L14 Mood Stabilisers

Question 1

What are the diagnostic symptoms of Mania?

Answer 1

Elevated Irritable Mood

• Risks
• Pressured Speech
• Racing Thoughts
• Distractible
• Grandiosity
• Self-confident
• Making plans
• Aggression
• Psychosis
• Impulsivity
• Social Disinhibition

Question 2

What are the symptoms of depression?

Answer 2

• Anhedonia
• Self Depreciation
• Hopelessness
• Suicidal ideas/ plans
• Loss of Interest
• Guilt

Question 3

How is Bipolar Disorder classified?

Answer 3

• Bipolar 1: —full manic and depressive episodes
• Bipolpar 2: —one hypomanic and one full depression
• Bipolar 3: —depressive episode with antidepressant induced mania
• Bipolar Depression
• Mixed states
• Rapid cycling
• Cyclothymia

Question 4

Bipolar Disorder - Epidemiology

Answer 4

—Common illness affecting 2% of the world population (5% if one includes spectrum disorders)

—6th leading cause of medical disability in the developed nations

Question 5

What are the problems associated with Bipolar disorder?

Answer 5

—Particularly recalcitrant mental health problem

—Symptomatic at least half the time

—Can have impaired social function even when symptom-free

—Prominent cognitive abnormalities

—> 50% alcohol and/or other substance abuse

—80% of patients exhibit significant suicidality, About 50% attempt suicide, About 15% succeed

Question 6

Outline the causes of Bipolar Disorder

Answer 6

• —Highly heritable (80% genetic contribution)
  
  • Multiple genes
  • 16 different chromosomal regions
• —Structural and Functional Brain Abnormalities
  
  • amygdala, anterior cingulate and prefrontal cortex, putamen, thalamus/hypothalamus

Question 7

Outline the Neurochemistry of mania

Answer 7

—In general there is evidence of increased hyperactivity of monoamines

—Circuits appear to be “Out of tune”

—There are difficulties in explaining co-existing depression and mania

—Neurchemistry is complex- dopamine, noradrenaline, serotonin and GABA are all involved

—Glutamate may also be involved

Question 8

The Dopamine Pathway

What occurs in mania?

Answer 8

—In mania there is an increase in dopamine transmission from the substantia nigra to the neostriatum which is associated with increased sensory stimuli and movement.

—Dopamine transmission in the ventral tegmentum and the tubero-infundibular, remains unchanged in mania compared with a non-diseased brain.

Question 9

Noradrenaline Pathways

What are the principle noradrenaline centres in the brain?

What happens in mania?

Answer 9

—the caudate nuclei and the locus coeruleus.

—The transmission of noradrenaline from both of these centres to all areas of the brain is thought to be increased in mania compared with a non-diseased brain.

Question 10

Serotonin Pathway

What happens in Mania?

Answer 10

—The transmission of serotonin is thought to be increased in mania compared with a non-diseased brain (throughout the brain).

Question 11

GABA Pathways

1. What is GABA
2. Where does it act?
3. What happens in mania?

Answer 11

1. the main inhibitory neurotransmitter in the central nervous system (CNS)
2. all levels of the CNS, including the hypothalamus, hippocampus, cerebral cortex and cerebellar cortex. —As well as the large well-established GABA pathways, GABA interneurones are abundant in the brain, with 50% of the inhibitory synapses in the brain being GABA mediated.
3. —decreased GABA function in all GABAergic pathways in depressed and manic states.

Question 12

What are the treatment challenges in Bipolar Disorder?

Answer 12

—Often unrecognized

—Often untreated

—Often misdiagnosed

—Often inadequately treated

—Exacerbated by incorrect treatment

Question 13

Outline Evolution of Therapies for Bipolar Disorder

Answer 13

Ect, Lithium, First Generation antiPs and antiDs (eg. Chlorpromazine), Anticonvulsants (Carbamazepine, Valproate), other Anticonvulsants (Lamotrigine), then Second Generation antiPs and antiDs (Clozapine)

Question 14

What is a mood stabiliser?

Answer 14

A medication that alleviates the frequency &/or intensity of manic, hypomanic, depressive or mixed episodes in bipolar disorder patients, and does not increase frequency or severity of any of the types of bipolar disorder episodes

Question 15

Outline the history of Lithium use

Answer 15

—Naturally occurring salt and was original mood stabiliser

—1845-1860 used in treatment of gout

—Late 1940’s and early 1950’s lithium salts used widely as a salt substitute in cardiac patients (a dangerous approach) and John Cade first used in psychiatric patients

