Antidepressant and Mood Stabilising Medication

Antidepressant and Mood Stabilising Medication

·        Indications for antidepressant use: 

o   Generally not indicated for mild disorder until monitoring, lifestyle changes and psychological therapies have been attempted 

o   Indicated for mild disorder when there is a history of severe episodes or in dysthymic disorder which is persistent and disabling 

o   For moderate, TCA or SSRIs equally indicated: depending on contraindications and toleration of side effects:

§  SSRIs where severe heart disease, significant anticholinergic problems, and where alertness is important

§  Amitriptyline and imipramine cause the most postural hypotension and AntiACH effects of the older TCAs. Good where sleep disturbance is a major symptom

o   For severe with melancholic features, TCAs at sufficient dose if side effects can be tolerated. Otherwise SSRIs (caution in pregnancy – risks not fully known)

o   If psychotic, use antipsychotic or consider ECT 

o   For moderate and severe, continue for at least 9 months. If more than one recent episode, consider continuing for up to 3 years 

o   During pregnancy: More experience with TCAs (ie more confident effects on fetus will be minimal)

o   Maintenance therapy at full therapeutic dose should be considered if high risk of relapse

o   Li in relapsing bipolar and as possible adjunct in relapsing unipolar depression

·        Mode of action of antidepressants:

o   Increase concentration of noradrenergic or serotonin neurotransmitters in the synaptic cleft. 

o   Leads to adaptive changes eg down regulation of post synaptic b and 5HT2A receptors (hence therapeutic delay) 

o   Older agents also had antimuscarinic and antihistaminic activity

·        Starting and stopping:

o   Onset of effect can take 1 – 2 weeks, with full effect possibly not for 4 – 8 weeks 

o   Dose-escalation is a trade-off between desire to reach therapeutic plasma levels as soon as possible while avoiding side-effects 

o   Rapid cessation of any antidepressant can cause a withdrawal syndrome from a few days resolving in about 4 weeks. Taper off treatment. (?Less risk with SSRIs due to longer T½)

·        Drug treatment has similar outcomes as psychological or combination treatment (BMJ 2000, 320: 27-30)

Tricyclic Antidepressants

·        Examples: Amitriptyline, Imipramine, Doxepin, Nortriptyline (least orthostatic hypotension)

·        Action: Inhibit reuptake of serotonin, noradrenaline or both

·        Use:

o   Clinical response takes 10 – 14 days.  Start with low dose and increase gradually. 

o   Relapse common Þ continue for 6 months

o   Not in acute MI.  Care if suicidal (overdose risk), mania, and variety of medical conditions

·        Pharmacokinetics: 

o  Very low Vd Þ dialysing for overdose ineffective 

o  Long T½ Þ once a day dose possible, but may split dose to reduce the dose dependent anti Ach effects 

o  Well absorbed.  Extensive 1^st pass metabolism to active metabolites.

o  Individual variability in metabolism ® difficulty setting dose.

o  Protein bound and large Vd. 

o  Long T½ (15 – 30 hours), prolonged in elderly. Can be given once daily, but high peak plasma levels ® ­side effects

·        Side effects of TCAs: Tricyclics

o  Inhibit reuptake of:

§  5HT ® anorexia, nausea, vomiting 

§  NA ® tremors, tachycardia, erectile and ejaculatory dysfunction, insomnia

§  DA ® less significant

o  Block: 

§  Ach ® dry mouth, urinary retention, blurred vision, constipation, tachycardia 

§  Alpha 1 ® postural hypotension (persistent in elderly). Delay in ejaculation and erectile dysfunction 

§  H1 ® sedation, weight gain 

o  Other: Possible convulsions, ataxia, manic reactions, respiratory depression, bundle branch block, delirium. Arrhythmias/arrest in overdose

o  There are marked differences in side-effect profile between people and between drugs

·        Withdrawal of TCAs:

o  GI: nausea, vomiting, abdominal cramps, diarrhoea

o  General somatic distress: lethargy, flu-like symptoms, headache

o  Sleep disturbance: insomnia, abnormal dreams including nightmares

o  Affective symptoms: anxiety, agitation, low mood 

o  Less commonly: movement disorders, mania, hypomania, arrhythmias, tachycardia, ventricular ectopic beats

