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]

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 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]

In adults, a definitive link has not been established between SSRIs and suicidal behaviour

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[10–12]
• 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.

Monitor suicide risk — especially in the early stages of treatment. Worsening depression and emergence of suicidality may occur with treated or untreated depressive illness

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)
• 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. www.moodgym.anu.edu.au)
• 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 invmoderate 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]

Combine antidepressants with psychological treatment in chronic and recurrent depression

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]

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 (www.psychsupport.com.au or call 1 800 200 588).

Visit the Royal Australian College of General Practictioners 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.

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.

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).

Table 1: Drugs that may be involved in serotonin syndrome[25,26]

 * Reported cases have involved intravenous chlorpheniramine (not available in Australia).[26]

Table 2: Clinical features of serotonin syndrome[26]

† Hypertonia and clonus are symmetrical and more obvious in lower limbs to begin with; clonus is the most important distinguishing feature in diagnosis.

Expert reviewers

Dr Chris Holmwood

Director, South Australian Prison Health Service

Associate Professor Geoff Riley

References

1. National Institute for Clinical Excellence. Depression:management of depression in primary and secondary care. Clinical Guideline 23. London: NICE, 2004. (accessed 20 June 2005).

2. Ellis PM, et al. Med J Aust 2002;176 (Suppl):S77–83.

3. Therapeutic Guidelines: Psychotropic. Version 5, 2003.

4. Diagnostic and statistical manual of mental disorders. 4th edn.Washington DC: American Psychiatric Association, 1994.

5. American Psychiatric Association. Am J Psychiatry 2003;160 (Suppl):1–60.

6. 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, 2004. (accessed September 2005).

7. Hammad TA. Review and evaluation of clinical data. FDA Center for Drug Evaluation and research, 2004.(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, 2004. (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, 2005.(accessed August 2005).

10. Adverse Drug Reactions Advisory Committee. Aust Adv Drug Reactions Bull 2005;24.

11. Committee on Safety of Medicines. Report of the CSM Expert Working Group on the safety of selective serotonin reuptake inhibitor antidepressants, 2004. (accessed January 2005).

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16. Paykel ES, et al. Psychol Med 2005;35:59–68.

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19. Hollon SD, et al. Arch Gen Psychiatry 2005;62:417–22.

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21. Nolan P, Badger F. J Psychiatr Ment Health Nurs 2005;12:146–53.

22. American Psychiatric Association. Am J Psychiatry 2000;157:1–45.

23. Gask L, et al. Br J Gen Pract 2003;53:278–83.

24. McManus PM, et al. Aust N Z J Psychiatry 2004;38:450–4.

25. Australian Medicines Handbook 2005.

26. 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. 37–49.