Acta Psychiatr Scand 2009: 119 (Suppl.

439): 8–26  2009 John Wiley & Sons A/S

All rights reserved ACTA PSYCHIATRICA
DOI: 10.1111/j.1600-0447.2009.01382.x SCANDINAVICA

Clinical overview
Clinical practice recommendations for
depression
Malhi GS, Adams D, Porter R, Wignall A, Lampe L, OÕConnor N,
Paton M, Newton LA, Walter G, Taylor A, Berk M, Mulder RT.
Clinical practice recommendations for depression.
Objective: To provide clinically relevant evidence-based
recommendations for the management of depression in adults that are
informative, easy to assimilate and facilitate clinical decision making.
Method: A comprehensive literature review of over 500 articles was
undertaken using electronic database search engines (e.g. MEDLINE,
PsychINFO and Cochrane reviews). In addition articles, book chapters
and other literature known to the authors were reviewed. The findings
were then formulated into a set of recommendations that were
developed by a multidisciplinary team of clinicians who routinely deal
with mood disorders. The recommendations then underwent
consultative review by a broader advisory panel that included experts
in the field, clinical staff and patient representatives.
Results: The clinical practice recommendations for depression
(Depression CPR) summarize evidence-based treatments and provide a
synopsis of recommendations relating to each phase of the illness. They
are designed for clinical use and have therefore been presented
succinctly in an innovative and engaging manner that is clear and
informative.
Conclusion: These up-to-date recommendations provide an evidence-
based framework that incorporates clinical wisdom and consideration
of individual factors in the management of depression. Further, the
novel style and practical approach should promote uptake and
implementation.
G. S. Malhi1,2,3, D. Adams1,2,
R. Porter4, A. Wignall5,
L. Lampe1,2,3, N. OÕConnor3,6,
M. Paton2, L. A. Newton2,
G. Walter3,5, A. Taylor2,
M. Berk7,8,9, R. T. Mulder4
1
CADE Clinic, Department of Psychiatry, Royal North
Shore Hospital, 2Northern Sydney Central Coast Mental
Health Drug and Alcohol, Northern Sydney Central
Coast Area Health Service, 3Discipline of Psychological
Medicine, University of Sydney, Sydney, NSW,
Australia, 4Department of Psychological Medicine,
University of Otago, Christchurch, New Zealand, 5Child
and Adolescent Mental Health Services, NSCCAHS,
6
Sydney South West Area Health Service, Sydney,
NSW, 7Barwon Health and the Geelong Clinic,
Melbourne University, 8Orygen Research Centre,
Melbourne University and 9Mental Health Research
Institute, Melbourne, Vic., Australia
Key words: major depression; treatment
recommendations; clinical practice guidelines;
evidence-based review
Professor Gin S. Malhi, CADE Clinic, Level 5, Building
36, Royal North Shore Hospital, St Leonards, Sydney,
NSW 2065, Australia. E-mail: gmalhi@med.usyd.edu.au

Clinical recommendations
• The management of depression should be based on a combination of data-driven evidence and
clinical experience.
• Management strategies should be tailored to the individual so as to SET A PACE for treatment that
matches the phase of illness.
• Consideration should be given to the clinical context, potential comorbidities and the quantification
of symptom severity using rating scales.
• Psychological strategies should be given greater consideration.

Additional comments
• The clinical practice recommendations (CPR) for depression should be used in conjunction with
other recognized sources to guide the management of depression.
• Practice recommendations or treatment guidelines cannot fully capture the myriad of variables
unique to each individual and thus need to be used flexibly alongside consideration of the person,
their sociocultural context and availability of resources.
• The Depression CPR focus on the management of depression in adults. Special populations,
comorbidities and novel treatments have not been reviewed in detail.

