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