Guidance on the use of Antidepressants for the Treatment of Unipolar Depression and Anxiety Spectrum Disorders in adults (Version 4.

Guidance on the use of Antidepressants for the Treatment of Unipolar Depression and Anxiety Spectrum Disorders in adults (Version 4.1 December 2018) Date of Preparation: January 2018 (with addition of guidance on stopping antidepressants added in December 2018) Date for next full Review: January 2021 Original Authors: Jed Hewitt, Chief Pharmacist Hilary Garforth, Clinical Pharmacist Miguel Gomez Clinical Pharmacist This Version Reviewed by: Grant Salvage Clinical Pharmacist Original version in association with: Dr Adrian Galea, Dr Sanjay Jain, Dr Richard Whale, Consultant Psychiatrist Consultant Psychiatrist Consultant Psychiatrist This updated guidance was approved by the Trust Drugs & Therapeutics Group in January 2018 with Drugs & Therapeutics Group Chairman s action in December 2018 to add discontinuation advice. If you require this document in an alternative format, ie, easy read, large text, audio, Braille or a community language please contact the Pharmacy Team on 01243 623349. (Text Relay calls welcome) 1

Contents Flow-chart: Suggested antidepressant treatment plan 1. General principles in the treatment of unipolar depression 2. Selecting an antidepressant 3. Treatment of refractory depression 4. Treatment of recurrent depression 5. Treatment of psychotic depression 6. Use of antidepressants during pregnancy 7. Use of antidepressants when breast-feeding 8. Use of antidepressants in cardiac, hepatic or renal dysfunction 9. Use of antidepressants in adults with autism 10. General principles in treatment of anxiety spectrum disorders 11. Antidepressants in generalised anxiety disorder (GAD) 12. Antidepressants in panic disorder 13. Antidepressants in obsessive-compulsive disorder 14. Antidepressants in social phobia 15. Antidepressants in post-traumatic stress disorder Appendix 1 Monitoring recommendations when using antidepressants Appendix 2 Switching guidelines Appendix 3 Antidepressant discontinuation symptoms and guidance on discontinuation of antidepressants Appendix 4 UKMi review of antidepressant-induced hyponatraemia Appendix 5 Serotonin syndrome Appendix 6 References 2

Suggested Depression treatment plan (1) (For special groups e.g. in pregnancy and breast-feeding, see later sections) Mild depression Generally, antidepressant drugs are not recommended as an initial treatment, and should only be offered when simpler methods (e.g. active monitoring, life style advice, guided self help or exercise) have failed. In the vast majority of cases mild depression will be treated in primary care. Discuss treatment choices with patient - therapeutic effects - adverse effects - discontinuation effects - give written information When switching be aware of interactions between antidepressants and the risk of serotonin syndrome 1 st line - in moderate to severe depression. Use a generic form of an SSRI. Ensure a recognised therapeutic dose is used. Assess efficacy over 3-4 weeks. If effective continue for at least 6 months at full treatment dose after remission of symptoms. Consider longer-term treatment in recurrent depression. (See below). 2 nd line choose a different generic SSRI, or mirtazapine. Ensure a recognised therapeutic dose is used. Assess efficacy over 3-4 weeks. If effective continue for at least 6 months at full treatment dose after remission of symptoms. Consider longer-term treatment in recurrent depression. (See below). 3 rd line mirtazapine, escitalopram, an SNRI, a tricyclic antidepressant, vortioxetine, or agomelatine. (Consider augmentation therapy if severe). Ensure a recognised therapeutic dose is used. Assess efficacy over 3-4 weeks. If effective continue for at least 6 months at full treatment dose after remission of symptoms. Consider longer-term treatment in recurrent depression. (See below). or Choice of treatments in refractory depression. To be considered if standard treatment has failed. Augment one antidepressant with another. Some evidence for SSRIs plus mirtazapine and for venlafaxine plus mirtazapine. Caution re: serotonin syndrome. or Other augmentation strategies, eg. lithium, CBT, atypical antipsychotics (see section 3) or Venlafaxine up to 375mg. Treatment should only be implemented by specialist practitioners for those requiring doses of 300mg or above. Recurrent Depression Continue maintenance therapy for at least two years and longer in some cases Consider use of psychological therapies. Psychotic Depression Usually augment with an antipsychotic. 3ECT is effective and may be protective against a relapse. Atypical Depression Consider phenelzine if failed to respond to alternatives. Care with side effects and dietary restrictions. Stabilise and provide information to the GP on coprescribing risks and on dietary advice before asking them to prescribe.