8

Introduction
Depression is a common illness that usually emerges
early in life and affects women more often than men.
Recurrent by nature, unipolar depression is associ-
ated with considerable morbidity and a significant
risk of mortality through suicide (1). Indeed,
amongst the causes for numbers of life years lost,
because of disability, illness and premature death,
unipolar depression ranks high and is predicted to
become the second most important contributor to
disability by the year 2020 (2). Surprisingly, despite
its prevalence and health costs, depression remains
under-diagnosed and poorly managed, partly
because it lacks definition as a disease, and prevail-
ing treatment is suboptimal.
In clinical practice the symptoms of depression
usually occur alongside symptoms of anxiety,
substance misuse and personality disorders (3).
Therefore, ideally, it would be best to develop
recommendations that address complex presenta-
tions such as coterminous anxiety and depression;
however, the evidence for treatments for depres-
sion stems largely from studies that examine
singular disorders.
Facts and figures
The statistics relating to depression vary according
to the diagnostic instrument and classification
system used to define the illness; however, some
useful key facts and figures are summarized in Box 1.
Box 1. Unipolar depression: facts and figures
Epidemiological statistics
• Depression is 1.5 to three times as common in females as in males (4–
6).
• Twelve-month prevalence rate is 5% and lifetime risk is 15% (6, 7).
• Lifetime prevalence of suicide is approximately 2% (hospitalized
cohorts 10–15%) (8).
Illness characteristics
• Mean age of onset is 27 years, but 40% have first episode by the age
of 20 years (9).
• Average duration of episodes is 3–4 months (7, 9).
• Forty per cent experience recurrence within 12 months (10).
Treatment responsiveness
• Antidepressant ⁄ psychological interventions are effective in around
50% (11, 12).
• Thirty-three per cent respond to placebo (11, 12).
• Thirty-three per cent fail to recover (13).
Depression CPR
The aetiology of depression is not fully understood
but is most probably multifactorial, involving not
only psychological and social factors, but also
biological determinants. In addition to the long-
standing monoamine hypothesis of depression that
postulates a lack of synaptic monoamines, theories
that implicate neuroendocrine, genetic and neural
markers of vulnerability have been posited (14).
Studies in these fields of research have attempted to
link depression to markers of psychosocial and
biological distress and suggest a complex and
varied pathophysiology (15).
Phases and phenomenology
In the absence of sufficient knowledge as regards the
neurobiology of depression, the best system of
diagnosis and classification remains uncertain.
Researchers and clinicians use both dimensional
and categorical approaches in investigational studies
and clinical practice. Added to this, a lack of
consensus amongst research groups that have used
differing criteria to define clinical depression has
made meaningful comparison of studies and the
interpretation of findings difficult. For instance, the
classification of putative depressive ÔsubtypesÕ has
occurred on the basis of symptom profile, severity
and chronicity of illness, along with treatment
responsivity and comorbidity. Diagnostic differen-
tiation has also been sought according to age of onset
and presumed aetiology, especially in the context of
medical illnesses. However, as yet, no satisfactory or
universally accepted taxonomy has emerged.
The two classification systems currently most
widely used in clinical practice and research are the
DSM-IV (16) and ICD-10 (2) and both use similar
symptoms to define clinical depression (see Table 1).
However, a closer examination of these two systems
immediately raises potential difficulties. For
instance, in ICD-10 ÔcategoriesÕ of mild, moderate
and severe depression that together essentially form
a ÔdimensionÕ are determined on the basis of numbers
of symptoms. However, in practice the symptoms of
clinical depression lack equivalence. Suicidal idea-
tion, for example, is usually a far more critical
symptom than most and yet it is counted and
weighted as equal to others when defining depres-
sion. The descriptors such as mild, moderate or
severe have therefore been used sparingly in these
recommendations but could not be omitted alto-
gether, as the majority of research in depression has
been conducted using either DSM-IV or ICD-10
definitions to categorize clinical populations.
Where possible, depression has been defined in
these recommendations according to parameters
that have treatment implications. For instance,
9
Malhi et al.

Table 1. DSM-IV (16) and ICD-10 (2) major depressive disorder diagnostic criteria: symptoms

Phases of Treatment Acute Continuation Maintenance

Relapse Recurrence
Pro diso
to

Relapse
gre rder
ssi
on

Symptoms

Syndrome
Treatment-resistance

Stages of IIIness Response Remission Recovery

Fig. 1. Course of illness in depression [adapted from Ref. (19)]. Stages of illness – Response: significant reduction in clinical
signs ⁄ symptoms (often quantified in studies as a 50% decrease in the score of a rating scale such as HAM-D ⁄ MADRS). Remission:
state of minimal or no signs ⁄ symptoms but lacking full functional recovery. Recovery: stable state of minimal or no signs ⁄ symptoms
with return to premorbid functioning. Relapse: re-emergence ⁄ worsening of signs ⁄ symptoms prior to having achieved recovery.
Recurrence: emergence of signs ⁄ symptoms following recovery. Phases of treatment – Acute Phase: initial phase of treatment with
active signs and symptoms. Treatment targets response. Continuation: following remission, treatment continues with a focus on
achieving functional improvement. Maintenance: treatment continues until signs and symptoms have fully remitted, and functional
recovery has been achieved. It is on this basis that continuation treatment prevents relapse and maintenance treatment prevents
recurrence. However, in practice depression does not always manifest as discrete episodes and therefore clinically, such a distinction
can be difficult. In many contexts, relapse and recurrence are used interchangeably.

