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"Psychopharmacotherpay
in the
management of Bipolar Disorders"
by
Prof. K.Y. Mak
(Chairman, Society for Advancement of Bipolar Disorders;
Chairman, Asian Network of Bipolar Disorders)
What is a mood-stabilizer?
• No formal definition
• 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 bipolar disorder episodes (Bowden C, 1998,
Neuropsychopharmacol, 19, 194-199)
• NB ECNP (2000) a mood stabilizer needs not be efficacious for acute
mania or depression
Classification of mood stabilizers
• Class A: the primary acute & prophylactic effect by
treating the depressed phase, preventing or delaying manic
episodes without destabilizing the overall course of the
illness by exacerbation of depression. E.g. lithium
• Class B: the primary acute & prophylactic effect by
treating the manic phase, preventing or delaying depressive
episodes without destabilizing the overall course of the
illness. By exacerbation of manic. E.g. lamotrigine
• Ref.: Ketter & Calabrese (2002) J. Clin. Psychiat., 63, 146-151.
I. Lithium
• 1st medication for manic-depressive disorder
• Discovered by Cade in Australia
• Neurotoxic if overdose – thus serum level
monitoring needed
• Common side-effects: polyuria & polydipsia, hand
tremor
• Toxic side-effects: neuroleptic malignant
syndrome (+ haloperidol)
• ?controversy as 1st line treatment (especially in
primary care)
II. Anti-epileptic Drugs
• It was noted that AED improves mood in some
epileptic patients, & was helpful in stabilizing
mood in patients with epilepsy & bipolar disorder
• Antiepileptic actions:
– 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
Various anti-epileptics
• valproate (divalproex) - esp. mania/mixed
• carbamazepine /oxcarbazepine - esp.
mania/mixed
• lamotrigine - esp. BP-D/rapid cycling
• topiramte - mania/mixed, esp. rapid cycling
• Gabapentine/pregabalin - analgesic
& ?anxiolytic effect
Common s/e
• GI upset: lithium valproate (SSRIs)
• Weight gain: valproate, lithium, carbamazepine;
clozapine, olanzapine, quetiapine & risperidone
• Glucose dysregulation: (antipsychotics)
• Sexual dysfunction: (SSRIs, antipsychotics)
• Cognitive impairment: lithium, topiramate,
carbamazepine (typical antipsychotics)
• Dermatologic reactions: lamotrigine, valproate,
carbamazepine
• Tremor: lithium, valproate
1. Sodium valproate (Epilim)
• Also in the form of divalproex sodium (delayed release)
• Dose range: start with 500 – 2000 mg per day
(25mg/kg/day)
• Normal blood level: 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 maybe more important).
• Contraindicated in acute liver disease or family history of
liver dysfunction, thus LFT at baseline and during first 6
months; perhaps pancreatic function
• Half-life shortened by CBZ & others
Comparing lithium with VPA
• Li > VPA in suicide (high risk in mixed state,
bipolar depression & those with comorbidities)
• VPA > Li in longterm maintenance Rx of mania &
prevent relapse
• VPA > Li in comorbid alcohol abuse (only 1 study
by Salbourn et al, 2005)
• VPA = Li in rapid cycling
• High dropout rate for Lamotrigine in rapid cycling
2. Carbamazepine (Tegretol)
• 600mg – 1600 mg/day (4-12 μg/ml serum level)
• S/e: nausea/vomiting, fatigue, dizziness, tremor, cognitive
changes; rash (15%), Stevens-Johnson syn (0.1-0.5%)
• plasma concentration can decrease over time even with
fixed dosage, because of autoinduction of liver enzymes
• drug-drug interaction (3A4 P450):
– increased concentration with verapamil, cimetidene,
erythromycin, isoniazid, etc
– decreased concentration with phenytoin,
phenobarbitone, etc.
