thirty two Prescribing Practice Review PPR Managing depression in primary care

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1 November 2005 PPR thirty two Prescribing Practice Review PPR For General Practice Managing depression in primary care Key messages Use non-drug therapy first in mild depression, as it is unclear if antidepressants are better than placebo The evidence that antidepressants are better than placebo is in moderate to severe depression Continue antidepressants in moderate to severe depression for at least 6 months after symptoms improve Advise patients what to expect from drug therapy: likely adverse effects, up to 4 6 weeks for effect and the expected duration of treatment Always ask about suicidal thoughts and assess risk, especially during initial treatment Establish the diagnosis of depression and its severity then treat accordingly Assess symptoms, severity, functioning and suicide risk The main deficiencies in prescribing these drugs [antidepressants] have been the undertreatment of patients with major depression and the inappropriate treatment of patients who are not clearly depressed. Therapeutic Guidelines: Psychotropic, 2003 The evidence for efficacy of antidepressants is in moderate to severe major depression. 1,2 There is insufficient evidence in mild depression to support the use of antidepressants, and non-drug therapy is first line. 1 3 Mild depression involves fewer symptoms* and minimal functional impairment. With increasing severity, there are more symptoms, of greater intensity (including suicidal intent) and more significant functional disability. 4 Assess drug and alcohol use when making the diagnosis; substance abuse may be primary or comorbid and affect treatment (see Table 1 for illicit drugs involved in serotonin syndrome). Also, check for psychosocial stressors that require non-drug interventions (e.g. bereavement). Seek psychiatric assessment and treatment for patients with significant suicide risk (urgent); psychotic symptoms; marked psychomotor agitation or retardation, which may suggest more severe (melancholic) depression; history of mania or evidence of bipolar depression. 3 * A diagnosis of major depression according to the DSM-IV requires at least 5 symptoms. Either depressed mood or loss of interest or pleasure must be present; other symptoms are appetite or weight change, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, feelings of worthlessness or guilt, impaired thinking or concentration, indecisiveness, and suicidal thoughts or thoughts of death. 4 National Prescribing Service Limited ABN l Level 7/418A Elizabeth Street Surry Hills NSW 2010 l PO Box 1147 Strawberry Hills NSW 2012 Phone: l Fax: l info@nps.org.au l web:

2 Evaluating suicide risk is a key aspect of assessing depression Always ask about suicide asking does not cause suicidal behaviour 5 When assessing suicide risk, consider: suicidal ideation suicidal intent whether there is a plan, or rehearsal of a plan access to means of suicide if there is a history of self-harm or suicide attempts. 3,5 Seek urgent psychiatric assessment and treatment for those with significant risk and closely monitor others. In children and adolescents, antidepressants may increase suicidal behaviour and have a poor benefit to harm ratio In adults, a definitive link has not been established between SSRIs and suicidal behaviour Monitor suicide risk especially in the early stages of treatment. Worsening depression and emergence of suicidality may occur with treated or untreated depressive illness In children and adolescents, antidepressants have little evidence of efficacy but an increased risk of suicidal thoughts and behaviour 4% for antidepressants compared with 2% for placebo (relative risk, 1.78; 95% CI, 1.14 to 2.77). 6,7 Fluoxetine has some evidence of efficacy but similar risk. No antidepressant is approved for paediatric depression in Australia. 8 Regulatory review in adults 9 continues key findings so far are: there is not conclusive evidence from randomised trials that selective serotonin reuptake inhibitors (SSRIs) increase suicidal ideation and behaviour compared with placebo, but an increased risk in some individuals cannot be completely ruled out for most adults with major depression treated with SSRIs, likely benefits outweigh likely harms 10,11 observational data show no apparent difference in rates of suicidal behaviour or self-harm between patients prescribed SSRIs or other antidepressants. 