(1, 14) 1. General principles in the treatment of unipolar depression 1.1 Antidepressants are not recommended for the initial treatment of mild depression, because the risk-benefit ratio is poor. However, in moderate depression antidepressants should be offered to all patients routinely, before psychological intervention. 1.2 Antidepressants may be used for mild depression of chronic duration, (eg. persisting for 3 months or more), where there is a history of moderate to severe recurrent depression, or where mild depression complicates the care of chronic physical health problems. 1.3 Antidepressants are not recommended for subthreshold depression unless the condition has been of at least two years duration, or there is prior history of moderate to severe recurrent depression. 1.4 Major depression is a common condition. Screening should be undertaken in primary care and hospital settings for depression in high-risk groups, for example those with a past history of depression, significant physical illness or other mental health problems such as dementia. 1.5 Patients, (especially those aged 30 years and under), should be asked directly about suicidal ideation and intent to harm, particularly during high-risk periods such as during initiation of, and changes to, medication. A maximum of one week s medication should be considered for those assessed at risk. Caregivers should be aware of the need to monitor for the emergence of suicidal thoughts and behaviour and seek medical advice immediately, especially at the start of treatment, during dose changes and when antidepressant treatment is being changed. 1.6 Patients with a single episode should be treated for at least 6 months (as an absolute minimum) after resolution of symptoms. Those who have experienced multiple episodes in the recent past should be advised to continue antidepressants for at least two years after remission. 1.7 If a patient fails to respond to the first antidepressant prescribed, consideration must always be given as to whether the drug has been taken correctly at the prescribed dose. 1.8 If response to a standard dose is inadequate and there are no significant side effects, the dose should be gradually increased according to the manufacturer s dosage schedule. 1.9 If there is no response after three-four weeks at therapeutic dose, consideration should be given to switching to another antidepressant. If there has been a partial response, the decision to switch should be delayed for a further two-week assessment period and then consideration given to increasing the dose if necessary. 1.10 For older patients the period of assessment should be a minimum of nine weeks, and longer in cases of partial response. 1.11 When prescribing for older patients, consideration must be given to the significantly increased risk of drug interactions, adverse effects and intolerance. 1.12 So far as possible, choice of antidepressant drug should be matched to individual patient requirements. Consideration should be given to both short-term and long-term effects, additional physical health disorders, overdose risk, previous exposure, tolerance and response, concurrent medication and patient preference. 1.13 When deciding on choice of treatment, consideration may be given to the re-introduction of any previous treatments that were used inappropriately, (eg. at sub-therapeutic dose). 4

1.14 The dose of antidepressant used for prevention of relapse will normally be the same as that at which acute treatment was effective. Downward titration of antidepressant dose following response is not considered normal practice. 1.15 When responsibility for continued prescribing is passed on to primary care, the GP must be given clear information regarding the treatment plan, the medication dosage and the expected duration of treatment. 1.16 Consideration should always be given to the possibility of using other treatment modalities during the episode of care, eg. exercise regimes, CBT, ECT etc. 1.17 Consideration should be given to the possibility of bipolar disorder, particularly bipolar II, where a hypomanic episode may not have been reported or diagnosed. Assessment of the patient should include questioning around possible episodes of hyperexcitability, increased activity and agitation. 1.18 Clinicians must ensure that women of childbearing potential with a severe mental health problem are given information at their annual review about how their mental health problem and its treatment might affect them or their baby if they become pregnant. Additionally, pregnant women with a previous severe mental health problem or any current mental health problem must be given information at their booking appointment about how their mental health problem and its treatment might affect them or their baby. The Stepped Care Model (1) Focus of Intervention Nature of Intervention Step 4. Severe and complex depression: risk to life, severe self-neglect. Medication, high-intensity psychological interventions, ECT, crisis service, combined treatments, multiprofessional and inpatient care. Step 3. Persistent subthreshold depressive symptoms or mild to moderate depression with inadequate response to initial interventions. Moderate and severe depression. Medication, high-intensity psychological interventions, combined treatments, collaborative care, and referral for further assessment and interventions. Step 2. Persistent subthreshold depressive symptoms. Mild to moderate depression. Low-intensity psychosocial interventions, psychological interventions, medication and referral for further assessment and interventions. Step 1. All known and suspected presentations of depression. Assessment, support, psycho-education, active monitoring and referral for further assessment and interventions. 5

2.Selecting an antidepressant (1,4,5,6,13) 2.1 Selective serotonin reuptake inhibitors (SSRIs) Minimum effective daily dose Licensed daily maximum, adult. (Elderly if different) Average cost for 28 days treatment at minimum effective dose. (NHS Drug Tariff: December 17) Citalopram 20mg 40mg (20mg) 1.45 Escitalopram 10mg 20mg (10mg) 1.14 Fluoxetine 20mg 60mg (40mg) 0.74 Fluvoxamine 50mg 300mg 9.05 Paroxetine 20mg 50mg (40mg) 1.26 Sertraline 50mg 200mg 0.80 Notes: 2.1.1 Citalopram and escitalopram appear to have the most effect on cardiac electrical conduction and are likely to be the most cardiotoxic of the group. 2.1.2 Sertraline has proven safety for use after myocardial infarction. 2.1.3 Fluoxetine and paroxetine carry greatest risk of causing agitation. 2.1.4 Citalopram and sertraline carry least risk of causing metabolic interaction. 2.1.5 Fluvoxamine carries greatest risk of causing gastrointestinal disturbance. 2.1.6 All SSRIs carry risk of causing gastrointestinal bleeds and this risk is significantly increased when taken concurrently with non-steroidal anti-inflammatory drugs, antiplatelets, and anticoagulants. (See also Trust guidance on Managing Patients with Musculoskeletal Disorders ). 2.1.7 All SSRIs can affect bone density and risk of fracture has been shown to be increased in those aged over 50 years. 2.1.8 Patients on SSRIs should be carefully monitored around the time of initiation and dose changes for signs of a worsening of their condition, impulsivity and suicidal ideation especially in those aged under 30 years. 2.1.9 All SSRIs have been associated with discontinuation reactions on stopping or reducing treatment. Paroxetine is the most likely to cause such reactions and is therefore not recommended for first-line use. (See appendix 3). 2.2 Mirtazapine (a presynaptic alpha-2 antagonist) Minimum effective daily dose Licensed daily maximum, adult. (Elderly if different) Average cost for 28 days treatment at minimum effective dose. (NHS Drug Tariff: December 17) Mirtazapine 15mg 45mg 0.58 (using half a 30mg tablet). Note prices are not proportionate for higher doses. Notes: 2.2.1 May cause significant sedation, especially at low dose, so should be given at night. 6