·        TCA Drug interactions:

o  Alcohol potentiates sedation

o  Potentiation of antimuscarinic drugs, adrenaline, noradrenaline and pseudoephedrine 

o  Anticholinergics: worsening of dry mouth, tachycardia, constipation, urinary retention, blurred vision, narrow angle glaucoma

o  Antihistamines, alcohol, anxiolytics: sedation (especially bad if driving)

o  Anaesthetics: arrhythmias and hypotension

o  Diuretics: postural hypotension

o  Antihypertensives: increased hypotensive effect

o  MAOIs: CNS excitation (look like they‟re thyrotoxic) and hypo-hypertension

o  SSRIs: Fluoxetine inhibits TCAD plasma levels/side effects

·        Tricyclic Overdose:

o  Gastric lavage up to 18 hours post ingestion, charcoal, support respiration

o  Symptoms:

§  Anticholinergic signs: rapid pulse, dilated pupils 

§  Cardiac: hypotension (a1 blocking effect), arrhythmia (PR and QRS intervals)

§  Neurological: CNS, seizures, sedation, extrapyramidal syndromes

§  Respiratory: depressed CNS

§  Other: ileus and urinary retention 

o  Sodium bicarbonate if life threatening arrhythmias, lignocaine for ventricular rhythms, magnesium. Beware use of physostigmine

SSRIs

·        = Selective Serotonin Re-uptake inhibitors

·        Action: Initially inhibit 5HT re-uptake.  Long term, normalise 5HT1A and 5HT2 receptor density

·        Pharmacokinetics: Well absorbed.  Fluoxetine: active metabolite with T½ of 7 – 10 days.  Others, T½

·        of Use: Therapeutic delay of 3 – 4weeks.  Can be given once a day

·        About 24 hours, inactive metabolites

·        Examples: Fluoxetine/Prozac, Paroxetine/Arapax, Citalopram (popular in the UK, not subsidised in NZ)

·        SSRI Side effects:

o   Common: 

§  Nausea 23%, headaches, diarrhoea 15%, anxiety (early in treatment, Fluoxetine more stimulant than Paroxetine), nervousness and insomnia 25% 

§  Sexual dysfunction is common

§  Weight loss 4%

o   Less common:

§  Postural hypotension uncommon, but can be significant 

§  Sweating, constipation, weight loss, EPS (akathisia, dystonias, tardive dyskinesia), hyponatraemia

o   Less affinity for aminergic receptors than TCAs

o   Lack of cardiac toxicity in overdose (significantly less than TCAs) – no effect on QTc 

o   May precipitate serotonin syndrome: fever, tremor, myoclonic jerks, convulsions, diarrhoea, hyper-reflexia. Can be fatal. NEVER prescribe MAOIs and SSRIs 

o   Care in variety of medical conditions

·        Withdrawal of SSRIs:  Withdraw slowly

o   GI: nausea, vomiting, diarrhoea, loss of appetites, abdominal pain, abdominal distress

o   General somatic distress: lethargy, flu-like symptoms

o   Sleep disturbance: insomnia, abnormal dreams including nightmares and decreased need for sleep

o   Affective symptoms: irritability, anxiety symptoms, agitation

o   Problems with balance: dizziness, vertigo, light-headedness, ataxia

o   Sensory abnormalities: paraesthesia, numbness, blurred vision/diplopia, visual lag

·        Interactions of SSRIs: 

o   Cytochrome P450 inhibition is a major risk factor: 2D6, 3A4, 2C – depending on drug type (eg Sertraline, Fluoxetine, Paroxetine 

o   2D6: 10% Caucasians lack it

§  Inhibited by Fluoxetine, Sertraline and Paroxetine 

§  TCAs plasma levels/effects ­ by 50 – 400%

§  Haloperidol levels may be increased (Fluoxetine most potent at this)

o   2C: 

