Antidepressants Sue Henderson Clinical Indications Mood disorders Anxiety

Antidepressants Sue Henderson

Clinical Indications • Mood disorders • Anxiety disorders • Eating disorders • Chronic pain • Incontinence

Personal perspective • “I don’t take Prozac for fun. And it has not changed my personality. I am not ridiculously happy but I do not spend most days miserable about being here, there or anywhere and no longer have a need to vomit before I have to talk to a work related colleague or deal with anything slightly stressful. ” (Dietz, 2000, p. 37)

Use of antidepressants in the Australian population, 1975– 2002 (Mant et al. , 2004)

Classes of antidepressant as proportion of total sales of antidepressants in the Australian population, 1990– 2002 (Mant et al. , 2004)

Utilisation of top-selling* antidepressants in the Australian population, 1990– 2002 (Mant et al. , 2004)

Major and sub-classes • • Based on 3 physiological actions: 1. Reuptake inhibition 2. Enzyme inhibition 3. Receptor blockade (Nash & Nutt, 2007).

Reuptake inhibitors • Selective Serotonin Reuptake Inhibitors( SSRI) • Tricyclic Antidepressants (TCAs) • Selective Serotonin and Nor. Adrenaline Reuptake Inhibitors (SNRI) • Nor-adrenaline Reuptake Inhibitor (NARI)

Enzyme inhibitors • The following antidepressant subclasses work by inhibiting the action of enzymes: • Reversible Inhibitors of Mono-Amine Oxidase type A (RIMA) • Mono-Amine Oxidase Inhibitors (MAOI)

Receptor blockers • Nor-adrenergic and Specific Serotonin Antidepressants (Na. SSA) work by blocking receptors.

Therapeutic effect • Time lag of 2 -4 weeks before antidepressant effect occurs. • Side effects & improved sleep occur earlier (Suicide risk). • 1 st episode: Up to 1 year following recovery. • Repeat episodes: Up to 3 years (Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Depression, 2004).

Stopping anti-d too early can lead to relapse Normal Mood Depression requiring treatment 2 -4 weeks relief depression 1 -3 weeks sex drive, self care, activity, memory 1 st week sleep Begin antidepressant anxiety

SSRIs available in Australia • • • Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline

Indications SSRIs • Mood disorders • Anxiety disorders Off label: • Premature ejaculation • Migraine headache, • Diabetic neuropathy • Fibromyalgia

SSRI’s Action 1. Normally serotonin, a brain chemical is released from a nerve cell. 2. Serotonin is then received by the next nerve cell. 3. Some serotonin is then reabsorbed into the 1 st nerve cell.

4. Not having enough serotonin may be associated with depression & anxiety disorders. SSRI’s block the reabsorbtion of serotonin into the 1 st nerve cell. 5. This blocking action results in an increased amount of serotonin being available at the next nerve cell.

SSRI’s block reuptake of serotonin into presynaptic neurone Neurotransmitter Re-uptake pump Receptor MAO Dendrite Axon Synapse Presynaptic storage vesicles

1 st person account • “Some people look upon medication and/or therapy as some sort of life sentence, but to me, the alternative is a life sentence. ” (Dietz, 2000, p. 37)

The hype of Prozac

Side-Effects: SSRI’s • Common: Nervousness & anxiety, insomnia (give dose in morning), drowsiness or fatigue, G. I nausea & diarrhoea, loss of appetite, weight loss, sexual dysfunction.

Common Side Effects: SSRI

Less common side effects • • • Apathy Extrapyramidal side effects (EPSEs) Increased prolactin levels Serotonin syndrome Hyponatraemia Bruising and bleeding Increased risk of gastrointestinal bleeding (Loke, Trivedi, & Singh, 2008).

Clinical response • SSRI’s produce a clinical response much more rapidly than tricyclic anti-depressants. True or False?

Serotonin syndrome • Prevention: do not co-administer SSRI’s and other drugs that increase serotonin. • Drug free interval before changing from SSRI to other serotonin drugs.

Antidepressant discontinuation symptoms • • • F = flu like symptoms I = insomnia N = nausea I = imbalance S = sensory disturbances H = hyperarousal (anxiety) in Carson, 2000, p. 432) (Gelenberg, 1998 cited

Advantages SSRI’s • • • Minimal cardiac toxicity Safe in overdose Mild side effects Non sedating SSRI’s reduce overall suicide rates in depressed patients significantly more than tricyclic antidepressants. True or False?

Tricyclic antidepressants: TCA’s Axon Dendrite • Tricyclics block reuptake of noradrenaline & serotonin into presynaptic neurone.

Tricyclics available in Australia • • Amitriptyline Clomipramine Dothiepin Doxepin Imipramine Nortriptyline Trimipramine

Indications • • Mood disorders OCD Panic disorder Neuralgia (nerve pain) - best available evidence is for amitriptyline (Saarto & Wiffen, 2007) • Nocturnal enuresis

TCA Action: 4 actions 1. Block presynaptic noradrenaline reuptake pump (black lines). 2. Block the presynaptic serotonin reuptake pump (red lines). 3. Block histamine receptors (yellow square) = Sedative side effects. 4. Block post synaptic acetylcholine receptors (grey square) = Dry mouth, confusion, memory impairments, blurred vision. • This blocking action results in an increased amount of nor-epinephrine & serotonin being available to the post synaptic neuron.