2.2.2 May increase appetite and lead to weight gain. 2.2.3 Risk of blood dyscrasia baseline full blood count recommended before use. 2.3 Tricyclic and related antidepressants These are the recommended choices; please see Trust formulary for other tricyclic options. Amitriptyline Lofepramine Trazodone Notes: Minimum effective daily dose 125mg (possibly lower in elderly). 140mg (possibly lower in elderly). 150mg (100mg in elderly). Licensed daily maximum, adult. (Elderly if different) 200mg 5.50 210mg 9.38 Average cost for 28 days treatment at minimum effective dose. (NHS Drug Tariff: December 17) 600mg 7.21 50mg/5mL liquid 150mg OD = 358 LIQUID SHOULD NOT BE ROUTINELY USED 2.3.1 Reviews have shown amitriptyline to have a favourable efficacy profile compared to SSRIs. 2.3.2 Lofepramine carries lower risk of toxicity in overdose than other TCAs. It is also only weakly anticholinergic and therefore may be suitable to use in elderly patients. 2.3.3 Trazodone has useful sedating properties. Doses greater than 300mg are only licensed in hospitalised patients. (Recommended that it be taken with or after food). 2.3.4 Dosulepin (dothiepin) should not be routinely prescribed and use in primary care is no longer supported, due to significant safety concerns in regards to increased cardiac risk and toxicity during overdose, which evidence suggests outweighs the benefits and tolerability relative to other antidepressants. 2.4 Serotonin and noradrenaline re-uptake inhibitors (SNRIs) Minimum effective daily dose Licensed daily maximum, adult. (Elderly if different) Duloxetine 60mg 60mg 3.73 Average cost for 28 days treatment at minimum effective dose. (NHS Drug Tariff: December 17) Venlafaxine 75mg Note below 150mg this drug is acting as an SSRI. 375mg 0.93 (37.5mg BD using half a 75mg tablet). Notes: 2.4.1 Both drugs should be used with caution in patients with cardiac disease. In particular, venlafaxine carries high risk of cardiotoxicity in overdose. 2.4.2 Blood pressure should be monitored in patients with known hypertension. In particular, venlafaxine may have significant effect on blood pressure when used in higher doses. 7

2.4.3 Venlafaxine has been associated with significant discontinuation syndrome. 2.5 Agomelatine - (a melatonin receptor agonist and a serotonin antagonist at 5HT2c receptors) Notes: Minimum effective daily dose Licensed daily maximum, adult. (Elderly if different) Agomelatine 25mg 50mg 30.00 2.5.1 See Trust guidance on the use of agomelatine for full information. https://www.sussexpartnership.nhs.uk/node/1445/attachment 8 Average cost for 28 days treatment at minimum effective dose. (NHS Drug Tariff: December 17) 2.5.2 Baseline liver function tests must be carried out for all patients. Further tests as per guidelines, (at 3, 6, 12 and 24 weeks), if treatment continues. 2.5.3 When increasing the dosage, liver function tests should be performed at the same frequency as when initiating treatment. 2.5.4 There is no formal agreement with GPs that they will take on the prescribing of agomelatine, therefore if started in an in-patient setting there needs to be agreement with the CMHT that they will take over the prescribing on discharge. 2.6 Vortioxetine - (a serotonin reuptake inhibitor, a serotonin antagonist at 5-HT 3, and a serotonin agonist at 5-HT 1A receptors) Notes: Minimum effective daily dose Licensed daily maximum, adult. (Elderly if different) Vortioxetine 5mg 20mg 27.72 Average cost for 28 days treatment at minimum effective dose. (NHS Drug Tariff: December 17) 2.6.1 Vortioxetine is recommended as an option for treating major depressive episodes in adults whose condition has responded inadequately to two antidepressants within the current episode. 2.6.2 The manufacturer advises caution when treating elderly patients with doses over 10mg daily due to limited trial data. 2.6.3 Treatment should be discontinued in patients who develop seizures or if there is an increase in seizure frequency. 2.6.4 Treatment with vortioxetine can be discontinued abruptly without the need for gradual dose reduction. During clinical trials there were no clinically relevant differences in the incidence or nature of discontinuation symptoms compared to placebo following abrupt discontinuation of either short or long-term treatment. 2.6.4 Sexual dysfunction has been seen as an adverse effect with the 20mg daily dose only during clinical trials, whilst symptoms were no different to placebo at lower doses 2.6.5 Treatment with vortioxetine has been associated with potential benefits in terms of cognition & functioning compared to placebo, with statistically significant results in shortterm placebo controlled studies using the Digit Symbol Substitution Test (DSST), the

