Case Study 10:

Depression

September 2000

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Scenario Mrs Bond is a 46 year old who is agitated, and complains of appetite loss and low mood over the previous two months. During the examination she is teary, complains of inability to sleep, and loss of interest in work and leisure activities. She has been stressed and unable to function at work. The patient denies any suicidal thoughts. Physical examination and other investigations are normal, and the diagnosis of major depression is made. You agree with Mrs Bond to schedule a series of appointments for counselling. Because of the severity of the symptoms, which meet diagnostic criteria for major depression, you decide to initiate antidepressant therapy.

Inside Results

In summary page 3 In detail page 4

Expert commentaries Dr Bill Lyndon page 9 A/Professor Dimity Pond page 12

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Case Study Results

Results in summary 1119 responses were received to this case study and the aggregate results of two hundred responses were compiled for feedback. Most respondents (74%) prescribed a selective serotonin reuptake inhibitor (SSRI) as initial antidepressant therapy. Sertraline (35%) and paroxetine (21%) were the most common. Tricyclic antidepressants (TCAs) were chosen for 11% of respondents and nefazodone, moclobemide and venlafaxine, combined, accounted for 14%. Over 88% of respondents indicated their choice of antidepressant was influenced by efficacy and adverse effect profiles. Reasons specified included proven effectiveness, past prescribing success and lower incidence of adverse effects with the SSRIs and newer antidepressants. Most prescribers (84%) of SSRIs would discuss the frequent adverse effects with the patient and of these 13% would also provide management advice for adverse effects, especially if symptoms persisted after 1-2 weeks. All the prescribers of nefazodone, venlafaxine and moclobemide would provide the patient with specific adverse effects. Half of these prescribers would also discuss management of adverse effects. The prescribers of TCAs would discuss the common adverse effects and included the warning to avoid alcohol and /or caution about driving machinery. Other important information given to the patient included delay in onset of action, timeframe of treatment, and importance of compliance. The majority of respondents would not prescribe any other drug therapy (64%). Of the 36% who would prescribe other drug therapy, 32% would prescribe a concomitant benzodiazepine. Only 4% indicated they would change antidepressant therapy if initial choice gave a poor response. Most respondents would maintain antidepressant therapy for a minimum of six months after initial response.

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Results in detail Question 1 What would you prescribe as initial antidepressant therapy? Choice of antidepressant and starting doses are shown in the table below.

Drug Brand name Starting dose Percentage respondents

SSRIs 25mg daily 1 25mg–50mg daily 2 50mg daily 30

Sertraline1 Zoloft

50mg-100mg daily 2 10mg daily 1 10mg-20mg daily 2

Citalopram2 Cipramil

20mg daily 8 10mg daily 3 10mg-20mg daily 1

Paroxetine1 Aropax

20mg daily 17 Fluoxetine Lovan, Prozac, Zactin

Auscap, DBL or SBPA Fluoxetine, Fluohexal

20mg daily 5

50mg daily 1 Fluvoxamine Luvox, Faverin 100 100mg daily <1

Other newer antidepressants 50mg twice daily 1 100mg twice daily 2 150mg twice daily 1

Nefazodone2 Serzone

300mg daily 1 75mg XR daily 3 Venlafaxine Efexor XR 150mg daily <1

Reversible monoamine oxidase A inhibitor 150mg twice daily 2 300mg twice daily 2 300mg daily <1

Moclobemide Aurorix, Arima, DBL Moclobemide

600mg daily <1 Tricyclic antidepressants

25mg daily4 3 50mg daily 1 75mg daily 4

Dothiepin Dothep, Prothiaden

75mg-150mg daily 1 Nortriptyline Allergon 75mg daily <1 Trimipramine Surmontil 75mg daily <1 Amitriptyline3 Endep, Tryptanol,

Tryptine, Amitrol 50mg daily <1

Doxepin3 Deptran, Sinequan 50mg daily <1 Other antidepressant therapy Mianserin Lumin, Tolvon 30mg daily <1 Other drug therapy

Oxazepam5 Murelax, Serepax, Alepam

15mg three times daily <1

1 One respondent gave a choice of either sertraline or paroxetine 2 One respondent gave a choice of either citalopram or nefazodone 3 One respondent chose either doxepin or amitriptyline 4 Five respondents would rapidly increase dose within a week to 75-150mg 5 One respondent chose oxazepam as initial therapy before prescribing an antidepressant

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Question 2 What influenced your choice of initial antidepressant drug therapy? Over 88% of respondents indicated their choice of antidepressant was influenced by efficacy and adverse effect profiles. The following table shows the reasons why prescribers chose one antidepressant over another.

