Clinical Guideline / Formulary Document Pharmacy Department Medicines Management Services DEPRESSION Pharmacological Treatment of Depression NICE guidelines suggest the following stepped care model also see appendix 1 Do not use antidepressants routinely to treat persistent sub-threshold depressive symptoms or mild depression because the risk-benefit ratio is poor. However they should be considered for people with: o A past history of moderate or severe depression OR o Initial presentation of sub-threshold depressive symptoms that have been present for a long period (typically at least 2 years) OR o Sub-threshold depressive symptoms or mild depression that persist(s) after other interventions o Mild depression that complicates the care of a chronic physical health problem Antidepressants should be considered for people presenting with moderate depression. Antidepressants should be considered for people with a chronic physical health problem and presenting with moderate depression, after other interventions have been attempted or rejected by the person Antidepressants should be considered for people presenting with severe depression Antidepressants may be augmented with an atypical antipsychotic (the optimum dose and duration of treatment are unknown) for treatment of psychotic depression. Antidepressants should be given for 3-4 weeks; if there is no response at the optimal dose, then the drug should be changed. If there is a partial response, then continue for 2-4 weeks then reassess. Consider switching the antidepressant if the service user prefers to change or side effects develop or response is inadequate after 6-8 weeks. Be aware that there may be a delay of up to 2 weeks before onset of antidepressant effect. People taking antidepressants should be regularly reviewed, initially at 2 weeks then at intervals of at least 2 to 4 weeks for the first 3 months of treatment, and then at longer intervals if response is good. Antidepressant treatment should be continued for at least 6 months, extending to at least 2 years if there is a high risk of relapse. There is little evidence of difference in efficacy between different drugs but there are differences in side effect profiles; potential for interactions and safety in overdose. If drugs are equal in efficacy and safety, then the cost should be considered. NICE recommends a generic selective serotonin reuptake inhibitor (SSRI) as first choice. There is a possibility of increased anxiety, agitation and suicidal ideation in the first few weeks of antidepressant treatment 1
Discuss antidepressant treatment choice, side effects and adherence with the service user and provide appropriate service user information leaflet. Appropriate psychological interventions (e.g. cognitive behavioural therapy, interpersonal therapy) should be considered, usually as an adjunct to antidepressants. Safety Warnings Antidepressants are associated with an initial worsening of anxiety/agitation and an increased risk of suicidal thinking and behaviour. Monitor closely, at 2 weekly intervals, particularly at the start of treatment and when the dose is changed. Patients with high suicide risk or younger than 30 years should be reviewed weekly and then frequently until the risk is no longer clinically important. Abrupt discontinuation (sometimes reduced or missed doses) of antidepressants can lead to a withdrawal syndrome. Symptoms include dizziness, numbness and tingling, gastrointestinal disturbances, headaches, sweating, anxiety and sleep disturbance. Gradual discontinuation is advised. Use antidepressants with care in glaucoma, bipolar disorder, prostate hypertrophy and seizures. Hyponatraemia has been associated with all antidepressants and should be considered in all those who develop drowsiness, confusion, or convulsions while on antidepressants. SSRIs and SNRIs can increase the risk of bleeding. Caution is required in older adults and when used in combination with NSAIDS, aspirin or anticoagulants. Gastroprotection may be required. Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs Serotonin syndrome (agitation, confusion, tremor, hypereflexia, myoclonus and hyperthermia) and Neuroleptic Malignant Syndrome (NMS)-like reactions can occur with antidepressants particularly when prescribing concomitantly serotonergic drugs agents (including SSRIs, SNRIs, triptans, lithium, tramadol) or with medicinal agents that impair metabolism of serotonin such as MAO-inhibitors (moclobemide) or with serotonin precursors (such as tryptophan supplements). Serotonin syndrome and NMS require emergency management. TCAs are contraindicated in patients with a heart block or during recovery period after myocardial infarction Venlafaxine and duloxetine are contraindicated in uncontrolled hypertension. Caution should be exercised in patients whose underlying conditions might be compromised by increases in blood pressure, e.g., those with impaired cardiac function. Driving For advice on DRIVING and health conditions, see DVLA. It is illegal to drive if medication impairs driving ability. See Drugs and driving: the law. It is an offence for a person to drive with certain levels of some medications in the blood. See https://www.gov.uk/government/collections/drug-driving#table-of-drugs-and-limits for up to date information. A guide to support medical professionals in assessing fitness to drive can be found at https://www.gov.uk/government/publications/assessing-fitness-to-drive-a-guide-for-medicalprofessionals 2
