CLINICAL OVERVIEW OF LITHIUM
Dr Rana Fahmy
Specialist Registrar
Wandsworth Early Intervention in Psychosis Service
• When should lithium be used?
• Mechanism of action
• Clinical use of lithium
• Lithium monitoring
• NPSA alert and launch of the patient lithium pack
Overview
• When should lithium be used? Bipolar disorder
• Mania• (bipolar depression)• Prophylaxis
Unipolar depression• Treatment refractory depression
Overview
Bipolar Mania
5
Treatment of acute mania:lithium or divalproex versus placebo
Bowden et al., JAMA 1994
30
14
Placebo
Divalproex
Lithium
Ma
nia
ra
tin
g s
cal
e
14 217Days
Effectiveness of lithiumPrevious Manic Episodes and Response
Swann et al, 2000
1010
88
66
44
22
0000 22 44 66 88 1010 1212 1414 1616 1818
Previous manic episodesMa
nic
sy
nd
rom
e s
core
imp
rov
eme
nt
PlaceboLithiumDivalproex
Effectiveness of lithium in acute mania
70
3030
35
6565
25
7575
00
1010
20203030
4040
5050
6060
70708080
9090
100100
.With ‘classic’ maniaWith ‘classic’ mania With mixed maniaWith mixed mania With rapid cyclingWith rapid cycling
Lithium respondersLithium responders Lithium non-respondersLithium non-responders
Adapted from: Calabrese, Bowden & Woyshville (1995)Adapted from: Calabrese, Bowden & Woyshville (1995)
Acute Mania: NICE guidelines
• Stop antidepressant (if taking) either abruptly or gradually
• Atypical antipsychotic (olanzapine, risperidone, quetiapine) for those with severe mania If ineffective consider adding Li or valproate
• Valproate or Li if previous good response and compliance Avoid valproate in women of child bearing
potential Li only if less severe
Bipolar Depression
Lithium in acute BP Depression: An 8 week, DB monotherapy study vs PLC
• n= 267 • Lithium did not
separate from PLC for any outcome
Young et al, presented at ISBD 2008, Delhi, Januar26-30
+
+ p< 0.123 vs PLC
• Guidelines (e.g. NICE, BAP) unclear due to current lack of evidence Suggestion that antidepressants of limited utility Most guidelines recommend optimisation of mood
stabilisers (e.g. lithium)
• Evidence re lithium Probably ineffective as monotherapy May be useful in combination (e.g. with lamotrigine) May decrease suicidality independently
Bipolar depression
Bipolar Prophylaxis
Lithium v placebo, maintenance in bipolar disorder
Bipolar prophylaxis: NICE guidelines
• First line: lithium, olanzapine or valproate
• If fails monotherapy over 6 months Li + valp, Li + olanz, Valp + olanz
• If combination fails Consider lamotrigine (esp. BPII), carbamazepine,
referral to tertiary centre
Unipolar depression:
Treatment refractory depression
Lithium augmentation in TRD: placebo controlled studies
Crossley & Bauer 2007
40% 17%Response
Treatment refractory depression: BAP guidelines
• consider adding lithium (A), olanzapine (A), quetiapine (B), risperidone (B), aripiprazole (B), tri-iodothyronine (B) or mirtazapine (B) Be aware that the evidence mainly
supports Li and T3 added to TCAs and the other drugs added to SSRIs
• When should lithium be used?
• Mechanism of action
• Clinical use of lithium
Overview
• When should lithium be used?
• Mechanism of action
• Clinical use of lithium Stopping/starting Side effects & toxicity Use in pregnancy
Overview
From Suppes et al, 1991.
Effects of Rapid discontinuation of Li in BP-I Patients
Pe
rce
nt
rem
ain
ing
in r
em
issi
on
100
80
60
40
20
0
0 10 20 30 40
Time after stopping Lithium (months)
Gradual (N=15)
Rapid (N=108)
Effect of lithium withdrawal on long term usage
00
2020
4040
6060
8080
100100
120120
00 33 66 99 1212 1515 1818 2121 2424 2727 3030Time (months)Time (months)
50% relapse brought forward 21 months50% relapse brought forward 21 months
6 months stable on Li6 months stable on Li
No LiNo Li LithiumLithium
Minimum 27 months treatment for benefit
Minimum 27 months treatment for benefit
27 months stable on Li27 months stable on Li
Goodwin (1994) B.J.Psych.