depression marked by particular features such as marked by melancholic, atypical or psychotic

atypical, melancholic or psychotic symptoms has
been described separately and where appropriate,
severity has been noted, with the accompanying
suggestion that further specificity be sought using
rating scales. Specifically, a score of 18–24 on the
17-item Hamilton Depression Rating Scale (HAM-
D) is regarded as moderate depression in adults
and a score ‡25 is considered to be severe (17, 18).
However, it is important to note that the Depres-
sion CPR generally apply to depression that is not
features and that, where there is evidence for
severity-related treatment specificity, an attempt
has been made to quantify depressive symptom-
atology using depression rating scale scores.
The graph in Fig. 1 shows the development of
depression and its progression through successive
stages with treatment. The initial acute phase of
treatment, during which there is usually a clinical
response, culminates with the remission of symp-
toms (note that remission as defined in clinical trials

10

as 50% reduction in rating scale score from base-
line, does not necessarily equate to clinical remis-
sion) and ongoing successful treatment, during the
subsequent continuation phase, ideally eventuates in
functional recovery. In practice, treatment often
continues into the maintenance phase to further
diminish the risk of future recurrence.
The Depression CPR have been structured
according to these phases of treatment. Additional
consideration has then been given to dealing with
specific subtypes and managing non-response.
Aims of the recommendations
The clinical practice recommendations for depres-
sion have been developed to provide a meaningful
synopsis of the management of clinical depression.
The recommendations have attempted to integrate
evidence-based findings and clinical wisdom, and
they are presented in a manner that is intended to
engage and facilitate uptake and implementation.
The recommendations have been structured in rela-
tion to each phase of depression with consideration
given to both individual factors and clinical context.
Material and methods
The Depression CPR have been developed by a
team of clinicians and researchers that routinely
treat depression in a variety of clinical settings [for
a detailed description of the methods see Ref. (20)].
The recommendations attempt to provide a prac-
tical overview of managing depression in adults,
beginning briefly with clinical assessment and
diagnosis. The treatment of depression is then
discussed in detail with additional consideration of
specific subtypes. Subsequent sections deal with
maintaining recovery and preventing relapse, and
the management of partial or non-response.
SET A PACE
Assesment:
Safety
- characterise
Education
- calibrate
Therapeutic - corroborate
relationship
- consider
Fig. 2. Schematic overview of the management of depression. See Boxes 2–4 for detailed explanation. ECT, electroconvulsive
therapy.
Depression CPR
Table 2. Definition of levels of evidence criteria used in recommendations
Level NHMRC level of evidence (21)
Level I Systematic review of all relevant randomized controlled trials (RCT)
Level II One or more properly designed randomized controlled trial
Level III Well-designed prospective trial (non-randomized controlled trial);
Comparative studies with concurrent controls and allocation not
randomized;
case-controlled or interrupted time series with a control group
Level IV Case series, either post-test or pretest ⁄ post-test
Level V Expert opinion
NHMRC, National Health and Medical Research Council.
The strength of the evidence within the Depres-
sion CPR has been rated according to the National
Health and Medical Research Council (NHMRC)
Levels of Evidence criteria (21) as listed in Table 2
[see Ref. (20) for further discussion].
Results
The management of depression: Set A Pace
The individual management of depression should
be evidence based and at the same time carefully
tailored to specific needs. The acronym SET A
PACE (see Fig. 2) therefore emphasizes the need to
consider the unique circumstances of every indi-
vidual and underscores the variability of clinical
depression in terms of its treatment responsivity.
ÔSETÕ-ting the foundation
From the outset, it is important to set the
foundation for effective treatment by ensuring
safety, providing education and facilitating the
formation of a therapeutic alliance (see Box 2).
These factors are of paramount importance in the
management of depression and should be consid-
ered throughout all stages of clinical care from
assessment through to maintenance treatment.
Psychological therapy (I)
Antidepressant treatment (I)
Combination (I)
ECT (I)
11
Malhi et al.