Adverse Effects and Interactions SSRIs are better tolerated and safer in overdose than other antidepressants. Common side effects of SSRIs are headache, nausea, and anxiety/agitation, especially when starting treatment (usually settle on continued treatment). Other side effects are insomnia, tremor, akathisia, sweating, paraethesias, sexual dysfunction, including diminished libido and difficulty with erection and orgasm, muscle/joint pain, hyponatraemia, bruising/bleeding, weight changes and manic or psychotic symptoms. Tricyclic antidepressants have similar efficacy to SSRIs but are more likely to be discontinued because of side-effects and are toxic in overdose. Common side effects of tricyclics include anxiety, drowsiness, dizziness, agitation, confusion, anticholinergic effects (dry mouth, constipation, urinary retention and blurred vision); cardiovascular effects (hypotension, tachycardia, arrhythmias and other ECG changes - baseline ECG is advised, where appropriate); hepatic effects, changes in blood sugar, increased appetite, weight gain and sexual dysfunction can occur. Monoamine Oxidase Inhibitors (MAOIs) can have dangerous interactions with some foods and drugs, and should be reserved for initiation by consultants. Service users prescribed MAOIs require careful monitoring (blood pressure) and advice on dietary and drug interactions. When changing antidepressants, a suitable washout period (usually at least 14 days) should be allowed before or after using MAOIs. Mirtazapine has few antimuscarinic effects, but causes sedation during initial treatment and is associated with weight gain and blood dyscrasias. Relevant NICE Guidance NICE Clinical Guideline (CG90). Depression: the treatment and management of depression in adults (update). October 2009. Last updated: April 2018. Available at https://www.nice.org.uk/guidance/cg90. UNDER REVIEW. NICE Clinical Guideline (CG91). Depression in adults with a chronic physical health problem: Treatment and management. October 2009. Available at https://www.nice.org.uk/guidance/cg91. NICE clinical guideline (CG28). Depression in children and young people. September 2005. Last updated: September 2017. Available at: https://www.nice.org.uk/guidance/cg28. NICE Pathways: Depression http://pathways.nice.org.uk/pathways/depression NICE quality standards: Depression in adults quality standard Mar 2011- https://www.nice.org.uk/guidance/qs8 Depression in children and young people Sept 2013. https://www.nice.org.uk/guidance/qs48 3
Depression First Line: Relative Cost Notes Citalopram Has less drug/drug interactions; prolongs QT interval; contraindicated with other drugs that prolong QT Escitalopram Has less drug/drug interactions; prolongs QT interval; contraindicated with other drugs that prolong QT Sertraline Sertraline has a superior tolerability and is preferred in cardiac disease Mirtazapine Tabs/Orodispersible / Fluoxetine Long half life useful if compliance is an issue. Drug/drug interactions common - Second Line: Relative Cost Notes Useful where weight is not a concern and sedation is preferable; caution in liver impairment. Rare cases of bone marrow depression. Use with caution where there are risk factors for QT prolongation Venlafaxine Tablets XL capsules/tablets More toxic in overdose than SSRIs; higher risk of discontinuation reaction. Dose-related increases in blood pressure have been commonly reported with venlafaxine. Prolonged release formulations XL are more expensive than immediately released formulations. Lofepramine Least cardiotoxic of TCAs Trazodone Useful in anxiety and agitation where sedation is required Significant costs associated with trazodone liquid. Duloxetine Brand Care needed to use correct dosage regimen; associated with nausea and headache, and can also increase blood pressure. Paroxetine Higher incidence of discontinuation symptoms. Drug/drug interactions common Vortioxetine For major depressive episodes in adults whose condition has responded inadequately to 2 antidepressants within the current episode Third Line: Relative Cost Notes [Discuss third line options with Consultant before prescribing] Amitriptyline Titrate slowly toxic in overdose Fluvoxamine Nausea a problem; drug/drug interactions common; Caution in hepatic or renal impairment; Bradycardia with ECG changes has been noted; Imipramine Less sedating than other tricyclics with moderate antimuscarinic activity; Expensive Clomipramine Useful if OCD symptoms are present as well Doxepin Moderate sedative effects Moclobemide Use alone need to be careful with diet difficult to switch from 4