—Early 1970’s first RCT

Question 16

Lithium

1. What are the indications?
2. What are the possible mechanisms of action?

Answer 16

1. —Acute mania and hypomania, —Prophylaxis in bipolar disorder and recurrent depression, Antidepressant augmentation, Aggression (controversial)
2. Signal Transduction beyond the post synaptic neurotransmitters may be key to efficacy:
   - Inhibits second messenger enzymes
   - Modulation of G proteins
   - Signal transduction cascades further down

(Also has a role in increasing synaptic plasticity)

Question 17

Lithium

1. What is the starting dose?
2. What should be monitored then?
3. How?

Answer 17

1. —400mg/day (200mg in elderly or renal impairment)
2. —Monitor plasma levels every 5-7 days until level 0.6-1.0 mmol/l. —Levels thereafter every 3-6 months unless reasons to be concerned.
3. —All samples 12 hours post dose

—Withdraw slowly

Question 18

Lithium

1. What are the precautions with excretion?
2. What are the other precautions?

Answer 18

1. —Excreted exclusively through kidneys and potentially nephrotoxic-small reduction in GFR in 20%, rare cases of interstitial nephritis. Also rarely causes nephrogenic diabetes insipidus-may inhibit ADH. —Changes in body salt concentrations are important. Check U&E and serum creatinine prior to commencement.
2. —Significant proportion develop hypothyroidism.

—Thyroid Function Tests before starting and at 6 monthly intervals.

—If problems develop treat with thyroxine.

—TFT’s usually return to normal after stopping lithium.

Question 19

Lithium

1. What are the contraindications?
2. What are the side-effects?

Answer 19

1. —Pregnancy

—Breast-feeding

—Renal impairment

—Thyroidopathies

—Sick sinus syndrome

2. —Nausea, GI upset

—Fatigue, muscle weakness

—Muscle weakness

—Polydipsia, polyuria

—Tremor (may respond to propranolol)

—Weight gain common (?related to thirst and intake of high calorie drinks)

—Cardiac arrhythmias (ECG prior to treatment)

—Acne, exacerbation of skin problems

Question 20

Lithium

1. What are the signs of toxicity?
2. What are the main drug interactions?

Answer 20

1. —nausea, vomiting, diarrohea, coarse tremor, ataxia. At higher levels: slurring of speech, convulsions, coma. treatment essential
2. —Antipsychotics-?increase in neurotoxicity/neuroleptic malignant syndrome with haloperidol (rare)

—Diltiazem/verapamil may also rarely be linked to neurotoxicity

—Diuretics-increase lithium concentrations

—ACE inhibitors-toxicity

—NSAID’s-toxicity (except aspirin and sulindac, low dose ibuprofen usually safe)

—Alcohol-increases peak concentration

Question 21

Lithium Levels should be monitored

1. What is the half life?
2. What is the target level?
3. What should the levels NOT exceed?

Answer 21

1. 18-24 hours; steady state 4-5 days; draw levels 12 hours post-dose, usually prior to the morning dose
2. 0.6-1/2mEq/L
3. —1.5mEq/L

Question 22

Anticonvulsant Drugs

1. Outline the main actions
2. How do they stabilise mood?

Answer 22

—

1. enhance inhibitory process (mainly GABA mediated), involving Cl- ion fluxes

——Decrease excitatory process (mainly glutamate mediated), involving Mg++ & Ca++ ion fluxes

—Modulate membrane cation conductance (Na+, Ca++ or K+) by effects on membrane receptors or transport mechanisms for these ions which modulate signal transduction in the neuron system

—2. It is unclear how anticonvulsants work to stabilise mood. It was noted that anticonvulsants improve mood in some epileptic patients, & are helpful in stabilising mood in patients with epilepsy & bipolar disorder

—Some theories indicate that these drugs work in the same way that they act to control seizure activity. The only difference is that they work on a different part of the brain.

Question 23

Carbamazepine

1. What is the starting dose?
2. What is the target range?
3. Why can concentration decrease over time?
4. When should it’s levels be monitored?

Answer 23

1. 200 mg bd, slowing increasing to 600-1000 mg/day.
2. —8-12 mg/l
3. —Induces own metabolism-plasma concentration can decrease over time even with fixed dosage, because of autoinduction of liver enzymes
4. —2-4 weeks until stable and then every 3-6 months

Question 24

Carbamazepine

1. What are the precautions?
2. What are the signs of toxicity?
3. What are the contraindictations?
4. What are the side-effects?

Answer 24

1. —Early leucopenia (20%) usually transient and benign but later problems may be serious, Warn about fevers and infections etc, Baseline FBC and every 2 weeks for first 2 months then every 3-6 months.
2. severe diplopia, nausea, ataxia, sedation
3. pregnancy, breast-feeding
4. —Nausea/vomiting, fatigue, dizziness, tremor, cognitive changes;

—Agranulocytosis: 1 in 20,000

—Aplastic anaemia: 1 in 20,000

—Hypersensitivity-hepatitis

—Rashes in 15% of cases-may be serious. Toxic epidermal necrolysis (Stevens-Johnson syndrome) in 1 in 20,000.