10,11 Such data cannot determine causality. The Adverse Drugs Reactions Advisory Committee advises that when an antidepressant is prescribed to an adult, child or young person: closely monitor patients for suicidality (suicidal thoughts and behaviours) in the first weeks of treatment and when changing dose consider changing or discontinuing therapy if there are new or worsening symptoms of suicidality advise patients and caregivers to monitor for worsening illness, suicidal or self-harm-related thoughts or behaviours and to seek medical assistance immediately if these occur. 10 Consider the role of non-drug treatments in the management plan In mild depression non-drug therapies are first line Provide information and education about depression to all patients with depression. The following non-drug strategies have some evidence supporting their use in mild depression: brief cognitive behavioural therapy (CBT) or interpersonal therapy (IPT) (6 8 sessions)

3 problem-solving therapy physical exercise (structured, supervised 2 3 sessions per week) guided self-help books based on CBT principles computer-based CBT (e.g. supportive counselling by a GP or other health professional. 1,13 These may also be considered as adjuncts to antidepressants in moderate depression. Consider CBT and IPT in moderate depression Combine antidepressants with psychological treatment in chronic and recurrent depression In moderate major depression, CBT and IPT have the best published evidence. These can be an effective alternative to antidepressants (16 20 sessions over 6 months). 1,3 In more severe depression, long-term or recurrent depression (chronic depression), antidepressants are usually required but a combination of psychological treatment and antidepressant drugs shows evidence of better outcomes than either therapy alone. 1 Full response to antidepressant drug treatment may take 4 6 weeks Monitor response to treatment in the first 4 6 weeks to guide ongoing treatment Some antidepressant effect is usually observed after 1 2 weeks, but full effects may take 4 6 weeks. 3 If there is a partial response after 4 6 weeks, a longer trial or increased dose of the same drug is reasonable. If there is no response at all after 4 weeks, response is unlikely. 1,14 Older people should be started at a lower dose and may take longer to respond; lower maximum doses may apply. If response to an adequate trial of the initial medication is poor, switch to a different drug class after checking compliance, correct diagnosis and other contributing factors. 3 If changing treatment because of adverse effects, it is reasonable to try another drug in the same class (see Therapeutic Guidelines: Psychotropic for comparative adverse effects). Treat depression beyond the acute phase of symptom remission Continue antidepressant treatment for at least 6 12 months in moderate to severe depression The goal of acute treatment is to reduce symptoms and improve functioning. The aim in the continuation and maintenance phase of treatment is to prevent relapse. Relapse is most likely in the early stages of recovery. About 40% of patients in antidepressant trials relapsed in the first 6 12 months after initial improvement, but the rate was halved in those who continued antidepressants, compared with those switched to placebo (odds ratio, 0.30; 95% CI, 0.2 to 0.4). This was mostly in those with a high risk of recurrence. 15 The likelihood of further depressive episodes increases with each recurrence; guidelines state that subsequent episodes require longer maintenance therapy of 2 3 years. 1,2 When reviewing ongoing need, consider the number of prior episodes, their proximity, related functional impairment and the presence of residual symptoms. 1,2

4 Consider psychological therapy for relapse prevention If residual symptoms exist after adequate treatment, or there was a long period of illness ( 2 years), adding CBT or IPT to continuing drug treatment can further reduce the risk of relapse for up to 4 years. 1,16 18 Booster sessions in the maintenance phase may preserve improvement in those who have responded to treatment. For example, 3 4 booster CBT sessions in the 12 months after remission was equivalent to ongoing drug therapy in preventing relapse, in a recent trial. 19 Depression can be a chronic condition 20 follow up and monitor Persistence with follow-up to achieve remission and prevent relapse may be more important than initial treatment choice. 2 Patients may be less likely to actively seek help when they are no longer acutely depressed. 21 Encourage patients to recognise signs of recurrence, avoid likely triggers and seek help early if symptoms recur. 