Psychiatria Danubina, 2017; Vol. 29, Suppl. 3, pp 667-671 Conference paper © Medicinska naklada - Zagreb, Croatia ANTIDEPRESSANTS IN USE IN CLINICAL PRACTICE Mark Agius1 & Hannah Bonnici2 1Clare College, University of Cambridge, Cambridge, UK 2Hospital Pharmacy St. James Hospital Malta, Malta SUMMARY The object of this paper, rather than producing new information, is to produce a useful vademecum for doctors prescribing antidepressants, with the information useful for their being prescribed. Antidepressants need to be seen as part of a package of treatment for the patient with depression which also includes psychological treatments and social interventions. Here the main Antidepressant groups, including the Selective Serotonin uptake inhibiters, the tricyclics and other classes are described, together with their mode of action, side effects, dosages. Usually antidepressants should be prescribed for six months to treat a patient with depression. The efficacy of anti-depressants is similar between classes, despite their different mechanisms of action. The choice is therefore based on the side-effects to be avoided. There is no one ideal drug capable of exerting its therapeutic effects without any adverse effects. Increasing knowledge of what exactly causes depression will enable researchers not only to create more effective antidepressants rationally but also to understand the limitations of existing drugs. Key words: antidepressants – depression - psychological therapies - social therapies * * * * * Introduction Monoamine oxidase (MAO) inhibitors í Non-selective Monoamine Oxidase Inhibitors Depression may be defined as a mood disorder that í Selective Monoamine Oxidase Type A inhibitors negatively and persistently affects the way a person feels, thinks and acts. Common signs include low mood, Atypical Anti-Depressants and other classes changes in appetite and sleep patterns and loss of inte- rest in activities that were once enjoyable. Treating Tricyclic and Tetracyclic Anti-Depressants depression may involve single drugs or combinations of Mechanism of action drugs, psychotherapy and electroconvulsive therapy, Inhibit the neuronal re-uptake of noradrenaline and alongside medical and familial support. The route of serotonin, thereby increasing their concentration within treatment chosen is dependent on numerous factors the synapses and enhancing neurotransmission. Their including the type of depression, whether it is acute, efficacy for the two types of neurotransmitter receptors chronic or recurrent, past positive responses to treat- varies and this results in different frequencies and ment, severity of the depression and so on (Azzopardi intensities of side effects (BNF 2016). 2010). The pathophysiology of depression mainly involves Table 1A. Tricyclic anti-depressants and their dose a reduction or functional deficiency of the brain neuro- ranges (BNF 2016) Adult daily dose range transmitters noradrenaline, serotonin and dopamine. Examples for depression (mg) Other factors that may contribute to depression include hormones, changes in circadian rhythm and neuro- Amitriptyline 75-200 peptides. This article focuses on the anti-depressants Clomipramine 10-250 that are available to doctors today (Fekadu 2016). Desipramine 25-300 Dosulepine 75-225 Doxepine 75-300 Classes of Anti-Depressants Imipramine 75-200 Anti-depressants may be divided into the following Lofepramine 140-210 Nortriptyline 75-150 classes: Protriptyline 10-60 Monoamine uptake inhibitors Trimipramine 50-300 í Tricyclic Antidepressants (TCAs) Maprotiline 25-225 í Tetracyclic Antidepressants Mianserin 30-90 í Selective Serotonin Reuptake Inhibitors (SSRIs) Dosulepine is Considered to be less suitable for prescribing due í Noradrenaline Reuptake Inhibitors (NARIs) to its relatively high toxicity in overdose without therapeutic í Serotonin-Noradrenaline Reuptake Inhibitors advantages over other tricyclics (NHS Dorset Clinical (SNRIs) Commissioning Group). í Noradrenaline - Dopamine Reuptake Inhibitors Lofepramine is Particular in that it is the only tricyclic which is not cardiotoxic in overdose, thus safer albeit less potent than others (NRDIs) within the same class (NHS Dorset Clinical Commissioning Group) S667 Mark Agius & Hannah Bonnici: ANTIDEPRESSANTS IN USE IN CLINICAL PRACTICE Psychiatria Danubina, 2017; Vol. 29, Suppl. 