Depression continued Fourth Line: Relative Cost Notes [Seek Consultant Opinion before prescribing] Phenelzine Dietary problems. Washout period required when switching. Useful for atypical depression Mianserin Regular blood counts needed Nortriptyline Less postural hypotension and lower cardiotoxicity than other tricyclics; Expensive Agomelatine Liver function test required before and during use; Expensive; Specialist initiation and hospital use only Reboxetine Poor response rate and low tolerability; May lower serum potassium; Not licensed in older adults. Other Notes [Seek Consultant Opinion before prescribing] ECT Consider for severe, life-threatening depression when a rapid response is required, or when other treatments have failed OR for moderate depression unresponsive to multiple drug treatments and psychological treatment Benzodiazepine Tablets s Short-term treatment (usually no longer than 2 weeks) if anxiety, agitation and/or insomnia are a problem; Avoid in chronic anxiety symptoms; Use with caution in people at risk of falls. Augmentation Relative Cost Notes [Seek Consultant Opinion before prescribing] Add Lithium - Use in treatment resistant depression baseline and routine monitoring and blood tests needed Add Tryptophan Use in treatment resistant depression blood tests needed; Unlicensed in the UK; Named patient only Add Antipsychotic - Useful for depression with psychotic symptoms; monitor weight, lipids, glucose levels, side effects Not Recommended Notes Dosulepin Avoid due to increased cardiac risk and toxicity in overdose. Should not be started in new patients. St John s Wort - Avoid due to uncertainty about appropriate dose, persistence of effect, variation in available preparations and risk of serious interactions with other drugs Augmentation with lamotrigine, carbamazepine, buspirone, pindolol - Not routinely recommended because of insufficient evidence of effectiveness Trimipramine Significant costs associated with trimipramine prescribing. 5
Treatment of Resistant or Refractory Depression This requires a flexible approach Escalate antidepressant doses for an adequate duration Switch drugs ensuring that all drug classes have been tried optimally Augment the antidepressant with other drugs or combine two antidepressants Assure compliance Manage ADRs that may reduce compliance Monitor and review outcome of treatment Offer high-intensity psychological interventions eg CBT Options include 1 st choice Add lithium well established recommended by NICE Use combinations of antidepressants e.g. mirtazapine & venlafaxine OR an SSRI Add liothyronine (T3) 20mcg 50mcg daily may be better tolerated than lithium Augmentation of current therapy with bupropion or buspirone (less evidence-based) Use other antidepressants e.g. nortriptyline (TCA) or tranylcypromine (MAOI) 2 nd choice 3 rd choice Add lamotrigine, max 200mg daily SSRI and up to 60mg buspirone daily Venlafaxine >225mg daily recommended by NICE; Consider ECT for severe, life-threatening depression when a rapid response is required, or when other treatments have failed OR for moderate depression unresponsive to multiple drug treatments and psychological treatment. For further options please contact the Pharmacy department 6
Usual Recommended Treatment of Depression in Chronic Medical Conditions Co-morbidity Post stroke Diabetes Cardiovascular disease Epilepsy Hepatic Old age Renal impairment Elderly Musculoskeletal disease Migraine Recommended treatment In all chronic conditions any possible drug interactions must be considered as a matter of priority SSRIs Mirtazapine (small effect on INR causing an increase to INR) SSRIs fluoxetine best supported by data Venlafaxine Mirtazapine SSRIs preferably sertraline especially if also prescribed flecainide, propafenone. SSRIs not recommended if also prescribed warfarin, heparin or aspirin Mirtazapine Check choices with Medicines Information before use of any antidepressant Paroxetine SSRIs Mirtazapine In Parkinson s disease do not use SSRIs with MAO-B inhibitors e.g. selegiline Check choices with Medicines Information before use of any antidepressant Consider lower doses and increase slowly. Also consider co-morbidity SSRIs not recommended to be used with NSAIDs. If essential use a gastroprotective agent at the same time In people receiving triptans use mirtazapine / trazodone / mianserin or reboxetine If the above options for recommended treatments in co-morbidity have been used without an improvement in symptoms, then please contact the Pharmacy Department for more detailed and individualised advice. 7
