M OOD S TABILIZERS Brian Gomoll, MD. G ENERAL O VERVIEW.

MOOD STABILIZERS

Brian Gomoll, MD

GENERAL OVERVIEW

BIPOLAR DISORDER

BIPOLAR DISORDER

BIPOLAR DISORDER

THEORETICAL PATHWAYS IN MANIA

The American Psychiatric Publishing Textbook of Neuropsychiatry and Behavioral Neurosciences, Fifth EditionEdited by Yudofsky SC, Hales RE. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org

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FIGURE 27–4. A proposed model of mood regulation: Different sets of brain regions are involved in different aspects of mood experience and modulation.

One example of a neural network model for depression is presented in Figure 27–4. In this model, the network is potentially modulated by dysfunction (or by treatment) at “critical nodes” that produce effects elsewhere in the network.

Numerous interconnections exist among these different regions, and the system is recognized to be dynamic and potentially modulated at any critical node. Different treatments for mood disorder syndromes may act primarily at different nodes within the system, with therapeutic downstream effects. PF9/46=dorsolateral prefrontal cortex; PM6=premotor area; Par40=dorsal parietal; hc=hippocampus; aCg24b=Brodmann area 24b/dorsal-perigenual anterior cingulate cortex; mCg24c=Brodmann area 24c/dorsal anterior cingulate cortex; pCg=posterior cingulate gyrus; mF9/10=medial frontal cortex; rCg24a=Brodmann area 24a/perigenual-subgenual cingulate cortex; oF11=orbitofrontal cortex; cd-vst=ventral caudate–ventral striatum; thal=thalamus; amg=amygdala; mb-sn=midbrain–subthalamic nuclei; sgCg25=Brodmann area 25/subgenual cingulate cortex; a-ins=anterior insula, hth=hypothalamus, bstem=brain stem; CBT=cognitive-behavioral therapy; DBS=deep brain stimulation of Brodmann area 25; MEDS=antidepressant medications.

MANIA – NOT JUST BIPOLAR DISORDER

MOOD STABILIZERS - USES

Bipolar Disorders Bipolar I Bipolar II Cyclothymic Disorder Other bipolar

Depressive Disorders Adjunctive Treatment

Psychotic Disorders (Antipsychotics) Adjunctive antiepileptics (controversial) Schizoaffective

Controversial, depends on agent

Subclinical / Comorbid Mood Symptoms Personality Disorders

Aggression / Impulsivity

Suicidality

Other Indications Seizures (antiepileptics) Headaches (antiepileptics, lithium) Tremor (topiramate)

SINGLE CLASS?

Can be considered four treatment indications: Acute mania Acute depression Maintenance / prevention of mania Maintenance / prevention of

depression

Multiple pathways and effects, different set of non-bipolar uses, different pharmacology

LITHIUM

LITHIUM – THE FIRST MOOD STABILIZER

Inorganic ion

Unknown mechanism of action Blockade of inositol triphosphate

formation, accumulation of intracellular inositol phosphate

Reduction of hormone-induced cAMP (though not pronounced in brain)

Proven to have prophylactic effect in re: recurrence of episodes

Less efficacious in treatment of acute bipolar depression

LITHIUM - BENEFITS

Strong evidence with multiple trials

Anti-suicidal

Avoids some side effects of anti-epileptic and antipsychotic medications Though has it own side effects

Adjunct for treatment-resistant depression

LITHIUM - MONITORING

Long half-life and relatively narrow therapeutic window

Requires monitoring of blood level, thyroid function, renal function

Patient needs to maintain relatively stable and adequate fluid and sodium intake

LITHIUM – ADVERSE EFFECTS

Nausea, vomiting, diarrhea

Neurologic Tremor Cognitive dulling

Renal Inhibition of ADH action Na+ retention Renal tubular damage may occur with

prolonged use

Thyroid enlargement and hypothyroidism

Weight gain

Cardiovascular EKG Changes (T-wave suppression,

irregular rhythm, aggravates sick sinus) Edema

Dermatologic Worsens acne, psoriasis Maculopapular and follicular rash

Teratogenic Ebstein’s anomaly*

Leukocytosis

LITHIUM - TOXICITY

Neurologic Tremor Cogwheeling Drowsiness Confusion Disorientation Fasciculations Ataxia Extrapyramidal side effects Seizure

Risk Factors: Fever Major Surgery Renal failure Low food/salt intake Age Acute overdose

Medications

LITHIUM & PREGNANCY

Increased risk of fetal cardiac abnormalities Ebstein’s anomaly 1:20000 live births 1:1000 with lithium

Transient CNS depression in newborn

Requires careful thyroid monitoring, lithium level changes

No long-term behavioral effects

No consensus, but usually not recommended in breastfeeding

LITHIUM – DRUG INTERACTIONS

NSAIDS Ibuprofen, indomethacin, naproxen, cox-

2 inhibitors

Thiazide diuretics Hydrochlorothiazide (HCTZ)

Nonthiazide diuretics

Antibiotics Tetracyclines

Calcium antagonists Verapamil

Xanthines Caffeine Theophylline

Osmotic diuretics Mannitol

Carbonic anhydrase inhibitors Acetazolamide

LITHIUM – WHY USE?