3, pp 667-671 Table 1B. Tetracyclic anti-depressants and their dose Table 3. Selective Serotonin Reuptake Inhibitors and ranges (BNF 2016) their dose ranges (BNF 2016) Adult daily dose range Adult daily dose range Examples Common Examples for depression (mg) for depression (mg) Amoxapine 100-600 Citalopram 20-40 Maprotiline 25-225 Escitalopram 10-20 Mianserin 30-90 Fluoxetine 20-60 Mianserin and Amoxapine are Often classed as Tricyclic Fluvoxamine 50-300 Anti-depressants and grouped with secondary amines Paroxetine 20-50 Sertraline 25-200 Their onset of action is delayed by seven to fourteen days. It is usual practice to start on low doses which Like the TCAs, their onset of action is also delayed are gradually increased until the patient is stable. by seven to fourteen days; Patients are advised not to stop taking suddenly due In comparison to TCAs, they are better tolerated, to the risk of withdrawal symptoms; safer in patients with cardiac defects, safe in They are more likely to be discontinued than SSRIs overdosageand have low seizurogenicity; due to their side-effects. They are also fatal in over- May be preferred to TCAs due to less frequent and dose; less severe side-effects (less weight gain, no anti- They are contra-indicated in patients with cardiac cholinergic side-effects) (Feighner 1999). defects due to their quinidine-like effects and pro- Discontinuation syndrome is more common with longation of the QT interval. They also have a rela- SSRIs than TCAs – the most common symptoms mani- tively high seizurogengenicity; fest as headaches, electric shock sensations in the head, May be preferred to SSRIs where sedation is requi- neck and spine, influenza-like symptoms, sweating, red although this varies from one TCA to another tinnitus, paraesthesia, fatigue, anxiety and dizziness. (Feighner 1999). When stopping an SSRI, it is common practice to switch to a drug like Fluoxetine that has a long half-life and is Table 2. Tricyclic anti-depressant side effects (BNF 2016) metabolised to an active metabolite, in order to reduce Pathway Effect the risk of this happening (BNF 2016). Adrenergic alpha-re- Orthostatic hypotension Table 4. Selective Serotonin Reuptake Inhibitor side ceptor antagonism effects (BNF 2016) Direct membrane Arrhythmia, Tachycardia Gastro-intestinal symptoms – abdominal pain, effects constipation, diarrhoea, dyspepsia, nausea, vomiting Histamine H1 re Sedation, Weight gain Sexual dysfunction – anovulation, amenorrhoea, ceptor antagonism decreased libido and/or sexual arousal, galactorrhoea Muscarinic M1 Anti-cholinergic symptoms - dry Syndrome of Inappropriate Anti-Diuretic Hormone receptor mouth, dry eyes, blurred vision, Secretion (SIADH) hyponatraemia manifesting as antagonism constipation, confusion, drowsiness, confusion, drowsiness, dizziness, seizures sedation, urinary retention Serotonin 5-HT2 re- Weight gain Noradrenaline Reuptake Inhibitors (NRIs or NERIs) ceptor antagonism Mechanism of action Inhibit the re-uptake of the neurotransmitters norepi- Serotonin Syndrome - Involves excessive central nephrine (noradrenaline) and epinephrine (adrenaline) and peripheral serotoninergic activity caused by a by blocking the action of the norepinephrine transporter, sudden dose increase, the addition of another sero- which leads to increased extracellular concentrations of toninergic drug or the replacement of one for another the two neurotransmitters.(BNF 2016) without an appropriate wash-out period in between. Risk of occurrence is more common with SSRIs than Table 5. Noradrenaline Reuptake Inhibitors and their with TCAs and the combination of SSRIs with MAOIs dose ranges is contraindicated (BNF 2016). Adult daily dose range Common Examples Selective Serotonin Reuptake Inhibitors (SSRIs) for depression (mg) Atomoxetineg / Mechanism of action Reboxetine 8-12 Inhibit the neuronal re-uptake of serotonin by Atomoxetine is Licensed for use in Attention Deficit specifically binding to 5-HT receptors within the Hyperactivity Disorder (ADHD). It is not efficacious in synapses. Their effects on noradrenaline are minimal clinically significant depression, however may improve (BNF 2016). global cognitive performance and daytime sleepiness (Weintraub 2010) S668 Mark Agius & Hannah Bonnici: ANTIDEPRESSANTS IN USE IN CLINICAL PRACTICE Psychiatria Danubina, 2017; Vol. 29, Suppl. 3, pp 667-671 Table 6. Noradrenaline Reuptake Inhibitor side effects Table 9. Noradrenaline-Dopamine Reuptake Inhibitor (BNF 2016) Bupropion Drug Effect Adult daily dose range Common Examples Atomoxetine Abdominal pain, anorexia, dry mouth, for depression (mg) dyspepsia, constipation, flatulence, Bupropion / nausea, taste disturbances, vomiting Bupropion is Marketed as an aid to smoking cessation, Increased blood pressure, palpita- however use in depression may be considered instead of tions, tachycardia SSRIs where Syndrome of inappropriate antidiuretic hormone secretion is a problem (BNF 2016) Reboxetine Constipation, dizziness, dry mouth, impaired visual accommodation, Table 10. Noradrenaline-Dopamine Reuptake Inhibitor urinary retention side effects (BNF 2016) Tachycardia, postural hypotension, agitation, anxiety, dizziness, dry mouth, gastro-intes-