Drugs used in mood disorders

Mood disorder characterized by periods of low mood (depression) and periods of elevated mood(Bipolar affective disorder).

Treatment of bipolar disorder
The main aim of treating bipolar affective disorder to treat the acute episode  (mania/ bipolar depression) and prevent future relapses (depression/mania). The class of drug here we use is mood stabilizers.

Mood stabilizers
A drug that is used treat an acute episode of bipolar affective disorder and it will prevent recurrence. 
That is, a medication that keeps the mood ‘stable'.

Categories of mood stabilizers
1. Lithium
2. Anticonvulsants as mood stabilizers

• Sodium valproate
• Carbamazepine
• Lamotrigine

3. Other

Lithium

Lithium is used for more than 50 years. It has 4 main actions:

• To treat an acute manic episode.
• (with or without combination of antipsychotics).
• To prevent relapses of bipolar affective disorder (Manic/ depressive relapses).
• Can be added to an antidepressant (to augment antidepressant action) in resistant depression.

Lithium is a small ion. Mode of action of Lithium is uncertain but it may influence second messenger systems (e.g. phosphatidyl inositol system), modulate G proteins and it may affect gene expression of growth factors- and neuronal plasticity. Lithium is effective treatment for acute manic episodes, and to prevent relapse. But it is less effective to treat bipolar depression. It may also be used to control aggressive behaviour (e.g. in patients with learning disability).

Pharmacokinetics
Lithium is rapidly absorbed from gut and it is not metabolized in body. It is excreted unchanged via kidneys.  Lithium is filtered and partly reabsorbed from proximal tubule in kidney. When proximal convoluted tubule(PCT) reabsorbs more water, Li absorption also increases. Therefore DEHYDRATION causes increased Li reabsorption from PCT (and retention in the body). In PCT, Lithium is reabsorbed in competition with sodium.  Therefore if Sodium less- Li absorption more. Lithium has a narrow therapeutic index. The therapeutic and toxic plasma concentrations are close together. Therapeutic serum lithium range: 0.5 to 1.0 mmol/l  (12 hour post-dose sample), (towards higher end for acute episode treatment, and lower end for prophylaxis). Symptoms of Lithium toxicity may be seen with levels >1.2mmol/l. Serious toxic effects appear with levels >2 mmol/l.

Side effects of Lithium
Soon after starting treatment, it may cause mild diuresis (due to increased Sodium excretion), dry mouth, metallic taste in mouth and mild tremor of hands. Also Lithium blocks the effect of ADH on kidney and may cause mild polyuria but it is usually not clinically significant, except in a few patients who may develop a diabetes insipidus-like syndrome. Also Lithium cause weight gain and less commonly hair loss and coarsening of hair.

Medium term side effects
In up to 5%-  thyroid gland enlargement may occur with Lithium and the gland shrinks again after Li is stopped. About 20% may develop hypothyroidism (risk more in women). Therefore check thyroid functions every 6 months if patient is on Li. If hypothyroidism develops the patient can be given thyroxine to Lithium. Hyperparathyroidism is a rare side effect with Lithium. There are reversible effects on ECG can occur which are similar to changes of hypokalaemia such as flattening of t waves, broadening of QRS.

Long term side effects
Irreversible decline in glomerular tubular function is a very rare long term effect with Lithium. Usually any decline in glomerular function is rare, and associated with Li toxicity. However because of the risk of this side effect, if patient is on Li it is wise to monitor plasma creatinine levels regularly.

Lithium toxicity
Risk of Lithium toxicity increased by dehydration (e.g. nausea/ vomiting/ reduced fluid intake), sodium depletion and with certain drugs such as thiazide diuretics, NSAIDs.

Features of Lithium toxicity:
With mild Lithium toxicity the patient can develop nausea, vomiting and coarse tremor. With higher Lithium levels they may develop, confusion, slurred speech, nystagmus, ataxia, poor coordination and this could be life threatening.

Treatment:  Stop Lithium
Mild toxicity:  Rapid infusion of Normal saline
Severe toxicity:  may need haemodialysis

Monitoring with Lithium Treatment
Since Lithium has a narrow therapeutic index, and is toxic at high levels it is necessary to monitor serum lithium levels regularly. Also check serum Lithium weekly for first 2-3 weeks (until lithium level is stabilized). Thereafter monitor lithium levels ever 3-6 months. It is mandatory to check 12 hour post-dose, because of risk of side effects and also need to monitor the renal functions and thyroid functions every 6 months.

Sodium valproate

Sodium valproate is used both as an anticonvulsant and mood stabilizer. Sodium valproate is using for acute treatment of a manic episode and for longer term prophylaxis to prevent relapse.In comparison to valproate, Lithium has been used for a longer period, and has more evidence base to show that it is effective. But Sodium valproate may be better than Lithium in Bipolar patients who have more depressive episodes and rapid cycling more than 4 relapses per year.

Mode of action
Its exact mechanism uncertain, but it may act by inhibiting voltage gated sodium channels and by increasing action of GABA (inhibitory NT) in the CNS.

Pharmacokinetics
It is rapidly absorbed by gut and metabolized in the liver(toxic levels not an issue, unlike lithium).
Dosage of Sodium valproate starting from 400-600mg daily up to 1-2 g/daily. It can be given twice/thrice daily and there is a slow release preparation that can be given once daily.

Side effects
The common side effects of Sodium valproate includes nausea, sedation, tiredness, tremor, weight gain, transient hair loss and elevation of liver enzymes. This is usually mild and not associated with hepatic dysfunction.  Treatment maybe continued while carefully monitoring liver functions.

Less common side effects:
The less common side effects includes thrombocytopenia, acute pancreatitis, amenorrhea and edema.

Carbamazepine

Therapeutic uses of Carbamazepine includes as an anticonvulsant, as a mood stabilizer to treat acute mania and as prophylaxis, to prevent relapses of Bipolar affective disorder. Compared to Li and Valproate, it is less commonly used as a mood stabilizer. Its mode of action is to blocks neuronal sodium channels.

Pharmacokinetics
Carbamazepine is a potent liver enzyme inducer, and can lower plasma concentrations of many other drugs. Carbamazepine can be given twice daily, oral and monitoring of carbamazepine serum levels is NOT routinely done.

Side effects
Side effects are common at start of treatment. Patient can develop, sedation, unsteadiness, ataxia, dizziness, leucopenia(in first few weeks of treatment), agranulocytosis(very rare, but could be life threatening, skin rashes(Rarely SJ syndrome), changes in liver enzymes(rarely- liver toxicity) and changes in cardiac conduction.

Lamotrigine

Lamotrigine is also use to treat epilepsy and used as a mood stabilizer too. It is used to prevent the relapse of bipolar disorder plus to treat an acute episode of bipolar depression. Its mode of actions are to reduces levels of glutamate neurotransmitter and also block voltage gated sodium channels.

Side effects
Usually the Lamotrigine is well tolerated. It causes skin rashes especially in first few weeks of treatment. In about 3% of patients will develop macular papular rash with fever. Lamotrigine rarely causes Steven Johnson Syndrome, mild nausea, headache, dizziness and tremor.

Use of mood stabilizers in pregnancy and in breast feeding women
This is always problematic as during Pregnancy:

• Sodium valproate:  neural tube defects (1st trimester).
• Lithium:  Cardiac defects (1st trimester), Neonatal goitre (3rd trimester).

Breast feeding:
Lithium contra indicated (breastmilk- toxic levels in neonate).