3. Oxcarbazepine (Trileptal)
• A prodrug (congener), improve tolerability cf to
carbamazepine
• May induce thrombocytopenia, but no need for monitor
haematologic parameters
• Start with 600mg bid up to 2,400mg/day (50% higher than
CPZ)
• 27% cross sensitivity with CPZ, some induction at
CYP3A4, less drug-drug interactions, leucopenia or rash
• Switching from CPZ can be immediate (overnight) or
progressive (in a few weeks), though high dose of CPZ
may be switched slowly because of its autoinduction
effects (Albani et al. Seizure, 2004, 13, 254-163)
4. Lamotrigine (Lamictal)
• As mono or adjunctive therapy, dosage: 100-400mg/day
(slow titration upwards); minimal s/e profile (esp body wt
& cognitive function), thus better compliance
• Acute Rx of bipolar depression I, as maintenance Rx &
for rapid-cycling BP II (no antimanic properties), &
perhaps BP I recently manic or depressed
• Less effective for mixed episode, rapid cycling
• perhaps for borderline PD & schizoaffective disorder, also
for migraine, impulsivity & compulsivity
• Linear pharmacokinetics & a half-life of 24 hours allows a
once-daily dosing; rapid absorption & no clinical
significant drug-drug interactions
Dosing of lamotrigine in adults &
adolescents (once daily nocte)
•
•
•
•
•
•
•
•
Week
Daily dose (mg)
1
25
2
25
3
50
4
50
5
100
6
200
NB 50% dose with valproate & 200% with carbamazepine;
cautin if on birth control pills (increased during the active
hormone days, but reduced during the off hormone days)
•
Ref: Calabrese et al, J Clin Psychiat 2002, 63, 1012-1019
5. Gabapentine (Neurontin)
• High therapeutic index: not bound to protein, no
hepatic metabolism
• benign s/e profile (somnolence, dizziness, ataxia
& fatigue)
• Other s/e: thyroiditis, renal impairment (nephrotic
syndrome), sex dysfunction, 1 case of catatonia
• Not potent as monotherapy mood stabilizer
(perhaps better for depression than with mania)
• Good: as adjunctive if comorbid anxiety (or
neuropathic pain)
6. Topiramate (Topamax)
• Minimal drug interactions, 200-300mg/day
• s/e: slow thinking (memory), sedation, nausea, diarrhoea,
headache, paraesthesia & tremor
• rare s/e: metabolic acidosis (carbonic anhydrase inhibition
increase excretion of bicarbonate) – urinary stones, acute
myopia & secondary angle closure glaucoma (mostly
reversible), metabolic acidosis and oligohidrosis
• a few reported cases of severe hepatotoxicty, but usually in
combination with other medications (Bjoror et al, Lancet, 1998, 352:
1119; Doan & Clendenning, Can J Psychiat, 2000, 45, 937-938)
Combination AEDs/Li
• Lithium + valproate: increasing use
(Solomon, 1997)
• Lithium + carbamazepine: effective for
resistant BAD (Bochetta 1997), for rapidcycling (Schifano); but risk of neurotoxicity
• Valproate + carbamazepine: synergistic
effect; but interaction via enzymatic
induction/inhibition
Monitoring of AED
• Lithium: serum level q3 months (0.4-0.8 mmol/l);
TSH & electrolytes, RFT q6-12mo
• CBZ: serum level q3 months (17-50umol/l); LFT
q3-6 mo; CBP q3-6mo; electrolytes q3-6mo
• VAP: serum level q3mo (300-700umol/l); LFT q36mo; CBP q3-6mo
• Lamotrigine: nil needed
•
Ref: Roayl Australian & New Zealand College of Psychiatrists Clinical Practice
Guidelines Team for Bipolar Disorder. ANZJPsychiat, 2004, 38, 280-305
III. Neuroleptics
• Usually during the acute manic stage (esp mixed
state), faster effect, similar efficacy as lithium,
good for control of severe anxiety, agitation
/aggression, hyperactivity and psychotic features
• Onset is faster, but high dosage needed, with risks
of EPS
• Typicals useful for manic episode, but may trigger
depressive swing
• Atypicals appears better including olanzapine,
quetiapine, ziprasidone, etc.
