Guidance on the use of Antidepressants for the Treatment of Unipolar Depression and Anxiety Spectrum Disorders in adults (Version 3 October 2014)

Guidance on the use of Antidepressants for the Treatment of Unipolar Depression and Anxiety Spectrum Disorders in adults (Version 3 October 2014) Date of Preparation: September 2014 Date for next full Review: September 2017 Authors: Jed Hewitt, Chief Pharmacist Hilary Garforth, Clinical Pharmacist Miguel Gomez 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 October 2014 and supersedes the 2011 version of the document. 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 Appendix 4 Serotonin syndrome Appendix 5 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 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 Or full treatment dose after remission of symptoms. Consider longer-term treatment in recurrent depression. (See below). Choice of treatments in refractory depression. To be considered if standard treatment has failed. # Escitalopram not approved in West Sussex CCGs for treatment of depression, other than by named patient application at the discretion of the clinician. 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, T3 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. ECT is effective and may be protective against a relapse. 3 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. 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), and where there is a history of moderate to severe recurrent depression. 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. 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) 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 14) Citalopram 20mg 40mg (20mg) 1.04 Escitalopram 10mg 20mg 1.98 Fluoxetine 20mg 60mg (40mg) 0.99 Fluvoxamine 50mg 300mg 7.91 Paroxetine 20mg 50mg (40mg) 1.76 Sertraline 50mg 200mg 1.75 Notes: 2.1.1 Citalopram and escitalopram appear to have the most effect on cardiac electrical conduction and is 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 Escitalopram is not currently approved in the West Sussex CCGs for the treatment of depression, other than by named patient application at the discretion of the clinician. 2.1.6 Fluvoxamine carries greatest risk of causing gastrointestinal disturbance. 2.1.7 All SSRIs carry risk of causing gastrointestinal bleeds and this risk is significantly increased when taken concurrently with non-steroidal anti-inflammatory drugs. (See also Trust guidance on Managing Patients with Musculoskeletal Disorders ). 2.1.8 All SSRIs can affect bone density and risk of fracture has been shown to be increased in those aged over 50 years. 2.1.9 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. 2.1.10 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 14) Mirtazapine 15mg 45mg 0.83 (using half a 30mg tablet). Note prices are not proportionate for higher doses. 6

Notes: 2.2.1 May cause significant sedation, especially at low dose, so should be given at night. 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 2.68 210mg 5.93 600mg 21.23 Average cost for 28 days treatment at minimum effective dose. (NHS Drug Tariff: December 14) 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). 2.4 Serotonin and noradrenaline re-uptake inhibitors (SNRIs) Minimum effective daily dose Licensed daily maximum, adult. (Elderly if different) Duloxetine 60mg 60mg 27.72 Average cost for 28 days treatment at minimum effective dose. (NHS Drug Tariff: December 14) Venlafaxine 75mg Note below 150mg this drug is acting as an SSRI. 375mg 2.32 (37.5mg BD). 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. 2.4.3 Venlafaxine has been associated with significant discontinuation syndrome. 7

2.5 Agomelatine - (a melatonin receptor agonist and a serotonin antagonist at 5HT2c receptors) Minimum effective daily dose Licensed daily maximum, adult. (Elderly if different) Agomelatine 25mg 50mg 30.00 Average cost for 28 days treatment at minimum effective dose. (NHS Drug Tariff: December 14) 2.5.1 See Trust guidance on the use of agomelatine for full information 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. 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 Comments Add lithium to existing therapy 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 MAOIs (Phenelzine is drug of choice) Combination of SSRI or venlafaxine with atypical antipsychotic Tri-iodothyronine (T3) High dose >200mg/day Up to maximum dose of each. 45mg, up to 90mg in hospitalised patients. Mostly studied with fluoxetine and venlafaxine 20-50 micrograms per day Consider risk of cardiotoxicity. BP monitoring. Discontinuation reactions common. Increased risk of serotonin syndrome, so patient should be informed. (See appendix 4). Dietary restrictions and risk of hypertensive crisis. Postural hypotension, dizziness, insomnia, headaches. 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. TFT monitoring required. 8

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. 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 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 A combination of an antidepressant and an antipsychotic is more effective than an antipsychotic alone but it is not clear if it is more effective than an antidepressant alone. 5.4 ECT has been shown to be the treatment with most favourable outcome. 6. Use of antidepressants during pregnancy (7,8) 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. (0191 232 1525). Alternatively contact Medicine Information Department at Worthing Hospital (01903 285222 x5471) 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 and fluoxetine. 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. Therefore, if clinically appropriate, the dose should be reduced 3-4 weeks prior to expected delivery date. If such dose reduction takes place, the patient must be carefully monitored for signs of relapse. 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 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). 6.9 Exposure to SSRIs may increase the rate of spontaneous abortion. 9

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 National Medicines Information service via their website: www.ukmicentral.nhs.uk 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. 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. (Pregabalin is licensed for GAD but is yet to be considered by the Trust s Drugs & Therapeutics Group). 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