Influenced by (%) Choice of initial antidepressant

Percentage respondents* Efficacy Adverse

effects Cost Other reasons

Sertraline 35 34 33 6 18 Paroxetine 21 18 16 3 10 Citalopram 11 9 11 4 3 Dothiepin 9 7 5 3 4 Moclobemide 5 5 5 2 1 Nefazodone 5 5 5 1 1 Fluoxetine 5 4 4 2 2 Venlafaxine 4 3 3 1 1 Fluvoxamine 2 2 2 1 1 Mianserin 1 1 1 1 0 Trimipramine 1 1 0 0 1 Nortriptyline 1 1 0 0 1 Amitriptyline 1 0 1 1 0 Doxepin 1 0 1 1 0 Oxazepam 1 1 0 0 0 * Several respondents gave more than one choice Common reasons given for choice of initial antidepressant are listed below: Efficacy

Proven effectiveness (literature or past experience) Equal efficacy to other antidepressants Quick onset of action Good for agitation and/or anxiety

Adverse effect profile

SSRIs Minimal adverse effects Less adverse effects than TCAs Better profile than other SSRIs

e.g. 40% of paroxetine prescribers and 24% of citalopram prescribers Causes less agitation Safer in overdose

Nefazodone Minimal adverse effects Better profile than SSRIs

e.g. of the nefazodone prescribers 55% indicated less insomnia, 27% less agitation, and 18% less sexual dysfunction.

Safer in overdose TCAs Benefit of sedation Better profile than SSRIs

e.g. less agitation Cost

SSRIs were comparable to others TCAs were cheaper

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Other influences Familiarity with prescribing the antidepressant SSRIs were considered better for compliance because of dosage schedule and

better adverse effect profile. Degree of sedation and anxiolytic properties Safety in overdose.

Question 3 What would be your target maintenance dose of antidepressant? The respondents’ choices of target maintenance doses are shown in the table below. Antidepressant Target maintenance dose Percentage

Respondents 50 mg daily 2 50-100 mg daily 18 100 mg daily 8 100-150 mg daily 3

Sertraline

max. 200 mg daily 3 20 mg daily 11 20-40 mg daily 7 40 mg daily 1 50 mg daily <1

Paroxetine

unspecified <1 20 mg daily 8 20-40 mg daily 2

Citalopram

max. 60 mg daily 1 20 mg daily 3 20-40 mg daily 1

Fluoxetine

40 mg daily 1 300 mg daily <1 Fluvoxamine 100-300 mg daily 1 100-150 mg daily 1 150mg-300mg twice daily 4

Nefazodone

200mg-300mg twice daily 2 75mg daily <1 75mg-150mg daily 1 150mg daily 2

Venlafaxine XR

max. 225mg daily <1 300mg-600mg daily 2 600mg daily 2

Moclobemide

600mg-1200mg daily 1 50mg-150mg daily 4

100mg-150mg daily 1 150mg daily 3

Dothiepin

150mg-200mg daily 1 Nortriptyline 75mg-150mg daily <1 Doxepin 150mg daily <1 Amitriptyline 150mg daily <1 Trimipramine 75mg daily <1 Mianserin 30mg-90mg daily 1 Question 4 What specific information about antidepressant therapy would you give the patient? From prescribers of SSRIs 84% of prescribers of SSRIs would discuss common adverse effects with the patient.