Box 2. ÔSETÕ: setting the foundation

ÔSÕ: Safety is a priority as depression is a significant risk factor for suicide (22). Ensure a comprehensive risk assessment is completed and ongoing, with
particular attention to risk of self-harm. Also consider risk of neglect to self or others (such as malnutrition or emotional neglect of children) and, if
applicable, document parental responsibilities. In instances where the risk is high and cannot be managed in the community, hospitalization may be
necessary.

ÔEÕ: Educate the affected individual and, where appropriate, the family ⁄ carer about the illness, treatment options and possible consequences.
Psychoeducation and structured problem solving are effective interventions for the treatment of depression in primary care (23–25) and should be routinely
provided. Recommend lifestyle changes (sleep hygiene, regular exercise, reduction in alcohol, smoking and illicit drugs and anxiety management) to assist
recovery (26–28).

ÔTÕ: Therapeutic relationship begins at the time of assessment and remains integral throughout treatment. Irrespective of the therapeutic modality used in
the treatment, the relationship between the therapist and patient is an important factor in the process that governs the outcome. Specifically, the quality of
the therapeutic relationship, as perceived by the patient, the therapistÕs overall expectation of change and continuity of care have been shown to
independently predict treatment outcome (29).

ÔAÕssessment
The factors that govern treatment choice (PACE) and treatment response are determined by a
comprehensive ÔAssessmentÕ (see Box 3).

Box 3. ÔAÕ: assessment

Foresee (4C) treatment outcome
It is important at the time of assessment to foresee (4C) treatment outcome. Factors that influence treatment response and determine prognosis need to be
assessed in detail:

ÔCÕ: Characterize: clinical symptoms and subtype

• Carefully characterize the symptom profile of depression noting, where possible, depressive subtype.

ÔCÕ: Calibrate: severity and chronicity

• It is important to gauge the extent (severity) and duration (chronicity) of depression as these factors affect treatment choice and response ⁄ outcome.
• Descriptors such as mild, moderate or severe are of limited value when used alone because they are poorly defined and difficult to apply with consistency.
• Rating scales* should be used to quantify severity and can serve as a baseline measure to monitor future treatment response.

ÔCÕ: Corroborate: comorbidities and context

• If possible, obtain corroborative history.
• Identify medical and psychiatric comorbidities.
• Consider psychosocial context and factors contributing to illness (e.g. unresolved grief, domestic violence, unemployment and interpersonal relationship issues).
• Conduct physical examination and relevant medical investigations (e.g. thyroid levels).
• Past treatment history is an important guide to treatment choice and prognosis.

ÔCÕ: Consider: coping style and consequences

• Identify adaptive factors such as personal strengths, support network, coping styles and willingness to engage in treatment.
• Assess social and occupational functioning. If marked impairment is evident, seek a more detailed assessment by an occupational therapist and ⁄ or social worker.

*Validated clinician-rated scales include Hamilton Depression Rating Scale (HAM-D) (30, 31), Montgomery–Asberg Depression Rating Scale (MADRS) (32) and the
Inventory of Depressive Symptomatology (IDS) (33).

treatment specificity and differential efficacy limits

ÔPACEÕ: Treatment options for depression
treatment choice (34).
The treatment options for depression include By design, the acronym PACE sequences the
psychological interventions, pharmacotherapy treatment of depression and places a priority on
and physical measures. Within these options, psychological treatments. However, ultimately,
there are further treatment choices, and combina- treatment choice should be determined by factors
tions of individual treatment can also be used. such as availability, individual preference and effec-
Therefore, potentially, there are a range of treat- tiveness (see Box 4).
ment options; however, in practice, a lack of

12
 Depression CPR

Box 4. ÔPACEÕ: treatment options for depression

The acronym ``PACE'' denotes the recommended treatment options for depression in the order they should be considered. However, treatment choice depends upon
individual factors and treatment availability.