Question 25

**Carbamazepine** What are the drug interactions?

Answer 25

—**Antipsychotics**: may add to CNS effects (drowsiness, ataxia etc) —**Lithium**: CNS effects and increased SE’s of both drugs —**Ca channel blockers**: CNS effects —**MAOI’s**: need 2 weeks washout —?toxicity with flu vaccine **—Enzyme inducer**(3A4 P450): -increased concentration with verapamil, cimetidene, erythromycin, isoniazid, etc -decreased concentration with phenytoin, phenobarbitone, etc.

Question 26

**Valproate** 1. What are the uses? 2. What are the advantages? 3. What forms are available?

Answer 26

1. —acute mania and maintenance treatment of bipolar disorder: 2. better tolerability than lithium, can be loaded rapidly, once-a-day formulation available 3. **—Sodium valproate** (Epilim)-licensed for treatment of **epilepsy** —**Valproic acid** (Convulex)-licensed for treatment of epilepsy **—Semisodium valproate** (Depakote)-licensed for treatment of **acute mania** but not for prophylaxis

Question 27

**Valproate** 1. What is the starting dose? 2. What is the dose range? 3. What is a normal blood level? What is it affected by? 4. What are the normal monitoring parameters?

Answer 27

1. —500mg daily (Epilim) or 250 mg tds (Depakote), then increase until plasma levels reach 50-100mg/l 2. 500 – 2000 mg per day (25mg/kg/day) 3. —45-125 μg/ml, but _level affected by protein binding_ (reduced in the elderly & those with renal/liver disease, and hyperlipidaemia (thus neurotoxicity can occur in apparently normal serum level, and free valproic acid level may be more important). 4. —Trough levels required —Other common monitoring parameters: **LFTs** at baseline then frequently, especially during 1st 6months or if suspected hereditary mitochondrial disease.

Question 28

**Valproate** 1. What are the contraindications? 2. What precautions need to be taken?

Answer 28

—1. Pregnancy —Breast-feeding —Hepatic disease 2. —**Check renal and hepatic function** at baseline and then 6 monthly —Contraindicated in acute liver disease or family history of liver dysfunction, thus **LFT** at baseline and during first 6 months; perhaps effect on pancreatic function **—Half-life shortened by CBZ** —Check **FBC** at baseline, then 6 monthly

Question 29

**Valproate** 1. What are the common side effects? 2. What are the rare side effects? 3. What are the drug interactions?

Answer 29

1. —-nausea, vomiting -mild sedation -moderate weight gain -hair loss 2. —-ataxia -headache -thrombocytopenia, platelet dysfunction, pancytopenia --pancreatitis 3. —**Complex interactions with other anticonvulsants** **—Potentiates activity of aspirin and warfarin** **—May increase MAOI and TCA levels** **—Increases lamotrigine levels**

Question 30

**Lamotrigine** 1. What is the starting dose? 2. What is the dose likely to be? 3. What allows for once-daily dosing? 4. What does dose depend upon?

Answer 30

1. 25mg START LOW, INCREASE VERY SLOWLY 2. —Not certain, likely to be close to that used in epilepsy (50-200 mg/day) 3. —Linear pharmacokinetics & a half-life of 24 hours allows a once-daily dosing; rapid absorption & no clinical significant drug-drug interactions 4. Concomitant medication —NB 50% dose with valproate 200% with carbamazepine; caution if on birth control pills (increased during the active hormone days, but reduced during the off hormone days)

Question 31

**Lamotrigine** 1. What precautions should be taken? 2. What are the contraindications? 3. What are the side effects? 4. What are the drug interactions?

Answer 31

1. —Monitor for **rash** -more likely in children; with valproate; if dose started too high or increased too quickly 2. Pregnancy and hepatic impairment 3. Rash, ataxia, vomiting, headache and diplopia 4. —**Valproate** _increases levels of lamotrigine_ —**Lamotrigine** may _increase levels of the active carbamazepine epoxide metabolite_

Question 32

What are the other Mood Stabilisers?

Answer 32

**omega-3 fatty acids/Fish oil** * —"Natural"; biggest known risk is "seal burps" * —Milder symptoms, can risk a weaker agent * —Willing to take a lot of pills, or swallow (flavored) fish oil **—verapamil** * —Possible alternative for **pregnancy** * —Low side effect risk

Question 33

How can pychoeducation act as a mood stabiliser?

Answer 33

—Reduces relapses of both mania or depression —Also reduces burden on family —Should be provided to patients and their carers

Question 34

What is dysthymia?

Answer 34

Persistent mild depression