University of California San Diego Performance-Based Skills Assessment (UPSA), and the Perceived Deficits Questionnaire (PDQ). However results were not statistically significant compared to placebo when evaluated using the Cognitive and Physical Functioning Questionnaire (CPFQ). 3. Treatment of refractory depression (1) 3.1 Combination of antidepressant medication with CBT should be considered if not already tried. 3.2 Common treatment options are listed below. (See Maudsley Prescribing Guidelines for further alternatives). Name Dose range Cost/30 days* Comments Add lithium to 800mg per day existing therapy 2.25 Aim for plasma level of 0.4-1.0mmol/l ECG before initiating. Needs baseline tests and continued monitoring. Venlafaxine Combination of SSRI or venlafaxine with mirtazapine High dose >200mg/day Up to maximum dose of each. 225mg/day IR - 2.80 M/R 6.50 (using 150mg +75mg M/R tablets) 30mg mirtazapine added 1.17 Consider risk of cardiotoxicity. BP monitoring. Discontinuation reactions common. Increased risk of serotonin syndrome, so patient should be informed. (See appendix 4). MAOIs (Phenelzine is drug of choice) See latest BNF for doses 15mg TDS 18.90 Dietary restrictions and risk of hypertensive crisis. Postural hypotension, dizziness, insomnia, headaches. Combination of SSRI or venlafaxine with atypical antipsychotic Mostly studied with fluoxetine and venlafaxine Addition of quetiapine 300mg/day IR - 36.72 XL - 85 Evidence for combination with quetiapine, olanzapine, risperidone and aripiprazole. Quetiapine is now licensed for treatment of major depressive episodes in bipolar disorder and for add-on treatment in MDD in those who have had suboptimal response to antidepressant therapy. Liothyronine Tri-Iodothyronine (T3) 20-50 micrograms per day 40 micrograms 516.40 TFT monitoring required. HIGH COST *Drug Tariff December 2017 3.3 Combinations of tricyclic plus SSRI antidepressants should only be used with extreme caution as this carries significant risk of cardiac toxicity, especially with fluoxetine and paroxetine combinations. 3.4 Liothyronine (T3) is a high cost medication (~ 516 per month) which should only be tried as a last resort in the treatment of refractory depression. 3.5 At the time of publication there is an ongoing debate as to whether GPs will continue to prescribe liothyronine for stabilised patients, which is awaiting a decision by each clinical commissioning group and area prescribing committee. 9

4. Treatment of Recurrent depression 4.1 In high risk patients, (more than 5 lifetime episodes and/or 2 episodes in the last few years), maintenance therapy should be continued for at least two years and for even longer in most cases, tailored to the individual. 5. Treatment of Psychotic depression (4, 9) 5.1 Long-term outcome is generally poorer for psychotic depression than non-psychotic depression. 5.2 Patients may have a poorer response to combined pharmacological and psychological treatment than those with non-psychotic depression. 5.3 Meta-analysis has shown that a combination of an antidepressant and an antipsychotic is more effective than either an antipsychotic alone or an antidepressant alone. 5.4 There is little information available in regards to optimal treatment duration with combination antipsychotic and antidepressant treatment in the management of depression with psychosis. 5.5 ECT has been shown to be the treatment with most favourable outcome. (4, 7, 8, 16) 6. Use of antidepressants during pregnancy 6.1 Always obtain up to date advice and look at each case individually. Experience with newer drugs is growing and a change in treatment may not be necessary or advisable. Contact The National Teratology Information Service for specialist advice. (0344 892 0909). 6.2 Do not introduce medication during pregnancy unless clearly necessary and only after careful consideration of the risk / benefit. 6.3 Patients already receiving antidepressants are at high risk of relapse and should be maintained on antidepressants during and after pregnancy. 6.4 There is most experience with amitriptyline, imipramine, sertraline, and fluoxetine, and there is a growing body of experience in the safe use of citalopram and escitalopram during pregnancy. However, the MHRA report in March 2010 advised of a small increased risk of congenital cardiac defects if fluoxetine is taken in early pregnancy. The frequency is similar to that seen with paroxetine, but evidence is not yet sufficient to confirm a class effect for all SSRIs. 6.5 All antidepressants have been linked with neonatal withdrawal syndrome. 6.6 Paroxetine should not be used due to high risk of neonatal withdrawal syndrome. It has also been more strongly linked to infant cardiac malformation than other SSRIs except for fluoxetine. 6.7 Recent evidence has suggested that the increased cardiac malformation rates observed with SSRIs in some studies may be explained by factors common to women with health conditions for which SSRIs are prescribed, rather than SSRI exposure. A causal association between use of SSRIs in pregnancy and any type of malformation in the offspring therefore remains unconfirmed. 6.7 There is some evidence that sertraline is the least likely of the SSRIs to cross the placental barrier. 6.8 Exposure to SSRIs in late pregnancy (after week 20) may increase the risk of persistent pulmonary hypertension of the newborn (PPHN). 10