ÔPÕ: Psychological treatment (level I)

• Consider psychological interventions especially if indicated by clinical features (e.g. presence of psychosocial issues, grief, loss and interpersonal problems).
• Psychological therapies have efficacy comparable with antidepressant medications in the treatment of depression (12, 35, 36), where depressive features are not
severe (HAM-D < 25), and there are no psychotic features (37).
• There is a substantive evidence base for CBT (level I) (38–41), IPT (level I) (42, 43) and BAS (level I) (e.g. activity scheduling) (26, 27). Refer to Table 4 for summary
of psychological therapies with levels I, II and III evidence in the treatment of major depression.

ÔAÕ: Antidepressant treatment (level I)

ÔRATEÕ: When selecting an antidepressant consider: Risk, Adherence, Tolerability and Efficacy.
ÔRÕ: Risk: TCAs and MAOIs are potentially lethal in overdose and can produce toxicity through interactions with other medications. SSRIs and other newer antidepressants
can rarely cause serotonin syndrome and the risk of this should be considered (see Fig. 7 for antidepressant side-effect profile).
ÔAÕ: Adherence: Adherence to the prescribed dose of antidepressant is essential. Dosing of medications should be as simple and convenient as possible in order to
enhance adherence. Psychological engagement improves medication adherence.
ÔTÕ: Tolerability: The side-effect profile of medications is a key determinant of antidepressant choice. Tolerability impacts upon adherence and outcome and should be
routinely assessed. Common treatment side-effects should be discussed at the outset of treatment (see Fig. 7).
ÔEÕ: Efficacy: Antidepressants may take up to 14 days to take effect but usually some improvement is discernible much earlier. Antidepressants are not addictive but abrupt
cessation can precipitate withdrawal symptoms (especially with paroxetine, venlafaxine and TCAs). Therefore, when withdrawn, antidepressants should be tapered gradually.

• SSRI (44–52). SSRIs are generally better tolerated than other classes of antidepressants and are suitable first-line. Sexual dysfunction and gastrointestinal
symptoms are common. Many SSRIs (especially fluoxetine and paroxetine) cause significant CYP450 inhibition and care is needed when co-prescribed with other
medications (53).
• NARI (reboxetine) (54–56). Reboxetine is suitable first-line. Common side-effects include hypersomnia, fatigue and nausea.
• NaSSA (mirtazapine) (57–60). Mirtazapine, a suitable first-line option, is associated with weight gain and drowsiness.
• SNRI (venlafaxine, desvenlafaxine and duloxetine) (61). SNRIs appear to be more effective than SSRIs in treating severe depressive symptoms (HAM-D ‡25) and
melancholia (62). In some cases, adverse effects may limit SNRIs to second-line treatment. However, if depression is severe (i.e. HAM-D >25), then SNRIs are a
suitable first-line option. Sexual dysfunction and gastrointestinal symptoms are common with venlafaxine.
• TCA (45–49, 63–65). In comparison with SSRIs, TCAs have a greater side-effect burden (anticholinergic and CNS) (66) and toxicity in overdose (53) and therefore
are considered second-line. However, TCAs (especially those that have both noradrenergic and serotonergic activity such as amitriptyline and clomipramine) may
be more effective when compared with other antidepressants in treating severe depressive symptoms (HAM-D ‡25), in particular patients with melancholia and
those hospitalized because of severe depression (67–72).
• MAOIs. Efficacious antidepressants but not recommended first-line because of risk of hypertensive crisis if necessary dietary and drug interaction restrictions are
not adhered to (Fig. 3).

Clinical Utility of Antidepressants

SSRIs
NARIs
NASSAs
First-line
SNRIs
Second-line Legend
TCAs
Key to Figure
MAOIs Acute efficacy
0 Tolerability difficulties

Fig. 3. Consideration of efficacy and tolerability for the principal antidepressant classes.†

ÔCÕ: Combining antidepressants and psychological therapies (level I)

Consider psychological and antidepressant combination treatment if response to single modality has been suboptimal or failed, or if indicated by clinical features.
• Combination therapies are more effective and reduce time to remission than either psychological or antidepressant treatment alone, especially in depression of
moderate or greater severity (HAM-D ‡18) and chronic depression (level I) (36, 73–77).

ÔEÕ: ECT (level I)

ECT is administered under general anaesthesia, either bilaterally or unilaterally, usually in an in-patient setting. The most common side-effect is cognitive impairment that
is usually transient; however, there is also evidence that suggests some risk of longer term memory impairment (78, 79).
• ECT is a safe and effective treatment (80–82), that is also effective when pharmacotherapy has failed (82, 83), although the risk of relapse remains.
• Consider ECT if there is a high risk of suicide, greater severity, significant psychotic symptoms or if there has been a previous response to ECT treatment.