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Specific adverse effects of SSRIs discussed Percentage respondents* Gastrointestinal disturbances / nausea 49 Sleep disturbances / insomnia 32 Agitation or anxiety 25 Sexual dysfunction 17 Headache 9 Nervousness / tremor 5 Dizziness 5 Serotonin syndrome 2 **Others 8 * Respondents may have indicated more than one adverse effect ** Several respondents indicated weight gain as an adverse effect of paroxetine Other specific information given to patients on SSRIs Other specific information on SSRIs Percentage respondents Delay in onset of action 60 Timeframe of treatment / time until maximum effect 33 Compliance & need for counselling or review 18 Drug interactions 15 Advised not to stop abruptly 11 Mode of action 12 Dosing schedule 7 No addiction 7 Caution with driving / machinery or alcohol 5 Other 7 For prescribers of nefazodone, venlafaxine & moclobemide All respondents mentioned specific common adverse effects. Gastrointestinal adverse effects were mentioned for nefazodone. Dry mouth and dizziness were specifically mentioned for moclobemide. Half of the respondents commented on adverse effect management, if problematic. Other information to be provided included delay in onset of action, timeframe of treatment and importance of compliance. For prescribers of TCAs The specific adverse effects mentioned by these respondents (11%) included sedation or drowsiness, gastrointestinal disturbances, anticholinergic effects and postural hypotension. Of these respondents 54% advised the patient to avoid alcohol and/or cautioned about driving machinery. Delay in onset of action, timeframe of treatment and the need for counselling were also commonly mentioned.

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Question 5 Would you prescribe any other drug therapy? If yes, what drug, dose and frequency? Most respondents (64%) would not prescribe any other drug therapy. One third of the respondents (36%) who considered prescribing other drug therapy interpreted the question in two ways. Concomitant therapy Some respondents (32%) who considered co-prescribing with an antidepressant chose benzodiazepines. The most common benzodiazepine prescribed was temazepam 10mg at night. Two-thirds of these prescribers also stated that the length of treatment should only be 1-2 weeks or short term to overcome initial insomnia. Alternative therapy if poor response A small number (4%) of respondents assumed that the question was about alternative selection of an antidepressant if there was a poor response to the first agent chosen. Examples of the suggested alternatives of antidepressant therapies are listed below. Other drug therapies prescribed if poor response to initial choice

Oxazepam to paroxetine Sertraline to paroxetine Sertraline to moclobemide Moclobemide to fluoxetine Moclobemide to doxepin Fluoxetine to nefazodone Citalopram to TCA Sertraline to TCA

Question 6 For how long after initial response would you expect to maintain antidepressant therapy? A minimum of six months was the most common length of treatment chosen. Summary of responses are shown below. Months of antidepressants therapy after initial response Percentage respondents 0-3 months 7 3-6 months 14 6 months 40 6-12 months 29 12 months 5 12-24 months 3 5% of respondents gave nonspecific answers or stated the duration of treatment depended on frequency of recurrent episodes.

