Mood-stabilizing drugs

Dr.safeya alchalabi

Mood-stabilizing drugs

Lithium

lithium is effective in a number of conditions, including the following:
the acute treatment of mania
the prophylaxis of unipolar and bipolar mood disorder
augmentation therapy in resistant depression
the prevention of aggressive behaviour in patients with learning disabilities.

Lithium

Despite problems with tolerability, lithium still remains the
gold
standard in the prophylactic treatment of bipolar affective disorder.

Lithium

Mechanism of action
lithium inhibits the formation of cyclic adenosine monophosphate (cAMP) . Through this actions lithium could exert profound effects on a wide range of neurotransmitter pathways.


Lithium
Dosage and plasma concentrations
Because the therapeutic and toxic doses are close together, it is essential to measure plasma concentrations of lithium during treatment.

Lithium

Interactions
angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor antagonists,
Analgesics (especially NSAIDs),
antidepressants (especially SSRIs),
antiepileptics,
antihypertensives (e.g. methyldopa),
Antipsychotics (especially haloperidol),
calcium channel blockers,
diuretics,
metronidazole.

Lithium

Interactions
antacids,
theophylline.
anti-arrhythmics (e.g. amiodarone: risk of hypothyroidism),
antidiabetics (may impair glucose tolerance),
antipsychotics ( risk of EPSEs),
muscle relaxants (enhanced effect),
parasympathomimetics (antagonizes neostigmine and pyridostigmine).


Guidelines on lithium therapy
Prior to commencing lithium therapy:
physical examination,FBC, U&Es, TFTs, renal function, baseline weight and height [body mass index (BMI)], if clinically indicated—ECG, pregnancy test.

Guidelines on lithium therapy

Prior to commencing lithium therapy:
Starting dose: usually 400–600mg given at night; weekly, depending on serum monitoring, to max 2g (usual dose 800mg–1.2g).

Guidelines on lithium therapy

Prior to commencing lithium therapy:
Monitoring: check lithium level 5 days after starting and 5 days after each change of dose. Take blood samples 12hr post-dose.

Guidelines on lithium therapy

Prior to commencing lithium therapy:
Once a therapeutic serum level has been established:continue to check lithium level/estimated glomerular filtration rate (eGFR) every 3mths, TFTs every 6mths, monitor weight (BMI), and check for side effects.

Guidelines on lithium therapy

Prior to commencing lithium therapy:
Stopping: reduce gradually over 1–3mths, particularly if the patient has a history of manic relapse (even if started on other antimanic agent).

Lithium

Unwanted effects
As lithium is a highly toxic ion, safe and effective therapy requires monitoring of serum levels.
Up to 75% of patients treated with lithium will experience some side effects.


Lithium
Dose-related side effects
Polyuria/polydipsia [reduced ability to concentrate urine due to antidiuretic hormone (ADH) antagonism],
weight gain (effects on carbohydrate metabolism and/or oedema),
cognitive problems (e.g. dulling, impaired memory, poor concentration, confusion, mental slowness),
tremor,
sedation or lethargy,
impaired coordination,
GI distress (e.g. nausea, vomiting, dyspepsia, diarrhoea),
hair loss,
benign leucocytosis,
acne,
oedema.

Lithium

Dose-related side effects
Management
Usually dealt with by lowering the dose of lithium, splitting the total daily dose, or changing the formulation.
If side effects persist, additional medications may be necessary, e.g. β-blockers (tremor),
thiazide or loop diuretics (polyuria, polydipsia, or oedema),
topical antibiotics or retinoic acid (acne).
GI problems can be managed by administering lithium with meals or switching from carbonate to citrate.


Lithium
Cardiac conduction problems
Usually benign ECG changes (e.g. T-wave changes, widening of QRS).
Rarely, exacerbation of existing arrhythmias or new arrhythmias due to conduction deficits at the sinoatrial (SA) or atrioventricular (AV) nodes (contraindicated in heart failure and sick sinus syndrome).

Lithium

Long-term effects
Renal function
Ten to 20% of patients on long-term therapy demonstrate morphological kidney changes (interstitial fibrosis, tubular atrophy, and sometimes glomerular sclerosis).
Over 1% may develop irreversible renal failure (rising serum creatinine levels) after 10yrs or more of treatment.
If urea and creatinine levels become elevated, assess the rate of deterioration
the decision whether to continue lithium depends on clinical efficacy and the degree of renal impairment;
seek advice from a renal specialist and a clinician with expertise in the management of bipolar disorder.

Lithium

Long-term effects
Subclinical/clinical hypothyroidism
Five to 35%, more frequent in women, tends to appear after 6–18mths of treatment, and may be associated with rapid-cycling bipolar disorder.
Although hypothyroidism is generally reversible on discontinuation of lithium, it is not an absolute contraindication for continuing lithium treatment, as the hypothyroidism is readily treated with levothyroxine.
In addition to the classic signs and symptoms of hypothyroidism, patients with bipolar disorder are also at risk of developing depression and/or rapid cycling as a consequence of suboptimal thyroid functioning.


Lithium
Teratogenicity
The much-quoted 400-fold increase risk of Ebstein’s anomaly (acongenital malformation of the tricuspid valve) due to first trimester lithium exposure
Other reported second and third trimester problems include polyhydramnios, premature delivery, thyroid abnormalities, nephrogenic diabetes insipidus, and floppy baby syndrome.

Lithium

Toxicity
The usual upper therapeutic limit for 12-hr post-dose serum lithium level is 1.2mmol/L.
With levels of >1.5mmol/L, most patients will experience some symptoms of toxicity;
>2.0mmol/L definite, often life-threatening, toxic effects occur.

Lithium

Toxicity
There is often a narrow therapeutic window where the beneficial effects outweigh the toxic effects (especially in older patients).

Lithium

Toxicity
Early signs and symptoms
Marked tremor, anorexia, nausea/vomiting, diarrhoea (sometimes bloody), dehydration, and lethargy.

Lithium

Toxicity
As lithium levels rise Severe neurological complications:
restlessness,
muscle fasciculation,
myoclonic jerks,
Choreoathetoid movements,
marked hypertonicity.
This may progress to 
ataxia,
dysarthria,
lethargy,
drowsiness, and
confusion/delirium.


Lithium
Toxicity
Hypotension and cardiac arrhythmias precede circulatory collapse, with emerging seizures, stupor, and coma (high risk of permanent neurological impairment or death).

Lithium

Management
Education of patients (methods of avoiding toxicity, e.g. maintaining hydration and salt intake, and being alert to early signs and symptoms).
Careful adjustment of dosage may be all that is required.

Lithium

Management
In severe toxicity [e.g. following overdose (OD)], rapid steps to reduce serum lithium level are urgently necessary (e.g. forced diuresis with IV isotonic saline) and, if accompanied by renal failure haemodialysis.