†
Many agents possess some degree of antidepressant properties and this list is not intended to be comprehensive.
CBT, cognitive behavioural therapy; IPT, interpersonal therapy; BAS, behavioural activation strategies; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant;
SNRI, serotonin and noradrenaline reuptake inhibitor; NARI, noradrenaline reuptake inhibitor; NaSSA, noradrenaline and specific serotonergic antidepressant; MAOI,
monoamine oxidase inhibitor; HAM-D, Hamilton rating scale for depression; ECT, electroconvulsive therapy.

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Malhi et al.

The above recommendations (PACE) apply to in particular those with treatment implications
depressive disorders as defined by the signs and are discussed briefly in Fig. 4 and Box 5.
symptoms in Table 1. Typically, unipolar depres- The precise criteria and treatment recommen-
sion is a recurrent episodic illness that causes dations for atypical depression lack widespread
significant functional impairment. However, the consensus; however, in practice, ÔatypicalÕ features
latter can also be caused by subsyndromal are not uncommon (see Box 5). In some
depression, which subsumes admixtures of epi- contexts, and somewhat confusingly, ÔatypicalÕ is
sodes that are brief (episodes of less than 2-week erroneously used to describe a depressive disor-
duration) and those marked by chronic symp- der with psychotic features. In these recommen-
toms of low intensity (dysthymia). Depression dations psychotic depression is used to refer to
can therefore manifest with a variety of Ôsub- the occurrence of delusions and ⁄ or hallucinations
thresholdÕ symptoms and such presentations can (usually mood-congruent) within the context of a
remain undetected and untreated because of depressive disorder. Further, it is important to
comorbid anxiety or personality disorders. As note that psychotic features confer a greater risk
such, subsyndromal depression is under- of suicide, and in this regard ECT may be
researched and it is difficult to make specific considered first-line because of its greater efficacy
detailed recommendations. in this ÔsubtypeÕ of depression (84, 85).

Depression subtypes
Other ÔsubtypesÕ of depression that have been
identified with somewhat greater consistency, and

Box 5. Recommendations for specific depression subtypes

Atypical features
Characterized by mood reactivity and two or more of the following: significant weight gain or increased appetite, hypersomnia, leaden paralysis, long-standing pattern of
sensitivity to interpersonal rejection (16).

• SSRIs are considered preferable as first-line (level II) (86).

• MAOIs appear to be more effective in this population (87) and can be considered in cases of non-response, but are not recommended as an initial option because
of increased risk of adverse effects, contraindications and dietary restrictions (86).
• Cognitive therapy has been demonstrated to be effective in atypical depression (level II) (88).

Melancholic features
Melancholia is characterized by psychomotor changes and somatic symptoms (16). Melancholic depression has a lower placebo response rate compared with depression
without melancholic features, suggesting lower rates of spontaneous recovery and a greater need for active treatment (89).

• Evidence suggests that TCAs and dual acting agents have superior efficacy when compared with SSRIs (62, 67, 90, 91).
• Depression with melancholic features appears to respond well to antidepressant and ECT treatment (80, 81).
• Limited data report mixed findings in relation to efficacy of psychological treatments in depression with melancholic features (92, 93). Adjunctive psychological
therapy may be of benefit for residual symptoms following an antidepressant response (refer to Box 7 ÔMaintenanceÕ section).

Psychotic features
Describes depression accompanied by delusions and ⁄ or hallucinations that are usually, but not always, mood congruent (16).

• TCAs appear to be more effective than other antidepressants in treating psychotic depression (94).
• Combining an antidepressant with an antipsychotic may be more effective than an antidepressant alone; some but not all studies support the benefit of this
combination (94).
• Antipsychotic monotherapy is not as effective as a combination of antipsychotic and antidepressant (level I) (94). ECT is an effective alternative (84, 85).

TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake inhibitor; ECT, electroconvulsive therapy.