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Expert commentary

Dr Bill Lyndon Psychiatrist, Mood Disorder Unit, Northside Clinic, Sydney Lecturer, Department of Psychological Medicine, University of Sydney This is a typical presentation of depression in general practice. Key points are that the symptoms meet diagnostic criteria for depression, so treatment is required, and that the severity of symptoms and degree of loss of psychosocial functioning are sufficient to warrant antidepressant treatment as part of the management. The suicide risk appears low, so management in the general practice setting is appropriate. Question 1 What would you prescribe as initial antidepressant therapy? There are no apparent comorbid medical or psychiatric illnesses present which might influence the choice of antidepressant. Nearly 90% of respondents chose one of the newer antidepressants over the tricyclics and the majority chose an SSRI. Any of the new antidepressants would have been an appropriate first choice and it is interesting that the SSRIs were favoured over nefazodone, moclobemide and venlafaxine. There are no apparent clinical features which would support choosing an SSRI over the other new drugs, so other factors are clearly relevant. Choosing a tricyclic first in a young healthy woman is not unreasonable, but the advantages of the newer drugs indicate that these are a better first choice for most cases. Most respondents chose an appropriate and standard starting dose. Some chose smaller starting doses and in an agitated, anxious patient or in a patient with a past history of antidepressant induced agitation this would be sensible. Starting with too high a dose is to be avoided because of the added side effect burden and probable loss of compliance. Some chose a large starting dose: for nefazodone ≥300mg, for moclobemide of 600mg and for dothiepin ≥75mg. These starting doses would be poorly tolerated by many patients. Question 2 What influenced your choice of initial antidepressant drug therapy? Most respondents accept that there is little if any difference in efficacy between the various antidepressants and based their choice on other factors, namely safety, side effect profile, simplicity of dosing and familiarity with the particular drug. Cost did not figure prominently, so presumably the advantages of the new drugs are considered to outweigh the cost advantages of the tricyclics. Most clinicians would also be aware that although the cost to the patient of TCAs is less, indirect costs as a result of non-compliance, side effects or iatrogenic illness associated with tricyclics tend to reduce the cost differential. The SSRIs have varying capacities for causing agitation, insomnia and sexual dysfunction and there is also wide individual variation among patients to develop side effects to a particular SSRI. It is therefore difficult to generalise about the side effect potential of a particular drug for a particular patient and clinicians should be prepared to switch from one SSRI to another if the first choice proves unacceptable. It is likely that those who chose a TCA did so because of the sedating properties and to avoid worsening the patient’s insomnia. While this is reasonable, it is important to note that sleep is not always worsened by the newer drugs; it is often improved and if there is a problem it is likely to be temporary and appropriately managed with short term use of a hypnotic. Similarly, the new

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antidepressants often have a calming effect on anxious, agitated patients and should not be avoided for this reason only. The side effect of sexual dysfunction was considered by a minority of respondents. While this may not be relevant to the majority of depressed patients in the acute phase, it is likely to become more of an issue after recovery and may become an important reason to consider changing antidepressant. Question 3 What would be your target maintenance dose of antidepressant? In general, antidepressants need to be given at full dosage for maintenance treatment and not reduced. The answers mostly are consistent with this. There was a trend for some antidepressants to be given at higher doses during the maintenance phase, which probably reflects an expectation that for SSRIs at least, doses would need to be increased above the starting dose to achieve remission. This trend was more noticeable for sertraline and paroxetine than for the other SSRIs and other new antidepressants. This suggests that doses for sertraline and paroxetine may be escalated too rapidly and unnecessarily. For most patients on SSRIs, the starting dose will be adequate to produce response and dose increases should not be necessary before 3-4 weeks. There is no doubt that some patients will require these higher doses but the majority will not. Doses given for nefazodone may be inadequate – 400-600mg will be needed for most patients. Similarly, the doses for the TCA dothiepin are low, less than 150mg mostly, and this would generally be considered to be subtherapeutic. It has long been appreciated that TCAs are generally used in inadequate doses in general practice. Question 4 What specific information about antidepressant therapy would you give the patient? Most respondents indicated they would give appropriate advice about the antidepressant, but the breakdown figures indicate that some important advice is not being given. A minority only would warn about insomnia, agitation, sexual dysfunction and abrupt discontinuation. The timeframe of response does not appear to be adequately discussed. All patients should be informed of the delayed onset of action and that response may not be achieved in less that 3-4 weeks or possibly 4-6 weeks. Unrealistic patient or doctor expectations of recovery may lead to non-compliance, premature discontinuation or pressure to increase doses or change drugs.