Atypical antipsychotics
• DA antagonistic effects help hypomania and
psychotic symptoms
• 5HT2A/2C antagonistic activities: improve
anxiety and mood symptoms
• Probably inhibit NE reuptake also improve mood
• Thus may also be called Mood Stabilizers
• especially good for acute mania & manic mixed
state, rapid cycling & perhaps treatment resistant
cases
AED cf neuroleptics (1)
• AED
– Avoid symptomatic Rx (whole life history)
– Prevent switching
– Evidence-based: lithium still most effective monoRx,
good for suicide (Goodwin et al, 2003, JAMA)
– Prevention after acute depression
– Neuroprotection
– Less expensive & side-effects profile good (for some)
AED cf neuroleptics (2)
• Atypicals
–
–
–
–
Early onset of action & symptom relief
Easy drug titration – relatively safe, especially atypicals
Some bimodal action
Wide spectrum of effects, particularly for agitation &
psychotic s/– Side-effect profile better (for some), though occasional
severe e.g. NMS
– A few available in IMI form (early or delayed effect)
– NB typicals may sometimes be more effective for acute
mania (in the short-term)
AED + atypicals
• Good for preventing swing
• Especially if antidepressants (TCA in
particular) given
• But lithium may induce side-effects of
antipsychotics, including TD
• Neuroleptic malignant syndrome?
Maintenance with atypicals
• After a severe psychotic manic episode
• Relapse after discontinuation of
antipsychotic
• Those with predominant manic episodes
• Partial/full refractory to mood stabilizers
• Those who tolerate antipsychotics well
• NB include long-acting injections
Clozapine (Clozaril)
•
•
•
•
•
No documented double-blind trials so far
Low D2 antagonist effect
Left ventricular shortening
Perhaps useful for acute mania
Can be an adjunctive to lithium & AED
Risperidone (Risperdal)
• Effective as monotherapy for moderately severe
mania; effective as combination therapy (with
anticonvulsants) for moderate & severe mania
• Adverse effects: somnolence, EPS, weight gain
• Use of risperidone monotherapy for severe mania
or in maintenance treatment remains to be
elucidated
•
Ref: Nguyen LN & Guthrie, SK (2006) Ann Pharmacother, 4f0, 674-682
Olanzapine-fluoxetine combination
• Atypical + SSRI for bipolar depression
• OFC (Symbyax) for BP I depression
found OFC statistically & clinically
significant cf to olanzapine or placebo,
without sig differences in treatmentemergent mania Ref: Token et al (2003) Arch Gen Psychiat,
60, 1079-1088
Quetiapine (Seroquel)
• Quetiapine is an antipsychtoic and antimanic by virtue of
its dopamine D2 and serotonin 5HT2A antagonism; and
• Low dose – antihistaminergic effect; high dose –
antidopaminergic effect
• appears to exert its antidepressant activity in bipolar
depression via its active metabolite norquetiapine (Ndesalkyl quetiapine), which is a potent inhibitor of NE
transporter & a partial agonist of 5HT1A receptor. (Goldstein et
al, Biological Psychiatry 2007;61:124S-125S)
• Nor-quetiapine also is a 5HT2C antagonist & alpha-2
adrenergic receptor antagonist.
Ziprasidone (Zeldox)
• A benziso-thiazolyl piperazine
• Potent 5HT2A & D2 antagonist
• A full agonist for 5HT1A & antagonist for %HT2C & 1D,
with >10-fold higher affinity than for DA
• Low affinity for α1-adrenoceptor – thus less orthostatic
hypotension
• Also in vitro SNRI (clinical extent not clear)
• Effective for bipolar I manic or mixed episodes with or
without psychosis
• Metabolised via CYP3A4, but minimal drug-drug
interaction
Aripiprazole (Abilify)
• 3 week, multicenter double-blind RCT 262 acute
manic /mixed episode
• 30mg/day aripiprazole (reduced to 15mg if needed
for tolerability) cf to placebo
• Results: statistically significant YMRS improved
(-8.2 vs -3.4) & higher response rate (40% vs
19%), efficacy obvious by day 4 & completion
rate was higher (42% vs 21%). Discontinuation &
changes in BW no difference
•
Ref: Keck et al (2003) Am J Psychiat, 160, 1651-1658).
