L14 Mood Stabilisers Flashcards
What are the diagnostic symptoms of Mania?
Elevated Irritable Mood
- Risks
- Pressured Speech
- Racing Thoughts
- Distractible
- Grandiosity
- Self-confident
- Making plans
- Aggression
- Psychosis
- Impulsivity
- Social Disinhibition
What are the symptoms of depression?
- Anhedonia
- Self Depreciation
- Hopelessness
- Suicidal ideas/ plans
- Loss of Interest
- Guilt
How is Bipolar Disorder classified?
- 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
Bipolar Disorder - Epidemiology
Common illness affecting 2% of the world population (5% if one includes spectrum disorders)
6th leading cause of medical disability in the developed nations
What are the problems associated with Bipolar disorder?
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
Outline the causes of Bipolar Disorder
- 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
Outline the Neurochemistry of mania
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
The Dopamine Pathway
What occurs in mania?
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.
Noradrenaline Pathways
What are the principle noradrenaline centres in the brain?
What happens in mania?
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.
Serotonin Pathway
What happens in Mania?
The transmission of serotonin is thought to be increased in mania compared with a non-diseased brain (throughout the brain).
GABA Pathways
- What is GABA
- Where does it act?
- What happens in mania?
- the main inhibitory neurotransmitter in the central nervous system (CNS)
- 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.
- decreased GABA function in all GABAergic pathways in depressed and manic states.
What are the treatment challenges in Bipolar Disorder?
Often unrecognized
Often untreated
Often misdiagnosed
Often inadequately treated
Exacerbated by incorrect treatment
Outline Evolution of Therapies for Bipolar Disorder
Ect, Lithium, First Generation antiPs and antiDs (eg. Chlorpromazine), Anticonvulsants (Carbamazepine, Valproate), other Anticonvulsants (Lamotrigine), then Second Generation antiPs and antiDs (Clozapine)
What is a mood stabiliser?
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
Outline the history of Lithium use
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
Lithium
- What are the indications?
- What are the possible mechanisms of action?
- Acute mania and hypomania, Prophylaxis in bipolar disorder and recurrent depression, Antidepressant augmentation, Aggression (controversial)
-
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)
Lithium
- What is the starting dose?
- What should be monitored then?
- How?
- 400mg/day (200mg in elderly or renal impairment)
- 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.
- All samples 12 hours post dose
Withdraw slowly
Lithium
- What are the precautions with excretion?
- What are the other precautions?
- 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.
- 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.
Lithium
- What are the contraindications?
- What are the side-effects?
- Pregnancy
Breast-feeding
Renal impairment
Thyroidopathies
Sick sinus syndrome
- 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
Lithium
- What are the signs of toxicity?
- What are the main drug interactions?
- nausea, vomiting, diarrohea, coarse tremor, ataxia. At higher levels: slurring of speech, convulsions, coma. treatment essential
- 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
Lithium Levels should be monitored
- What is the half life?
- What is the target level?
- What should the levels NOT exceed?
- 18-24 hours; steady state 4-5 days; draw levels 12 hours post-dose, usually prior to the morning dose
- 0.6-1/2mEq/L
- 1.5mEq/L
Anticonvulsant Drugs
- Outline the main actions
- How do they stabilise mood?
- 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.
Carbamazepine
- What is the starting dose?
- What is the target range?
- Why can concentration decrease over time?
- When should it’s levels be monitored?
- 200 mg bd, slowing increasing to 600-1000 mg/day.
- 8-12 mg/l
- Induces own metabolism-plasma concentration can decrease over time even with fixed dosage, because of autoinduction of liver enzymes
- 2-4 weeks until stable and then every 3-6 months
Carbamazepine
- What are the precautions?
- What are the signs of toxicity?
- What are the contraindictations?
- What are the side-effects?
- 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.
- severe diplopia, nausea, ataxia, sedation
- pregnancy, breast-feeding
- 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.
Carbamazepine
What are the drug interactions?
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.
Valproate
- What are the uses?
- What are the advantages?
- What forms are available?
- acute mania and maintenance treatment of bipolar disorder:
- better tolerability than lithium, can be loaded rapidly, once-a-day formulation available
- 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
Valproate
- What is the starting dose?
- What is the dose range?
- What is a normal blood level? What is it affected by?
- What are the normal monitoring parameters?
- 500mg daily (Epilim) or 250 mg tds (Depakote), then increase until plasma levels reach 50-100mg/l
- 500 – 2000 mg per day (25mg/kg/day)
- 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).
- Trough levels required
Other common monitoring parameters: LFTs at baseline then frequently, especially during 1st 6months or if suspected hereditary mitochondrial disease.
Valproate
- What are the contraindications?
- What precautions need to be taken?
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
Valproate
- What are the common side effects?
- What are the rare side effects?
- What are the drug interactions?
- -nausea, vomiting -mild sedation -moderate weight gain -hair loss
- -ataxia -headache -thrombocytopenia, platelet dysfunction, pancytopenia –pancreatitis
- Complex interactions with other anticonvulsants
Potentiates activity of aspirin and warfarin
May increase MAOI and TCA levels
Increases lamotrigine levels
Lamotrigine
- What is the starting dose?
- What is the dose likely to be?
- What allows for once-daily dosing?
- What does dose depend upon?
- 25mg START LOW, INCREASE VERY SLOWLY
- Not certain, likely to be close to that used in epilepsy (50-200 mg/day)
- Linear pharmacokinetics & a half-life of 24 hours allows a once-daily dosing; rapid absorption & no clinical significant drug-drug interactions
- 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)
Lamotrigine
- What precautions should be taken?
- What are the contraindications?
- What are the side effects?
- What are the drug interactions?
- Monitor for rash -more likely in children; with valproate; if dose started too high or increased too quickly
- Pregnancy and hepatic impairment
- Rash, ataxia, vomiting, headache and diplopia
- Valproate increases levels of lamotrigine
Lamotrigine may increase levels of the active carbamazepine epoxide metabolite
What are the other Mood Stabilisers?
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
How can pychoeducation act as a mood stabiliser?
Reduces relapses of both mania or depression
Also reduces burden on family
Should be provided to patients and their carers
What is dysthymia?
Persistent mild depression