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Question 5 Would you prescribe any other drug therapy? If yes, what drug, dose and frequency? Short-term use of a hypnotic such as temazepam can be very useful to assist with the insomnia of depression or antidepressant induced insomnia. Most respondents accept the usefulness of this strategy. Benzodiazepine anxiolytics were nominated by a small number of respondents only and this is consistent with good practice. There is no history of anxiety with this patient and therefore no reason to prescribe an anxiolytic. In particular, there are no panic symptoms and alprazolam therefore does not have a place. Anxiolytics may at times be a helpful addition, but the anxiety associated with depression will usually settle quickly once treatment has commenced, even with the SSRIs. If a patient develops severe agitation with an antidepressant, which does not settle, changing antidepressant should be considered as an alternative to adding an anxiolytic. Changing if poor response This raises some interesting points of how to manage this problem. Some (4%) of respondents volunteered that they would change to another antidepressant if the first choice was ineffective. If the first choice is ineffective, then a second trial with a different antidepressant, preferably from a different class, is the correct action. There is inadequate evidence to support the efficacy of combining antidepressants and there are significant risks of drug-drug interactions leading to delayed metabolism and potentially dangerous serum levels (e.g. SSRIs + TCAs), as well as serotonin syndrome (combine SSRIs + MAOI, SSRI + SSRI). Combining antidepressants is not a strategy for use in general practice and it is debatable whether it is appropriate in psychiatric practice. Question 6 For how long after initial response would you expect to maintain antidepressant therapy? Assuming this is a first episode and the patient does not suffer from recurrent depression, then the medication should be continued for 6 months. With recurrent depression, 6-12 months or longer, possibly indefinitely, is more appropriate. Six to12 months would also be appropriate following severe episodes with profound loss of functioning especially if the risk of suicide is high. A significant minority of respondents elected to continue medication for greater than 6 months, which would be unnecessary for the patient described, provided that full remission is achieved and there are no ongoing unresolved risk / aetiological factors.

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Associate Professor Dimity Pond Société Professor in General Practice, Faculty of Medicine & Health Sciences, University of Newcastle This is a typical case in General Practice, although in real life I would like to look at current stressors as well as noting the symptoms of depression during the first consultation. I would also assess her for any symptoms of psychotic depression (e.g visual or auditory hallucinations) as well as for suicidality. The presence of either would increase the likelihood that I would refer her for specialist review. Question 1 What would you prescribe as initial antidepressant therapy? 88% of respondents would prescribe one of the newer antidepressant agents as initial drug therapy. I would tend to agree with them. Question 2 What influenced your choice of initial antidepressant drug therapy? My choice would be influenced by the superiority of the newer agents in the case of overdose. Although this patient denies suicidality, this possibility should always be considered in a case of major depression. Many GPs commented on the side effect profiles of SSRIs compared with tricyclics. While SSRIs avoid many of the unpleasant side effects of the tricyclics, such as dry mouth and drowsiness, there are still a number of possible side effects with all the newer agents, including agitation and sexual dysfunction, and these should be discussed with the patient. The agitation this patient is already exhibiting might provide a rationale for prescribing one of the older more sedating tricyclics. However, this needs to be balanced against her need to function at work and home and the risk of suicide. Question 3 What would be your target maintenance dose of antidepressant? The target maintenance dose should be that which maintains the patient’s function and keeps her as free as possible from the symptoms of depression, provided that side effects are taken into account. Question 4 What specific information about antidepressant therapy would you give the patient? I believe it is essential to discuss possible side effects with the patient and refer her to the consumer medicines information (CMI) leaflet to ask her to ring if she experiences any symptoms she doesn’t understand. It is also very important to emphasise that all antidepressants take time to work, and it may be a number of weeks before she notices an improvement. I like to support patients to follow up visits during this period of waiting. Furthermore, I usually point out that counselling is an important part of treating depression, and that there may be some ways in which she can learn to help herself through this difficult illness. I would also tell her that she would need to stay on the therapy for at least six months, and that she should not stop it suddenly, or she may suffer from discontinuation effects.

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Question 5 Would you prescribe any other drug therapy? If yes, what drug, dose and frequency? I wouldn’t prescribe any other drug therapy at this stage. Later in the course of the illness, of any initial drug therapy had failed over sufficient time (e.g 3-6 months), then I would consider changing her to a different class of agent. Some respondents suggested the use of benzodiazepine in this setting. Benzodiazepines can be used to tide a patient over until the antidepressant starts to work, but the possibility of addiction and of withdrawal agitation needs to be balanced against the short-term benefit. Question 6 For how long after initial response would you expect to maintain antidepressant therapy? In my view, antidepressant therapy needs to be regarded as long term. I would not consider cutting down on the maintenance dose in under 3 months, and normally expect patients to stay on this therapy for at least six months. Some patients may need to stay on antidepressants longer than this.