22 I just think what s the point in going back to see [the doctor]? He can t do anything. Nobody can do anything. It s just... something I ve got to work through myself isn t it? Person with depression when asked about her need for GP review 23 GPs can access extra remuneration, training and services for treating depression The Better Outcomes in Mental Health Care initiative includes: education and training for GPs: required for participation the 3 Step Mental Health Process: a Service Incentive Payment for GPs focussed psychological strategies: MBS item numbers for trained GPs providing these therapies access to allied psychological services: funding of additional psychological services through participating local divisions of general practice access to psychiatrist support: new MBS items (291 and 293) for psychiatrists to provide a one-off assessment and GP management plan. Access to non-urgent psychiatric opinion through GP Psych Support ( or call ). See or your local division of general practice for more information. Advise patients about what to expect from antidepressant drugs Empower patients by treating them as active partners in understanding and managing depression In Australia, 1 in 2 patients who start antidepressant therapy will no longer be taking any antidepressant 2 months later. 24 People with depression may respond negatively to the suggestion of antidepressant medicine from their doctor, be unconvinced of benefits or feel stigmatised by the prescription. 21 The health professional s conviction that treatment can be effective may help counter negative thoughts and attitudes due to depression. I feel if I had not been asked specifically to come back, I would not have done so when you are very depressed your self-esteem is in the gutter and you feel that no one is interested in how you are getting on. Taking tablets endlessly makes you feel that there is no end in sight and you need constant encouragement 57-year-old woman with depression 21

5 Be familiar with the adverse effects of antidepressants and address concerns at follow-up visits Advise patients: that some adverse effects are likely, describe what these are and that most will subside after 1 2 weeks it can take up to 4 6 weeks for antidepressants to work fully that antidepressants will need to be continued for at least 6 months after symptoms improve, to prevent a relapse to return to their doctor if they are concerned by adverse effects they experience that there are other treatments that can be tried not to stop taking antidepressants abruptly, as this can cause unpleasant adverse effects that non-prescription and complementary medicines may interact with antidepressants. Reinforce medication advice at subsequent visits or with written information. Suggest or provide the consumer medicine information (CMI) for the drug prescribed. An information leaflet for patients who have been prescribed an antidepressant has been developed by NPS; photocopy the enclosed insert or download from (follow the links to this PPR). Start low to limit adverse effects Anxiety and agitation are common adverse effects of SSRIs and venlafaxine, especially at initiation. To limit these and other adverse effects, start with a lower dose (50% of the usual starting dose) and titrate over 2 4 weeks, especially in patients with comorbid anxiety. 22 See the Australian Medicines Handbook for a list of common adverse effects. 25 Watch for serotonin syndrome Encourage patients to: tell other doctors and pharmacists about their antidepressant when another drug is prescribed or purchased ask if they are safe to use together Serotonin syndrome (see Table 2) is not an idiosyncratic response; it is a toxic effect resulting from too much serotonin. It has been observed with: overdose of a single agent (usually SSRIs) simultaneous use of two drugs that increase serotonin levels or serotonergic transmission failing to observe an adequate washout period when switching antidepressants. 26 Fatalities have most often occurred through use of two drugs with different mechanisms for increasing serotonergic activity for example monoamine oxidase inhibitors (MAOIs) or moclobemide used with any drug that inhibits re-uptake of serotonin (SSRIs, some tricyclic antidepressants (TCAs), tramadol). The first drug may have been discontinued weeks earlier in some cases hence the need for washout periods. 26 Risky situations include prescribing of interacting drugs by other doctors, use of over-the-counter (OTC) medicines such as St John s wort or dextromethorphan, and use of illicit drugs such as ecstasy (see Table 1).