6.9 Maternal SSRI use in pregnancy has been associated with an increased risk of spontaneous abortion, low birth weight and preterm delivery in some, but not all studies. A causal association between in utero SSRI exposure and an increased rate of spontaneous abortion remains unproven. 7. Use of antidepressants when breast-feeding (7) 7.1 The benefits of breast-feeding to the mother and infant must be weighed against the risks due to drug exposure in the infant. However, treatment of maternal illness is usually the highest priority. 7.2 The treatment regime established during pregnancy should be continued after delivery if still required. 7.3 Up to date advice should be obtained and the lowest effective dose used. Specific enquiries about use of medication during lactation can be addressed to the UK Drugs in Lactation Advisory Service at either: Trent Medicines Information Centre 0116 258 6491 OR West Midlands Medicines Information Centre 0121 424 7298 OR ukdilas.enquiries@nhs.net 7.4 Greatest amounts of drug usually occur in the first quantities of milk (and foremilk) expressed. Therefore, infant exposure can be reduced by pumping and discarding a small amount of milk before each feed. Also, wherever possible, feeds should be timed to avoid peak drug levels. 8. Use of antidepressants in cardiac, hepatic or renal dysfunction 8.1 See current editions of the BNF and of the Maudsley Prescribing Guidelines for product specific information. 9. Use of antidepressants in adults with autism (12) 9.1 Depression commonly exists with autism. However, there is often poor recognition of symptoms and consequently suboptimal treatment. 9.2 Little is known about the extent of the use of antidepressants, adherence to treatment or its effectiveness in this patient group. Moreover, concerns have been raised about the increased sensitivity of people with autism to the side effects of SSRIs and other antidepressant drugs and therefore patients should be closely monitored. 9.3 Antidepressants should not be used in the routine management of core symptoms of autism in adults. 11

10. General Principles in treatment of anxiety spectrum disorders 10.1 In co-morbid anxiety and depression, the depression should be treated as a priority. 10.2 If benzodiazepines are prescribed in the treatment of an anxiety disorder they should not normally be used for longer than two to four weeks. Although benzodiazepines may be useful in the emergency management of panic disorder, they should not normally be prescribed for the long-term treatment of this condition. 10.3 Whilst CBT has the strongest evidence base in the treatment of Generalised Anxiety Disorder (GAD), antidepressants may also be considered. Current licensed options are escitalopram, venlafaxine, duloxetine, paroxetine and trazodone. Other licensed and locally approved treatments include hydroxyzine and buspirone. 10.4 In the treatment of Panic Disorder, although the evidence base is strongest for the use of CBT, SSRI antidepressants are also effective treatments. Current licensed options are citalopram, escitalopram and paroxetine. The tricyclic antidepressants clomipramine and imipramine have also been shown to be effective, although they are not licensed for this indication. 10.5 When treating moderate to severe Obsessive-Compulsive Disorder (OCD), SSRIs should be offered as a treatment option if CBT fails or is unsuitable. The daily dose usually needs to be high and response can be slow. 8-12 weeks at full dose should be allowed before assessing response. Relapse is common on discontinuation and minimum of 1-2 years treatment is recommended. 10.6 SSRIs should not be stopped abruptly, as patients with anxiety spectrum disorders are particularly sensitive to discontinuation symptoms. As paroxetine is commonly associated with discontinuation symptoms it is rarely used in practice. (See appendix 3). 11. Antidepressants in Generalised Anxiety Disorder (GAD) (13) Name Sertraline Dose range (elderly if different) 50mg-200mg per day (Unlicensed indication, recommended by NICE CG113) Average cost for 28 days treatment at min effective dose. (NHS Drug Tariff: Dec 17) 0.80 Paroxetine 20-50mg per day. (Up to 40mg) 1.26 Escitalopram 10mg daily increasing if necessary to 20mg. (Up to 10mg) 1.14 Duloxetine Venlafaxine (XL) Modified release 30-60mg per day. (If necessary, dose escalation up to 120mg may be considered). 2.76 75mg - 225mg per day 2.60 Notes: 11.1 See section 2.4 for notes on use of duloxetine and venlafaxine. 11.2 Pregabalin is an anticonvulsant drug also licensed for the treatment of GAD in adults. The dose range is 150mg-600mg daily in divided doses. ( 3.98 for 28 days of 75mg BD, 2.87 for 28 days of 150mg BD, 8,48 for 28 days of 300mg BD 11 ). 12