§  Phenytoin (up to 3 fold ­)

§  Tolbutamide (hypoglycaemia with Sertraline)

§  Warfarin (­ INRs on sertraline and paroxetine)

§  Diazepam (sedation with fluoxetine) 

o   3A4: involves many drugs, including triazolam, carbamazepine, erythromycin, terfenadine, midazolam. Potential for multiple interactions

·        Nefazodone: An SSRA + 5HT2 antagonist.  Not really an SSRI but similar action.  Side-effects similar

·        to TCAs: nausea, dry mouth, dizziness, constipation, blurred vision

·        St John‟s Wort (Hypericum): inhibits re-uptake of 5HT, noradrenaline and dopamine. In correct dose is as effective as imipramine and significantly better than placebo. Adverse effects include nausea, but no antimuscarinic effects. With SSRI can cause mild serotonin syndrome. Mild enzyme inducer ® ­metabolism of warfarin, and others

MAOIs (Monoamine Oxidase Inhibitors)

·        Action: 

o   Inhibits MAO, which breaks down 5HT and noradrenaline intracellularly. Isoenzymes in gut and liver (type A) and brain (type B) all inhibited 

o   MAO-A (intestine, placenta): selectively oxidises NA, Ad and 5HT

o   MAO-B (platelets): oxidises phenylethylamine

o   Tyramine and Dopamine are substrates for both forms

·        Types: 

o   Standard MAOIs are irreversible. Eg Tranyl-cypromine, Phenelzine inhibit MAO-A. Selegiline (deprenyl) irreversibly inhibits MAO-B 

o   Reversible inhibitor of MAO - A (RIMA), eg Moclobemide. Similar efficacy to TCAs and SSRIs. Given 3 times a day

·        Use:

o   MAOIs rare as first line treatment.  Use moclobemide instead

o  Therapeutic delay for about a month

·        Pharmacokinetics: 

o  MAOIs: Well absorbed. Pharmacokinetics of little importance as kinetics depends on irreversible inhibition

o  RIMAs: Well absorbed. Wears off quicker than MAOIs. Fairly extensive 1^st pass metabolism. 50% protein bound. Large Vd. T½ is 2 hours

·        MAOI side effects.  MAO inhibition ® ­ catecholamine levels:

o  Postural hypertension, urinary hesitancy, dry mouth, blurred vision

o  Impotency and anorgasmia 20%

o  Hepatotoxicity

o  Carpal tunnel like syndrome

o  CNS: agitation, anxiety, hypomania, headache, tremour,

o  Other: weight gain, insomnia.

o  Contraindicated/caution in variety of medical conditions

·        Food interaction: tyramine rich foods: 

o  Foods include avocado, aged cheddar, yoghurt, meat, red wine, chocolate, yeast extracts, some beers, vegemite, pickled herrings, chicken liver. 

o  Tyramine a precursor to dopamine and nor-adrenaline. Normally tyramine metabolised in gut by MAO. 

o  If inhibited ® ­plasma conc. ® ­noradrenaline ® hypertensive crisis, subarachnoid haemorrhage, etc. Adrenaline breaks down to HMMA, which can be detect in the urine. 

o  RIMAs have 10 times the capacity to metabolise tyramine (ie food much less of an issue)

·        Drug Interactions: 

o  Sympathonimetics, including indirectly acting sympathonimetics (eg in cough mixtures such as ephedrine): hypertension 

o  Opiod analgesics: hypo/hypertension

o  Antihypertensives: loss of effect, exacerbation of hypertension

o  Anticholinergics: increased effects

o  SSRIs and pethidine: serotonergic syndrome (fever, sweating, convulsion, confusion)

o  L-Dopa: dopaminergic crisis

o  Potentiate oral hypoglycaemics (sulphonylureas)

·        MAOI Overdose: 

o  Symptoms: CNS hyperactivity, sweating, hyperthermia, tachycardia, hyperventilation, muscle rigidity +/- dystonic facial and limb movements 

o  Treatment: a and b blockers, chlorpromazine + supportive management