10.5 When treating moderate to severe Obsessional-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) Name Dose range (elderly if different) Average cost for 28 days treatment at min effective dose. (NHS Drug Tariff: Dec 14) Paroxetine 20-50mg /day. (Up to 40mg) 1.76 Escitalopram 10mg daily increasing if necessary to 20mg. (Up to 10mg) 1.98 Duloxetine Venlafaxine (XL) Modified release 30-60mg / day. (If necessary, dose escalation up to 120mg may be considered). 22.40 75mg -225mg / day 10.45 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. ( 64.40 for 28 days, all doses, if prescribed in BD regime. 11 ). 12. Antidepressants in panic disorder 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 14) 1.04 1.98 3.16 1.75 5.26 11

13. Antidepressants in obsessive-compulsive disorder (3) Name Escitalopram Dose range (elderly if different) 10mg daily increasing if necessary to 20mg. (Up to 10mg) Average cost for 28 days treatment at minimum effective dose (NHS Drug Tariff: Dec 14) 1.98 Fluoxetine 20 60mg per day. (Up to 40mg) 0.99 Fluvoxamine 100 300mg per day (in BD dosing if >100mg). 15.82 Paroxetine 20 60mg per day. (Up to 40mg) 1.76 Sertraline 50 200mg per day. 1.75 Clomipramine 250 300mg daily. (Unlicensed indication). 17.66 14. Antidepressants in Social Phobia Name Escitalopram Dose range 10mg daily initially, adjusted after 2-4 weeks. Usual dose, 5-20mg daily. Average cost for 28 days treatment at minimum effective dose (NHS Drug Tariff: Dec 14) 1.98 Fluoxetine 20 60mg per day. (Unlicensed indication). 0.99 Paroxetine 20 60mg per day. 1.76 Venlafaxine (XL) Modified release 75mg per day 10.45 Moclobemide 300mg initially, increased after 4 days to 300mg BD. 26.12 15. Antidepressants in Post Traumatic Stress Disorder (PTSD) Dose range Average cost for 28 days treatment at Name minimum effective dose (NHS Drug Tariff: Dec 14) Paroxetine 20 60mg per day. 1.76 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. 1.75 12

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. 13

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 MAOIs Other TCA Mirtazapine SSRIs Venlafaxine Duloxetine Agomelatine MAOIs TCA Mirtazapine Other SSRI Venlafaxine Duloxetine Agomelatine MAOIs TCA Mirtazapine Venlafaxine Duloxetine Agomelatine MAOIs TCAs SSRIs Mirtazapine Duloxetine Agomelatine MAOIs TCA Agomelatine SSRIs, venlafaxine, mirtazapine MAOIs TCAs SSRIs, Venlafaxine Duloxetine Agomelatine MAOIs TCAs SSRIs, venlafaxine, mirtazapine Duloxetine Withdraw and wait one week Halve dose, add SSRI and withdraw slowly, start with venlafaxine 37.5mg, start with 6omg alternate days 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 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 and wait at least one week with very low dose TCA with low dose SSRI Withdraw, start at 60mg alternate days increase slowly Withdraw and wait one week with very low dose TCA Withdraw then start new drug Withdraw and wait one week Withdraw then start tricyclic Withdraw, start at 60mg alternate days increase slowly Withdraw and wait one week 14

Appendix 3 - Antidepressant discontinuation symptoms MAOIs TCAs SSRIs & SNRIs Symptoms Common Agitation, irritability, ataxia, movement disorders, insomnia, somnolence, vivid dreams, cognitive impairment, slowed speech, pressured speech Occasionally Hallucinations, paranoid delusions Common Flu-like symptoms (chills, myalgia, excessive sweating, headache, nausea), insomnia, excessive dreaming Occasionally Movement disorders, mania, cardiac arrhythmias Common Flu-like symptoms, shock-like sensations, dizziness exacerbated by movement, insomnia, excessive (vivid) dreaming, irritability, crying spells Occasionally Movement disorders, problems with concentration and memory Drugs most commonly associated with discontinuation symptoms All [Note: Tranylcypromine is partly metabolised to amfetamine and is therefore associated with a true withdrawal syndrome ]. Amitriptyline Imipramine Paroxetine Venlafaxine Treatment. 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 re-introduced, (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. 15

Appendix 4 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. 16

Appendix 5 - 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 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). 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, 11th edition. 5. Psychotropic Drug Directory 2014. Stephen Bazire. 6. The British National Formulary. 66th Edition, September 2013-March 2014. 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. 9. Evidence based guidelines for treating depressive disorders with antidepressants. (Revision). British Association for Psychopharmacology. 2008. 10. Evidence based guidelines for the pharmacological treatment of anxiety disorders. British Association for Psychopharmacology. 2005. 11. NHS Electronic Drug Tariff. December 2014. 12. Autism: recognition, referral, diagnosis and management of adults on the autism spectrum. NICE Clinical Guideline 142. June 2012. 17