14
 Depression CPR

Summary of Recommendations
Atypical Melancholic Psychotic
Depression
features features features

Fig. 4. Summary of specific treatment

recommendations for subtypes of
depression. CBT, cognitive behavioural
therapy; IPT, interpersonal therapy;
ECT, electroconvulsive therapy; SSRI,
selective serotonin reuptake inhibitor;
SNRI, serotonin and noradrenaline
reuptake inhibitor; MAOI, monoamine
oxidase inhibitor; TCA, tricyclic anti-
depressant.

avoided relapse (see Box 6), it is important to sustain

Continuation and maintenance treatment
Long-term continuing treatment gradually melds
into maintenance. The return of depression prior to
recovery is described as relapse, whereas thereafter it
is termed recurrence. Having achieved recovery and
emotional and physical wellbeing and prevent the
recurrence of depression (see Box 7). Integral to this
process is a strong therapeutic relationship that
facilitates engagement in treatment and permits
ongoing monitoring and risk assessment.

Box 6. Continuation treatment

General considerations
• Following an initial response, treatment should be continued with a focus on stabilizing or achieving further improvement.
• Combining psychological and pharmacological treatments improves clinical outcome and, during longer term treatment (>12 weeks), enhances adherence (75).
• Planned follow-up should be scheduled with regular monitoring of side-effects and adjustment of treatment dosage as needed.
Continuing treatment
• Evidence of an antidepressant effect is most likely to occur within the first 2 weeks of treatment (95–97). If no response occurs within this time period or if the
patient fails to respond adequately within a reasonable time frame (up to 6 weeks), a treatment change is indicated. If remission is not achieved by 3 months, seek
consultation or a second opinion and continue active treatment (level V).
• Expert consensus recommends continuation of antidepressant treatment for at least 1 year following the onset of symptoms for an initial episode and 3 years for
recurrent episodes (level V). If an initial episode included psychotic features, then continue treatment for at least 3 years (98).
• If there are residual negative cognitions or relationship issues, consider psychological interventions such as CBT ⁄ IPT.

Risk of acute relapse: ROAR

• Relapse rates are the highest immediately following remission and diminish with time (99).
• The risk of relapse during the continuation phase of treatment is relatively high and is increased by a variety of factors (see Table 3).

Table 3. Factors increasing the risk of acute relapse (ROAR) in depression

ÔROARÕ risk factors (100–109)

Concurrent factors Symptoms

Comorbid medical illness Greater severity of depression
Life events ⁄ social stress Residual symptoms
Female gender Presence of psychosis
Depressive episodes Outcome factors
Greater number of prior episodes Treatment-resistance
Longer duration of current episode Residual symptoms

CBT, cognitive behavioural therapy; IPT, interpersonal therapy.

15
Malhi et al.

Box 7. Maintenance treatment

General considerations
• Review with the patient, the benefits and burdens of maintaining ongoing treatment vs. the risk of recurrence.
• Work collaboratively to identify warning signs and develop a patient recovery ⁄ wellness plan to reduce risk factors for recurrence.
• Assist patient to identify and work towards their own recovery-based goals (level V).
• Re-evaluate treatment plans and address any comorbid conditions, psychosocial stressors (residual grief and loss) and functional impairment.
• Ensure proactive follow-up to detect recurrence of depressive symptoms.
Maintenance treatments
Psychological
• CBT has the largest evidence base in maintenance treatment. See Fig. 5 and Table 4 for an overview of evidence-based psychological therapies with potential
specificity to phase of depression.
• CBT can reduce the risk of relapse, with benefits sustained for several years beyond treatment (level II) (110–112).
• IPT may be effective in those who have responded to acute IPT monotherapy (113).
• MBCT has been effective in reducing relapse in patients with recurrent depression (level II) (114, 115).

Phases of Treatment Acute Continuation Maintenance

MBCT

CBT

IPT

BAS

Fig. 5. Schematic demonstrating the potential phase-specific application of psychological therapies with level I evidence.† See Table 4 for further details.
†
In the light of its phase-specific application, MBCT (level II) has also been included.
Psychosocial
• Address psychosocial ⁄ lifestyle factors (accommodation, social support, employment).
• Ensure social supports are in place or assist patient to link into support networks.
• Consider occupational therapy or vocational support where there has been disengagement from activities.