III. Benzodiazepines
• Clonazepam, diazepam & lorazepam act on
GABA post-synaptic receptor complexes,
enhancing release of GABA & opening of
Cl channels
• Good for acute mania (as for neuroleptics)
as brief adjunct therapy, but high dose
needed
• Not recommended for maintenance dose
IV. Antidepressants for BP
• Antidepressants are effective, but may trigger a
switch into mania (especially TCA, SNRI)
• Combine antidepressant with a mood stabilizer (Li
or anticonvulsant or antipsychotic) to avoid mania
• Paroxetine/fluoxetine & risperidone may increase
risperidone serum level, but decrease level of its
active metabolite, thus lower dosage of risp &/or
SSRI
V. Guidelines - acute mania
• CBZ, VPA & Li are equipotent, but
limitations as monotherapy
• Li relatively ineffective in mixed disorder
• Oligotherapy (minimal number of
medications used) rather than polypharmacy
is better: mood stabilizer & neuroloptics &
another mood stabilizer (eg Li & CBZ)
Guidelines for BP depression
• Lithium or lamotrigine
• 2nd mood stabilizer (especially for rapid cyclers);
• Adjunctive antidepressants (not recommended except with
lithium for more serious condition or those intolerant of
high lithium dose)
• Adjunctive antipsychotics if psychotic features present
(though quetiapine found useful as monotherapy)
• Atypicals for refractory condition (or psychotic features)
• Augmentation with tri-iodothyronine may be considered
• BDZ for coexisting anxiety or insomnia
• ECT & TMS (transcranial magnetic stimulation)
Guidelines for maintenance Rx
• Monotherapy with lithium or valproate
• Newer atypicals as alternatives
• Optimize medications effective in most
recent episode
• Combination therapy for sub-threshold
symptoms or breakthrough mood episodes
• Avoid antidepressants as monotherapy
Discontinuation of maintenance
• Risk-benefits balance e.g. planned
pregnancy
• Should be tapered down, at least 2 weeks
• Abrupt withdrawal of lithium often induce
manic episode
• Risk of relapse remains, even after years of
sustained remission
AED & pregnancy
• Safest is ECT
• Crude rates for risk of major congenital
malformation were 4% for 1 drug, 6.3% if
>1, cf. to 0.9% for those not on AED
• Lthium (Epstein’s cardiac anolomy); CPZ &
VLP (renal tube defects, thus add folic acid
0.4mg/day)
• CPZ: 2.3%, valproate: 7.2%, lamotrigine:
3%; other drugs not known
•
Ref: NICE. Epilepsy. 2nd Consultation, March 2004http://www.nice.org.uk/page.aspx?o=108913
AED & breastfeeding
• Woman’s historical response as guidance
• Carbamazepine & valproate but not lithium have generally
been considered compatible with breastfeeding, but data
are scarce
• Beware sof sudden withdrawal seizure
• Neurotoxic effect: floppy baby, EPS
• May increase prevalence of NNJ
• A review (Chaudron & Jefferson, 2000, J Clin Psychiat., 61, 79-90) found 11
lithium cases (2 had toxicity in infants), 39 valproate (1
report low PL & RBC), 50 CPZ (2 hepatic dysfunction), 1
gabapentin & 3 lamotrigine use.
Psychoeducation is mood stabilizer?
• Reduces relapses of both mania or
depression
• Also reduces burden on family
• Should be provided to patients and their
carers
Conclusion
• Early treatment is important
• Maintenance is recommended to prevent relapse
• Frequent relapse cause enduring brain damage and
refractory to treatment
• Monotherapy is now steadily replaced by
polypharmacy (synergy)
• Besides medications, psychosocial therapies are
important (including compliance therapy)