Lithium Discontinuation: Suicide Risk
N = 310 310 185 133
Lithium Pharmacokinetics
• Carbonate or citrate salts rapid absorption in upper GIT peak levels after 2-3 hours total absorption may take 8 hours Preparations have differing bioavailability
• Narrow therapeutic index• Renal excretion at a constant rate proportional to
GFR• Steady state after 5-7 days• Levels obtained at 12 hours• Levels increased by NSAIDs, diuretics, ACE
inhibiters
Lithium Drug Interactions
DRUG GROUP MAGNITUDE OF EFFECT
TIMESCALE
ACE INHIBITORS •Unpredictable•Up to 4-fold increases in [Li]
Develops over several weeks
THIAZIDE DIURETICS
•Unpredictable•Up to 4-fold increases in [Li]
Usually apparent in first 10 days
NSAIDS •Unpredictable•From 10% to >4-fold increase in [Li]
Variable; few days to several months
Lithium dose in maintenance
• Multicentre study of patients with bipolar disorder randomised to low lithium levels (0.4 to 0.6 nmol/l) or higher levels (0.8 to 1.0)
• higher rates of adverse effects and poorer compliance in high levels group
• 2.6 fold higher rate of relapse with low lithium levels
• but highest risk of relapse was in those whose lithium levels were reduced
Gelenberg et al 1989; Rosenbaum et al 1992
Adverse effects of lithium
• Occur in 75% of patients• thirst, polydipsia, polyuria• weight gain and tremor• precipitates or worsens skin problems• mild impairment of attention and memory• T wave flattening/inversion in 30% patients• GI disturbance• leucocytosis
Adverse effects of lithium (cont)
• hypothyroidism and non-toxic goitre [5%] may lead to depression and/or rapid-cycling
• impaired renal tubular function [5-10%]
• impaired glomerular function [possible]
Lithium toxicity• usually inadvertent• signs appear at levels above 1.3 mmol/l• early
worsened side effects, nausea and vomiting, marked tremor, blurred vision, vertigo, confusion, hyperreflexia
• late disorientation, dysrythmia, convulsions, coma
• death results from cardiac effects or pulmonary complications
• can occur at therapeutic levels• EEG changes can be diagnostic
Use in pregnancy and lactation
• Major congenital anomalies in early pregnancy 4-12 % of births (cf 2-4% in untreated comparison groups)
• Cardiovascular anomalies in 0.05-1% includes Ebsteins anomaly [downward displacement of tricuspid
valve, arrhythmia, heart failure]
• Ebsteins is rare 1 in 2000 with Lithium (estimate) 1 in 20 000 in general population
• Use contraindicated in breast feeding Li excreted in breast milk
Lithium Monitoring
Source Serum Lithium
Target range (mmol/L)
U&Es and TFTs
BAP guideline 2003
3-6/12 0.5-1.0 (up to 1.5 in acute mania)
Every 12 months
NICE guideline bipolar 2006
3/12 0.6-0.8 (option of up to 1)
Every 6 months (U&Es more often if interacting drugs prescribed)
QOF targets
In last 6/12
‘in therapeutic range’
Within last 15 months
POMH UK
• Prescribing observatory for mental health UK• National case note audit of lithium monitoring
(Topic 7) (n= ~3000)• Renal function, thyroid function, lithium levels
and weight/BMI/waist circumference• Used NICE standards• 1 in 10 had no lithium level documented. 70%
did not meet NICE standard for lithium levels• Issues of documentation, shared care, access to
pathology results
Actions:1. Patients prescribed lithium are
monitored in accordance with NICE guidance
NICE specifies lithium blood levels are used to adjust dosage at least every 3 months and that thyroid function tests and renal function tests are undertaken every 6 months.
This level of monitoring is required as clinically observable side effects may not be apparent even with toxic levels
Actions:2. There are systems in place to
ensure that the results of blood tests are communicated between laboratories and prescribers.
Whether in primary or acute setting, levels must be available when dosing decisions are taken
Actions:
3. At the start of lithium therapy and throughout their treatment patients receive appropriate ongoing verbal and written information and a record book to track lithium blood levels and relevant clinical tests.
The NPSA with POMH-UK and the NPA have developed support material for this action
Actions:4. Prescribers and pharmacists
check that blood test are being monitored regularly and that test results are safe before issuing or dispensing repeat prescriptions.
Standard Operating Procedures (SOPs) will describe clear processes for both prescribing and dispensing that must be adhered to if monitoring falls below safe standards or patient are unwilling to share information.
Actions:5. Systems are in place to identify
and deal with medicines that might adversely interact with lithium therapy.
SOPs, decision support systems, patient medication records, patient records, inpatient charts, medication administration records reflect the need to identify and deal with potential interacting medicines whether on prescription or brought over-the-counter
• http://www.nrls.npsa.nhs.uk/alerts/?entryid45=65426