12. Antidepressants in panic disorder (13) Name Citalopram Escitalopram Paroxetine Sertraline Imipramine or clomipramine Dose range (elderly if different) 10mg for one week, increasing up to maximum of 40 mg daily. (Up to 20mg) 5mg daily increasing after 7 days to 10mg. Maximum dose 20mg. (Up to 10mg) 10mg per day increasing gradually in steps of 10mg up to a maximum of 60mg daily. (Up to 40mg). 25mg daily increasing after 7 days to 50mg. Maximum dose 200mg 10mg per day increasing gradually to 200mg per day. (Unlicensed indication). Average cost for 28 days treatment at minimum effective dose. (NHS Drug Tariff: Dec 17) 1.45 1.14 2.52 0.80 Imipramine 200mg 6.48 Clomipramine 200mg 7.76 Notes: 12.1 Many patients with panic disorders experience intensified anxiety symptoms at the start of treatment with antidepressants. This paradoxical initial increase in anxiety is most pronounced during the first few days of treatment and generally subsides within two weeks. 12.2 A low initial starting dose is recommended to minimise the potential worsening of panic symptomatology. 12.3 Patients with panic disorder should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months or even longer. 13. Antidepressants in obsessive-compulsive disorder Name Escitalopram Dose range (elderly if different) (3, 13) 10mg daily increasing if necessary to 20mg. (Up to 10mg) Average cost for 28 days treatment at minimum effective dose (NHS Drug Tariff: Dec 17) 1.14 Fluoxetine 20 60mg per day. (Up to 40mg) 0.74 Fluvoxamine 100 300mg per day (in BD dosing if >150mg). 19.01 Paroxetine 20 60mg per day. (Up to 40mg) 2.52 Sertraline 50 200mg per day. 0.80 Clomipramine 250 300mg daily. (Unlicensed indication). 9.70 13

14. Antidepressants in Social Phobia (13, 15) Name Dose range Average cost for 28 days treatment at minimum effective dose (NHS Drug Tariff: Dec 17) Sertraline 50 200mg per day. 0.80 Escitalopram 10mg daily initially, adjusted after 2-4 weeks. Usual dose, 5-20mg daily. 1.14 Fluoxetine 20 60mg per day. (Unlicensed indication). 0.74 Paroxetine 20 60mg per day. 1.26 Venlafaxine (XL) Modified release Moclobemide 75mg per day 2.60 300mg initially, increased after 4 days to 300mg BD. 27.98 15. Antidepressants in Post Traumatic Stress Disorder (PTSD) (13) Name Dose range Average cost for 28 days treatment at minimum effective dose (NHS Drug Tariff: Dec 17) Paroxetine 20 60mg per day. 1.26 Sertraline Others 25mg daily, increasing after 7 days to 50mg. Maximum dose 200mg. Several other antidepressants including other SSRIs, mirtazapine, amitriptyline and phenelzine have also been successfully used in the treatment of PTSD but are not licensed. 0.80 14

Appendix 1 - Monitoring recommendations when using antidepressants Prior to treatment: A full medical history and physical examination should be considered, with specific focus on personal and family cardiac history, including undue breathlessness, exercise syncope or sudden death in young relatives. An ECG is indicated if any such cardiac history or examination abnormalities are identified. Blood tests: FBC, U&Es, LFTs, TFTs. (B12 and folate should be considered, particularly in the elderly and where poor nutritional state is suspected). Following treatment initiation: Clinical parameters Response. Clinical response should be monitored one to two weeks from initiation and at each subsequent review, ideally with a basic scale (CGI, BDI, HAMD, MADRS etc) Suicidality / impulsivity / hostility. Clearly identified as greater at case level, particularly in younger adults and children. Should be assessed at every clinical contact and dictates more frequent reviews in younger groups (weekly). Other common side effects should be enquired of at each clinical review, especially those related to sexual dysfunction, as these problems are often not reported without prompting. Physical parameters Drug level monitoring may be appropriate for TCAs when potential exists for toxicity, (eg at high dose or use of concurrent interacting medication). ECGs should also be considered in such cases. Drug level monitoring may also assist with assessing drug concordance, however, the availability of TCA assays is often limited. FBC, U&Es, and LFT should be conducted at least annually and more frequently if clinically indicated. Hyponatraemia is documented with most antidepressants, with clinical signs including dizziness, lethargy, cramps, and seizures. It should be monitored for regularly (3 monthly) in those most susceptible (eg. >80yrs, previous history, reduced GFR or associated drugs and comorbidities). Clinicians prescribing to women of child bearing potential not using contraception should be mindful of potential teratogenic effects Antidepressant specific. TCAs and venlafaxine - cardiac features should be monitored regularly. L-Tryptophan - FBC should be conducted, particularly if any features of eosinophiliamyalgia syndrome arise. MAOIs education and monitoring of diet Lithium - Pre-testing and monitoring of use as specifically outlined in the BNF. Agomelatine- LFTs at baseline then at 3, 6, 12 and 24 weeks. Discontinue if transaminases increase to three times upper limit of normal. 15