Side Effects: TCA’s Common • Sedation (give dose at night) • Dry mouth • Blurred vision • Weight gain • Constipation • Sweating.

TCA S/E. Less common but important • postural hypotension • urinary retention • sexual dysfunction • raised intra-ocular pressure.

Side Effects: TCA’s • Cardio-vascular effects in people with cardiac disease. • Impaired Cognitive function in dementia. • Precipitate a manic swing in bipolar. • May be fatal in O/D. Admit ICU, cardiac monitor

Tetracyclics: Mianserin SE • Common: as for TCA’s, plus vivid dreams. • Less common: anti-cholinergic effects, plus jaundice, neutropenia, agranulocytosis, effect glucose tolerance & insulin levels

Tetracyclics: Mianserin SE • Report sore throat & flu like symptoms. • Regular blood glucose tests. • May be fatal in O/D

Selective Serotonin and Nor. Adrenaline Reuptake Inhibitors (SNRI) Venlafaxine • Low doses inhibits serotonin • Medium dose inhibits nor-adrenaline • High dose inhibits dopamine • Nor-adrenergic drugs tend to have alerting and energising effects • Wide therapeutic index – tolerability similar to SSRIs • Monitor for elevated blood pressure on high doses

Nor-adrenaline Reuptake Inhibitor (NARI) • NARI available in Australia • Reboxetine • Reasonable tolerability – similar to TCAs

Enzyme inhibitors • Mono-Amine Oxidase Inhibitors (MAOI) – The first antidepressants discovered • Alternative mechanism for increasing synaptic availability of monoamines. • MAOI & RIMA prevent intracellular destruction of monamines by MAO • MAOI’s available in Australia • Phenelzine • Tranylcypromine

MAOI & RIMA prevent intracellular destruction of monamines by MAO Neurotransmitter Re-uptake pump Receptor MAO Dendrite Axon Synapse Presynaptic storage vesicles

Side Effects: MAOI’s • Common: as for TCA’s, plus agitation/excess stimulation (do not give dose after 3 p. m. ) • Rare but serious: Hypertensive crisis caused by ingesting tryramine containing foods or a drug interaction (cough & cold remedies, nasal drops & sprays, diet pills, pethidine).

Side Effects: MAOI’s • Prevention: Follow MAOI diet. Check with Dr before using OTC medication, notify Dr or dentist prior to anaesthetic. • Potential for abuse (amphetamine like properties) • Not well tolerated in > 65 y

MAOI: Diet • Avoid tyramine containing foods (often in foods requiring aging): banana peel (banana flavouring), broad bean pods, sauerkraut, matured cheeses, aged meats, smoked or pickled fish, vegemite, brewers yeast.

MAOI: Diet • Limited quantity: raspberries, avocado, soy sauce, commercial soups, coffee substitutes, wine, port, beer, chocolate.

Reversible Inhibitors of Mono. Amine Oxidase type A (RIMA) • RIMAs more selective than older MAOIs • Do not cause serious dietary and drug interactions (except at high doses). • Have greater safety & tolerability compared to MAOIs but are not as effective in treatment resistant depression. RIMA available in Australia • Moclobemide - Not effective for OCD

Receptor blockers: Antagonists • Noradrenergic and Specific Serotonergic Antidepressant (Na. SSA) • Work by completely blocking (antagonist) the serotonin and nor-adrenaline receptors, preventing them from latching on to serotonin and nor-adrenaline (thereby allowing the neurotransmitters to build up). Na. SSA available in Australia • Mirtazapine

Debate • What effect have SSRIs had on suicidal ideation, attempts and completed suicide?

Summary • Lag time 1 – 4/52 before initial response • Newer antidepressants better tolerated, safer in OD (less cardiotoxic) • Caution in switching from 1 to another (drug free intervals) to prevent serotonin syndrome, P 450 problems • Continue for adequate time • All anti-depressants can precipitate mania • Increase psychomotor activity before mood elevation (risk suicide)

References Carson, V. B. , (2000). Mental Health Nursing: The nurse patient journal. (2 nd ed. ), Philadelphia: W. B. Saunders. Dietz, M. (2000). Managing depression: A consumers view. Australian Health Consumer, 3, 36 -37. Fortinash, K. M. , & Holoday-Worret, P. A. (2000). Psychiatric mental health nursing ( 2 nd ed. ). St. Louis: Mosby. Galbraith, A. , Bullock, S. & Manias, E. (2001). Fundamentals of pharmacology (3 rd ed. ). Melbourne: Prentice Hall. Hickie, I. (2000). An approach to managing depression in general practice. Medical Journal of Australia, 173: 106 -110. Loke, Y. K. , Trivedi, A. N. , & Singh, S. (2008). Meta-analysis: Gastrointestinal bleeding due to interaction between selective serotonin uptake inhibitors and non-steroidal anti-inflammatory drugs. Alimentary Pharmacology & Therapeutics, 27(1), 31 -40.

References Mant, A. , Rendle, V. A. , Hall, W. D. , Mitchell, P. B. , Montgomery, W. S. , Mc. Manus, P. R. , et al. (2004). Making new choices about antidepressants in Australia: the long view 1975 -2002. Medical Journal of Australia, 181(7 Suppl), S 21 -24. Nash, J. , & Nutt, D. (2007). Antidepressants. Psychiatry, 6(7), 289 -294. Weitzel, C. , & Jiwanlal, S. (2001). The darker side of SSRIs. RN, 64(8), 43 -48.