Appendix 1 The Stepped-Care Model The least intrusive, most effective intervention is provided first. If a person does nor benefit from that intervention, or declines an intervention, they should be offered an appropriate intervention from the next step Focus of the intervention Nature of the intervention Step 4 Severe and complex depression 1 ; risk to life; severe self neglect Medication, high-intensity psychological interventions, electroconvulsive therapy, 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 2 and referral for further assessment and interventions Step 2 Persistent subthreshold depressive symptoms; mild to moderate depression Low-intensity psychological and psychosocial interventions, medication and referral for further assessment and interventions Step 1 All known and suspected presentations of depression Assessment, support, psychoeducation, active monitoring and referral for further assessment and interventions 1 Complex depression includes depression that shows an inadequate response to multiple treatments, is complicated by psychotic symptoms and/or is associated with significant psychiatric comorbidity or psychosocial factors 2 only for depression where the person also has a chronic physical health problem and associated functional impairment 8
Appendix 2 Relative Side Effects of Antidepressants Drug Some of the main side effects Drowsiness Weight gain Nausea Anticholinergic Sexual Cardiac effects effects problems Citalopram + + +++ + +++ + Sertraline + + +++ + +++ + Fluoxetine + + +++ + +++ + Escitalopram + + +++ + +++ + Mirtazapine +++ +++ o o o + Venlafaxine + + +++ ++ +++ ++ Moclobemide + + ++ ++ + ++ Amitriptyline +++ ++ ++ +++ ++ +++ Clomipramine +++ ++ ++ +++ ++ +++ Imipramine ++ ++ ++ ++ ++ +++ Nortriptyline ++ ++ ++ ++ ++ +++ Lofepramine ++ ++ ++ + ++ +++ Trazodone +++ + ++ o + +++ Paroxetine + + +++ + +++ + Fluvoxamine + + +++ + +++ + Reboxetine o o o +++ + ++ Duloxetine + + +++ ++ +++ ++ Vortioxetine - - ++ - - - Phenelzine + + ++ ++ ++ +++ Agomelatine o o o o o ++ Tryptophan + o + o o + Lithium + ++ + o o + +++ = relatively common; ++ = moderately common + = uncommon 0 = little or no effect 9
References 1. NICE Clinical Guideline (CG90). Depression: the treatment and management of depression in adults (update). http://www.nice.org.uk/guidance/cg90. 2. NICE Clinical Guideline (CG91). Depression in adults with a chronic physical health problem: Treatment and management. http://www.nice.org.uk/guidance/cg91. 3. NICE clinical guideline (CG28). Depression in children and young people http://www.nice.org.uk/guidance/cg28 (rapid update March 2015). 4. NICE technology appraisal guidance. Vortioxetine for treating major depressive episodes (TA367)November 2015. https://www.nice.org.uk/guidance/ta367 5. BAP Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2008 British Association for Psychopharmacology guidelines 2015. https://www.bap.org.uk/pdfs/bap_guidelines-antidepressants.pdf 6. BNF online (British Medical Association and the Royal Pharmaceutical Society of Great Britain). Online BNF online at: https://www.medicinescomplete.com/mc/bnf/current/ 7. Martindale The complete drug reference online at: http://www.medicinescomplete.com/mc/ [subscription required] 8. SPCs for all the drugs referred to in this guideline can be found in the Electronic Medicines Compendium (http://www.medicines.org.uk/emc/). 9. Bazire. Psychotropic Drug Directory 2016. Lloyd-Reinhold Communications. 10. The Maudsley Guidelines 12 th edition and online at The Maudsley Guidelines 11th edition and online at http://www.library.nhs.uk/booksandjournals/ebooks/ (NHS athens password required) 11. MHRA Drug Safety Update. Antidepressants: risk of fractures http://www.mhra.gov.uk/safetyinformation/drugsafetyupdate/con085136 12. MHRA Drug Safety Update. Agomelatine (Valdoxan): risk of liver toxicity reminder to test liver function before and during treatment http://www.mhra.gov.uk/safetyinformation/drugsafetyupdate/con468288 13. MHRA Drug Safety Update. Citalopram and escitalopram: QT interval prolongation new maximum daily dose restrictions (including in elderly patients), contraindications, and warnings http://www.mhra.gov.uk/safetyinformation/drugsafetyupdate/con137769 14. MHRA Drug Safety Update. Antidepressants: suicidal thoughts and behaviour - summary report. http://www.mhra.gov.uk/safetyinformation/drugsafetyupdate/con085185 15. NHS England. Items which should not routinely be prescribed in primary care: Guidance for CCGs. https://www.england.nhs.uk/wpcontent/uploads/2017/11/items-which-should-not-be-routinely-precscribed-in-pc-ccg-guidance.pdf 10