Appendix 2 - Switching antidepressants Where there is no response, poor response or tolerability problems, the following table may assist when switching to an alternative therapy. For more detailed information see the current edition of The Maudsley Prescribing Guidelines. From To Advice MAOIs Any other drug Withdraw and wait two weeks Tricyclic antidepressants (TCA) SSRIs (except fluoxetine) Fluoxetine Venlafaxine Duloxetine Mirtazapine Agomelatine Vortioxetine When switching to another antidepressant reduce dose over one week to 10mg/day, then can be abruptly stopped. MAOIs Other TCA Mirtazapine SSRIs Venlafaxine Duloxetine Agomelatine Vortioxetine MAOIs TCA Mirtazapine Other SSRI Venlafaxine Duloxetine Agomelatine Vortioxetine MAOIs TCA Mirtazapine Venlafaxine Duloxetine Agomelatine Vortioxetine MAOIs TCAs SSRIs Mirtazapine Duloxetine Agomelatine Vortioxetine MAOIs TCA Agomelatine SSRIs, venlafaxine, mirtazapine Vortioxetine MAOIs TCAs SSRIs, Venlafaxine Duloxetine Agomelatine Vortioxetine MAOIs Withdraw and wait one week Halve dose, add SSRI and withdraw slowly, start with venlafaxine 37.5mg, start with 60mg alternate days Halve dose, add vortioxetine and withdraw slowly Withdraw wait 2 weeks with low dose TCA Withdraw, then start new drug, start venlafaxine 37.5mg at night Withdraw, start at 60mg alternate days, increase slowly, starting with low dose vortioxetine Withdraw and wait 5-6 weeks Withdraw, wait 4-7 days, start TCA at very low dose, increase slowly Withdraw, start venlafaxine at 37.5mg, increase very slowly Withdraw, wait 4-7 days, start at 60mg alternate days, increase slowly Withdraw, wait 4-7 days, then start with low dose vortioxetine Withdraw and wait at least one week with very low dose TCA with low dose Withdraw, start at 60mg alternate days increase slowly starting with low dose vortioxetine Withdraw and wait one week with very low dose TCA Withdraw then start new drug, starting with low dose vortioxetine Withdraw and wait one week Withdraw then start tricyclic Withdraw, start at 60mg alternate days increase slowly Withdraw and wait one week TCAs SSRIs, venlafaxine, mirtazapine Duloxetine Vortioxetine Withdraw and then start vortioxetine Limited experience with vortioxetine and extra precaution required. Particularly when switching to or from 2D6 inhibitors such as fluoxetine and paroxetine. MAOIs Withdraw and wait three weeks TCAs, starting with low dose TCA SSRIs Mirtazapine Venlafaxine Duloxetine Agomelatine, starting with low dose SSRI, starting with low dose venlafaxine, starting with low dose duloxetine 16

Appendix 3 Antidepressant discontinuation symptoms and guidance on discontinuation of antidepressants Symptoms MAOIs TCAs SSRIs & SNRIs Common Flu-like symptoms (chills, myalgia, excessive sweating, headache, Common Agitation, irritability, ataxia, movement disorders, insomnia, somnolence, vivid dreams, cognitive impairmen slowed speech, pressured speech nausea), insomnia, excessive dreaming Common Flu-like symptoms, shock-like sensations, dizziness exacerbated by movement, insomnia, excessive (vivid) dreaming, irritability, crying spells Drugs most commonly associated with discontinuation symptoms Occasionally Hallucinations, paranoid delusions All [Note: Tranylcypromine is partly metabolised to amfetamine and is therefore associated with a true withdrawal syndrome ]. Occasionally Movement disorders, mania, cardiac arrhythmias Amitriptyline Imipramine Occasionally Movement disorders, problems with concentration and memory Paroxetine Venlafaxine For more detailed information see the current edition of The Maudsley Prescribing Guidelines. Discontinuation of antidepressants (4) When considering discontinuation of antidepressants, and where patients are not switching to alternative antidepressant treatments, the following should be borne in mind to help reduce the risk of discontinuation symptoms: Patients who have been taking antidepressants for 8 weeks or longer are at greater risk of discontinuation symptoms. The antidepressant dose should be tapered down over a minimum of four weeks, although there are a few exceptions to the rule. Fluoxetine due to its long half-life can usually be stopped abruptly from a 20mg dose with minimal reports of discontinuation symptoms. Vortioxetine can be discontinued abruptly without the need for gradual dose reduction, according to clinical trials data. Agomelatine may also be stopped abruptly. Some patients may require longer than four weeks to reduce and to stop their antidepressant, as symptoms may not appear until further on in the reduction process when the dose has been more substantially reduced relative to the original dose. The taper may need to be slowed further towards the end of the reduction process, depending upon the patient s progress & symptoms. 17

