g., increased tremor, severe nausea, confusion), understanding the importance of regular blood tests for lithium levels and kidney/thyroid function, and being aware of potential medication and dietary interactions that can alter lithium levels.

Neuroprotective Effects of Lithium

The demonstrated ability of lithium to protect brain cells from damage, promote neuronal health, and enhance brain resilience, particularly in conditions like bipolar disorder. This multifaceted effect is believed to involve mechanisms such as inhibiting GSK-3ß, increasing levels of neurotrophic factors (e.g., BDNF), reducing oxidative stress, inhibiting excitotoxicity, and promoting neurogenesis, thereby potentially reducing neurodegeneration and improving overall cognitive and mood outcomes.

Plasma Levels of Lithium

The concentration of lithium measured in a patient's blood plasma ('trough levels'), which is critically monitored through regular blood tests (typically drawn 12 hours post-dose). This monitoring ensures an effective therapeutic dose is achieved while avoiding toxic levels, given lithium's narrow therapeutic range. Target therapeutic ranges vary by indication: for acute mania, levels are typically targeted at 0.8-1.2 ext{ mEq/L}; for maintenance therapy and depression, target levels are generally 0.6-1.0 ext{ mEq/L}. It is noted that plasma levels for depression are not always well correlated with treatment efficacy alone. ¡thium levels:

¡Check 4-7 days after starting or changing dose

Acute setting usually 4-5 days ; Outpatient setting usually 7 days

Once stable -1 month, then 6-12 months

No standard guidelines for frequency

Check at TROUGH levels (~12 hrs after last dose)

Thyroid and Renal:

Frequency: Baseline, 1 month after starting, every 6-12 months

If symptoms arise: CBC, calcium, electrolytes

Know level of when stability is achieved

Monitor weight, consider re-testing metabolic with significant weight gain

Drug Interactions with Lithium

The potential for other medications to significantly alter lithium levels or effects, necessitating careful consideration and monitoring. Examples include NSAIDs (e.g., ibuprofen, naproxen), ACE inhibitors, and diuretics (especially thiazides), which can all increase lithium levels and the risk of toxicity. Conversely, caffeine can increase renal clearance of lithium, potentially decreasing its levels and reducing its efficacy. Certain antipsychotics and antidepressants may also increase the risk of specific side effects or neuroleptic malignant syndrome.

Mood Stabilization

The primary therapeutic goal in treating bipolar disorder, involving medical interventions (primarily pharmacotherapy with mood stabilizers like lithium) aimed at reducing the frequency, intensity, and duration of mood swings—both manic/hypomanic and depressive episodes. The objective is to achieve more stable and balanced emotional states, minimize functional impairment, and improve overall quality of life for individuals living with the condition.

Cognitive Dysfunction

A frequently reported and often impactful side effect of lithium therapy, as well as a feature of bipolar disorder itself, characterized by a general slowing of thought processes ('cognitive dulling'), impaired memory (especially short-term), difficulty concentrating, reduced verbal fluency, and a potential reduction in creativity. These effects can significantly impact daily mental agility, academic performance, and occupational functioning.

Mechanism of Action of Lithium

Though not fully understood, lithium's profound therapeutic effects in mood stabilization are believed to involve complex and widespread modulations of multiple neuronal signaling pathways and neurotransmitter systems within the brain. Key proposed mechanisms include the inhibition of critical enzymes like Glycogen Synthase Kinase 3 beta (GSK-3ß) and Inositol Monophosphatase (IMPase), regulation of G-protein coupled receptors, alteration of intracellular calcium signaling, and significant neuroprotective effects that shield brain cells from damage, promote their survival, and enhance brain plasticity.

Long-term Use of Lithium

Continuous treatment with lithium over extended periods is a cornerstone for preventing recurrent mood episodes in bipolar disorder. While highly effective for mood stabilization, long-term use requires meticulous and ongoing management due to the undeniable potential for significant adverse effects, particularly on renal function (leading to reduced glomerular filtration rate and potentially chronic kidney disease) and thyroid function (often leading to hypothyroidism), necessitating regular monitoring and careful patient counseling.