Best efficacy for mania, maintenance treatment

One of two medications known to have anti-suicidal properties The other being clozapine

Adjunctive treatment of depression

Though has multiple side effects, many patients tolerate it well and may prefer lithium’s potential side effects to others

Pregnancy (with risk/benefit)

ANTI-EPILEPTICS

ANTI-EPILEPTICS

Valproic Acid / Divalproex Depakene, Depakote

Carbamazepine Tegretol

Lamotrigine Lamictal

Oxcarbazepine Trileptal

ANTI-EPILEPTICS:

Valproic Acid First drug since lithium to be approved Better than lithium for mixed states or rapid-

cycling? (Controversial) Beneficial in manic phase, not as beneficial

in depression

Carbamazepine Comparable to valproic acid, often used in

treatment-resistant

Lamotrigine Not useful for acute therapy, but has efficacy

in bipolar depression and maintenance

ANTI-EPILEPTICS: ADVERSE EFFECTS

ANTI-EPILEPTICS: ADVERSE EFFECTS

ANTI-EPILEPTICS: NEWER AGENTS?

Mostly unsuccessful use of other anti-epileptics

Gabapentin (Neurontin) had some hope but has not shown efficacy Though can be helpful for anxiety

Topiramate (Topamax) use also unclear Helps with weight loss

Oxcarbazepine (Trileptal) Some good evidence (along line of

carbamazepine)

BENZODIAZEPINES

Use in acute mania and psychosis in context of bipolar disorder

Lorazepam (Ativan) PO/IM

Clonazepam (Klonopin) Longer acting

Increased abuse potential in bipolar patients with long-term use

ANTIPSYCHOTICS

ANTIPSYCHOTICS

First generation / Typical Not used in maintenance, may be used

in acute psychosis/mania Haloperidol (Haldol) PO/IM

Second generation / Atypical Increasing use as monotherapy /

combination therapy in bipolar patients Unclear mechanism in bipolar

Due to greater 5-HT2 antagonism? Subcortical DA dysfunction?

ANTIPSYCHOTICS - EXAMPLES

Risperidone (Risperdal) More “typical” than most atypicals Comes in PO, dissolving tab, long-acting

IM

Olanzapine (Zyprexa) Combination with SSRI (fluoxetine,

Symbyax) approved for bipolar depression Has long-acting IM and short-acting IM Long-acting IM difficult to give

Aripiprazole (Abilify) Has long-acting IM

Quetiapine (Seroquel) Sedation may help with sleep

Ziprasidone (Geodon) Somewhat more weight-neutral

Clozapine (Clozaril) Anti-suicidal Multiple side effects Requires blood monitoring Most efficacious antipsychotic

ANTIPSYCHOTICS – ADVERSE EFFECTS

EPS

Increased risk of tardive dyskinesia in mood disorder patients

Neuroleptic Malignant Syndrome

Hyperprolactinemia (typicals, risperidone)

Sedation (worse in clozapine, olanzapine, quetiapine)

Akathisia

Weight gain / Metabolic Syndrome

Seizures (at increased doses)

Anticholinergic effects

Decreased sexual drive and functioning

Leukopenia / Agranulocytosis

Cognitive Effects

OTHER TREATMENTS

Electroconvulsive Therapy Extremely good efficacy for mania,

melancholic depression

Transcranial Magnetic Stimulation Being researched for mania

Psychotherapy Different protocols with various evidence Adjunct to medications in vast majority

Lifestyle Changes Maintain consistent, good sleep schedule Avoid stimulants and other triggers

OVERVIEW – MECHANISMS?

BOOKS REFERENCED

“Essential Psychopharmacology” by Stephen M. Stahl

“Principles and Practice of Psychopharmacotherapy” by Janicek et al

“The American Psychiatric Publishing Textbook of Neuropsychiatry & Behavioral Neuroscience” by Yudofsky et al

“Massachusetts General Hospital Handbook of General Hospital Psychiatry” by Stein el al

“Marbles: Mania, Depression, Michelangelo & Me” by Ellen Forney

Also recommended: “Psychiatric Tales” by Daryl Cunningham