Certain antidepressants such as paroxetine, venlafaxine, and tranylcypromine may require much slower & more prolonged reduction regimens due to their pharmacokinetics & pharmacodynamics, which increase the risk of discontinuation symptoms. Patients should also be offered the option of abrupt discontinuation of treatment as part of an informed decision making process, however abrupt discontinuation increases the risk of relapse in any underlying illness. Discontinuation symptoms may not occur in all cases of abrupt discontinuation, and some patients still suffer from discontinuation symptoms despite very slow and prolonged reduction regimens. Certain patients may prefer to face a week or two of intense symptoms rather than months of less severe discontinuation symptoms. Treatment (4) Treatment of discontinuation symptoms is pragmatic. If symptoms are mild, it may be enough to simply reassure the patient that such symptoms are not uncommon and that they normally pass in a few days. If symptoms are more severe, the original antidepressant should be reintroduced, (or another from the same class but with a longer half-life), and then tapered off much more gradually while closely monitoring for further symptoms. 18

Appendix 4 UKMi review of antidepressant-induced hyponatraemia Included below is a summary of the suggested management of antidepressantinduced hyponatraemia produced by UK Medicines Information (UKMi). This summary should not be used in isolation, and the full literature review and Q&A from UKMi should be viewed before acting on this information. This document can be accessed online in the medication related guidance section of our public website, or at the following link: https://www.sussexpartnership.nhs.uk/node/4878/attachment Summary Most antidepressants are associated with hyponatraemia, with the highest risk being with SSRIs and lowest risk being with mirtazapine. If the hyponatraemia is mild (125-134mmol/litre serum sodium) and there is no other cause for the hyponatraemia, discontinue the antidepressant and monitor serum sodium levels daily until they are within normal range or if asymptomatic, consider fluid restriction. If the patient has serum sodium below 125mmol/litre, discontinue the antidepressant immediately and treat medically for hyponatraemia. After serum sodium levels have normalised, choose another appropriate antidepressant. If the patient developed hyponatraemia whilst on an SSRI or venlafaxine, consider changing to a TCA or an MAOI. The increased risk of overdose, adverse effects, and drug interactions of these antidepressants must be considered before prescribing. Mirtazapine may also be considered due to low incidence of hyponatraemia. Monitor serum sodium levels weekly initially. Consider ECT if none of these options are appropriate, or the patient still remains hyponatraemic while on antidepressant therapy. Limitations This review has looked at adult patients only. Special consideration will need to be given to patients with disorders likely to cause electrolyte disturbance. If the antidepressant is being used for other indications such as pain or anxiety, then the substitutions suggested above may not be appropriate. 19

Appendix 5 Serotonin Syndrome The symptoms of serotonin syndrome are as follows. In terms of increasing severity: Agitation and restlessness Sweating Diarrhoea, nausea and vomiting Tremor Fever Shivering Hyper-reflexia Myoclonus Tachycardia Confusion Convulsions Death Serotonin syndrome is most likely to occur when more than one serotonin enhancing drug is used, when such drugs are used in high dosage or in overdose. It is also more common when switching and cross-tapering serotonergic antidepressants and when fluoxetine or paroxetine are used in combination with a TCA. Treatment is to firstly discontinue all identifiable serotonergic drugs, (including over-the-counter sympathomimetics cold and flu remedies etc.), and provide symptomatic support, e.g. cooling blankets. Benzodiazepines may also be useful. More severe cases will require acute medical referral. 20

Appendix 6 References 1. Management of Depression in Primary and Secondary Care. Clinical Guideline 23. National Institute for Health and Clinical Excellence. December 2004 and CG90 Update October 2009, & April 2016 2. Management of Anxiety (Panic Disorder, with or without Agoraphobia, and Generalised Anxiety Disorder) in adults in Primary, Secondary and Community Care. Clinical Guideline 22. National Institute for Health and Clinical Excellence. December 2004. (Amended April 2007), and CG113 January 2011 3. Core interventions in the treatment of obsessive-compulsive disorder. Clinical guideline 31. National Institute for Health and Clinical Excellence. November 2005. 4. The South London and Maudsley NHS Trust Prescribing Guidelines, 12th edition. 5. Psychotropic Drug Directory 2016. Stephen Bazire. 6. The British National Formulary, accessed online January 2018, https://bnf.nice.org.uk 7. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. Briggs. 9th edition, 2011. 8. Antenatal and postnatal mental health. Clinical Guideline 45. National Institute for Health and Clinical Excellence. April 2007, and CG192 December 2014, updated August 2017. 9. Evidence based guidelines for treating depressive disorders with antidepressants. British Association for Psychopharmacology. 2008. Revised 2015 10. Evidence based guidelines for the pharmacological treatment of anxiety disorders. British Association for Psychopharmacology. 2005. Revised 2014 11. NHS Electronic Drug Tariff. December 2017. 12. Autism: recognition, referral, diagnosis and management of adults on the autism spectrum. NICE Clinical Guideline 142. June 2012, updated 2016 13. Summary of Product Characteristics accessed online January 2018 at https://medicines.org.uk/emc 21

14. Depression in adults with a chronic physical health problem: recognition and management, NICE CG91, National Institute for Health and Clinical Excellence, October 2009. 15. Social anxiety disorder: recognition, assessment and treatment, NICE CG159, National Institute for Health and Clinical Excellence, May 2013 16. UK Teratology Information Service monographs Accessed January 2018 https://www.toxbase.org 22