6 Table 1: Drugs that may be involved in serotonin syndrome 25,26 Antidepressants MAOIs, mirtazapine, moclobemide, SSRIs, TCAs (especially clomipramine, imipramine), venlafaxine Analgesics OTC and complementary medicines dextropropoxyphene, pethidine, tramadol brompheniramine, chlorpheniramine*, dextromethorphan (in many cough/cold preparations), panax ginseng, St John s wort, S-adenosylmethionine (SAMe) Stimulants diethylpropion, hallucinogenic amphetamines, methylphenidate, phentermine Anti-migraine drugs Others Illicit drugs dihydroergotamine, naratriptan, sumatriptan, zolmitriptan buspirone, linezolid, lithium, selegiline, sibutramine, tryptophan MDMA (ecstasy), LSD, cocaine * Reported cases have involved intravenous chlorpheniramine (not available in Australia). 26 Table 2: Clinical features of serotonin syndrome 26 Mental Neuromuscular Autonomic confusion, agitation, hypomania, hyperactivity, restlessness clonus (spontaneous, inducible or ocular), hyperreflexia, hypertonia, ataxia, tremor hyperthermia, sweating, tachycardia, hypertension, mydriasis, flushing, shivering Hypertonia and clonus are symmetrical and more obvious in lower limbs to begin with; clonus is the most important distinguishing feature in diagnosis. Reviewers Dr Chris Holmwood Director, South Australian Prison Health Service Associate Professor Geoff Riley Head, School of Psychiatry and Clinical Neuroscience Faculty of Medicine and Dentistry University of Western Australia References 1. National Institute for Clinical Excellence. Depression: management of depression in primary and secondary care. Clinical Guideline 23. London: NICE, (accessed 20 June 2005). 2. Ellis PM, et al. Med J Aust 2002;176 (Suppl):S Therapeutic Guidelines: Psychotropic. Version 5, Diagnostic and statistical manual of mental disorders. 4th edn. Washington DC: American Psychiatric Association, American Psychiatric Association. Am J Psychiatry 2003;160 (Suppl): FDA Center for Drug Evaluation and Research. FDA Public Health Advisory. Suicidality in children and adolescents being treated with antidepressant medications. Washington: US Department of Health and Human Services, cder/drug/antidepressants/ssripha htm (accessed September 2005). 7. Hammad TA. Review and evaluation of clinical data. FDA Center for Drug Evaluation and Research, b1-10-TAB08-Hammads-Review.pdf (accessed September 2005). 8. Adverse Drug Reactions Advisory Committee. Use of SSRI antidepressants in children and adolescents (Dated 15 October 2004). Canberra: Commonwealth of Australia, adr/adrac_ssri.htm (accessed September 2005). 9. FDA Center for Drug Evaluation and Research. FDA Public Health Advisory. Suicidality in adults being treated with antidepressant medications. Washington: US Department of Health and Human Services, htm (accessed August 2005). 10. Adverse Drug Reactions Advisory Committee. Aust Adv Drug Reactions Bull 2005; Committee on Safety of Medicines. Report of the CSM Expert Working Group on the safety of selective serotonin reuptake inhibitor antidepressants, afetymessages/ssrifinal.pdf (accessed January 2005). 12. Gunnell D, et al. BMJ 2005;330: Jorm AF, et al. Med J Aust 2002;176 (Suppl):S Quitkin FM, et al. Arch Gen Psychiatry 1996;53: Geddes JR, et al. Lancet 2003;361: Paykel ES, et al. Psychol Med 2005;35: Klein DN, et al. J Consult Clin Psychol 2004;72: Fava GA, et al. Am J Psychiatry 1996;153: Hollon SD, et al. Arch Gen Psychiatry 2005;62: Andrews G. BMJ 2001;322: Nolan P, Badger F. J Psychiatr Ment Health Nurs 2005;12: American Psychiatric Association. Am J Psychiatry 2000;157: Gask L, et al. Br J Gen Pract 2003;53: McManus PM, et al. Aust N Z J Psychiatry 2004;38: Australian Medicines Handbook Gillman K, Whyte IM. Serotonin syndrome. In: Haddad P, et al, eds. Adverse syndromes and psychiatric drugs: a clinical guide. Oxford: Oxford University Press, 2004; pp The information contained in this material is derived from a critical analysis of a wide range of authoritative evidence. Any treatment decisions based on this information should be made in the context of the clinical circumstances of each patient. National Prescribing Service Limited (NPS) is a member-based organisation providing accurate, balanced, evidence-based information and services to health professionals and the community on Quality Use of Medicines (QUM). To achieve this we work in partnership with GPs, pharmacists, specialists, other health professionals, government, pharmaceutical industry, consumer organisations and the community. NPS is an independent non-profit organisation funded by the Australian Government Department of Health and Ageing. NPSP0151