Pharmacological
• Antidepressant treatment diminishes the risk and severity of depressive relapse (116, 117); however, even with ongoing maintenance administration, recurrences
may occur (118).
• Lithium monotherapy is an effective alternative maintenance treatment option in unipolar depression (119) and may be considered if antidepressants cannot be
tolerated (e.g. because of sexual dysfunction). However, long-term administration of lithium is associated with serious side-effects such as renal dysfunction (120)
and therefore lithium levels should be closely monitored.
Maintaining antidepressant treatment
• Maintain therapeutic dose that was effective during acute treatment because this dosage is generally more efficacious in preventing relapse or recurrence than
lower Ômaintenance dosesÕ (121–124).
• Assess and monitor for tolerability, adverse effects and adherence to treatment.
Stopping antidepressant treatment
• Discontinuation symptoms may emerge following the cessation of all classes of antidepressants. Therefore, although the optimal regime remains unclear,
antidepressant treatment should be discontinued gradually.
• The risk of discontinuation symptoms is the greatest with higher doses of antidepressants and longer duration of treatment (up to 2 months); however, symptoms
are usually transient and mild, and resolve with antidepressant reinstatement (125).
• Amongst the antidepressants, discontinuation is more likely with venlafaxine (126, 127) and short-acting SSRIs (e.g. paroxetine) but less likely with fluoxetine (128,
129).
• Abrupt cessation of TCAs may cause cholinergic-rebound phenomena (flu-like illness, myalgia and abdominal cramps).

ECT
• There is limited evidence for long-term ECT treatment (130); however, maintenance ECT has been shown to be as effective as combined nortriptyline and lithium
and superior to placebo in preventing relapse ⁄ recurrence (131, 132).
• Review on an individual case-by-case basis and seek consultation (level V).

BAS, behavioural activation strategies; IPT, interpersonal therapy; CBT, cognitive behavioural therapy; MBCT, mindfulness-based cognitive therapy; SSRI, selective serotonin
reuptake inhibitor; TCA, tricyclic antidepressant; ECT, electroconvulsive therapy.

16
 Depression CPR

Table 4: Glossary of psychological therapies with level I–III evidence in depression

Maintenance ⁄ relapse Basic principles

Therapy Acute phase prevention

Cognitive Behavioural Level I (38–41) Level II (110–112) CBT employs a combination of cognitive and behavioural techniques to target
Therapy (CBT) maladaptive thinking, deficits and factors predisposing to and perpetuating
depressed mood.
Interpersonal Level I (42, 43) Level III (113) IPT emphasizes the correlation between depression and the social
Therapy (IPT) environment. The therapy focuses on the current context and attempts to
bring about active changes to help the individual to find solutions for, or
adapt to, interpersonal problems.
Behavioural Activation Level I (26, 27) – BAS strategies targets behaviours that maintain or worsen depression,
Strategies (BAS) particularly inertia and loss of pleasure and achievement. It involves, for
example, scheduling activities and graded task assignments.
Mindfulness-based – Level II (114, 115) MBCT differs from traditional CBT in that it does not focus on the content of
Cognitive Therapy (MBCT) thoughts. Rather, it emphasizes the process of attending to thoughts and
feelings and experiencing and tolerating these without judgment.
Cognitive Behavioural Analysis Level II Level III (135) The focus of CBASP is to apply situational analysis techniques to social
System of Psychotherapy (133, 134) interactions and remedy the thought and behaviour patterns that lead to a
(CBASP) disconnection between the patient and their environment. Thus far, therapy
has been largely studied in patients with chronic depression.
Internet-based Self- Level II (136) – A structured treatment approach delivered online applying CBT principles with
management CBT the aim of developing new types of behaviour and cognition. Can be deliv-
ered with or without therapist support (usually via online email or forum).
Short-term Psychodynamic Level II (137). – Strategies include the use of the triangle of conflict (feelings, anxiety and
Psychotherapy defence) and the triangle of person (past, therapist and present). Short-term
psychodynamic psychotherapy differs from longer term psychodynamic
analysis in that it applies therapeutic focus, active therapist involvement and
time restriction.
Family Therapy Level II (138–140) – Family therapy refers to a range of approaches including psychoeducational,
systemic, behavioural and psychoanalytical models. Essentially, family ther-
apy for depression aims to help family members disengage from destructive
forms of communication, and through that process, reduce the symptoms of
depression.
Marital Therapy Level II (141) – Marital therapy, derived from social learning theory, aims to modify negative
interactional behaviours between the couple and increase mutually sup-
portive aspects of the relationship.

With respect to psychological interventions, it is important to consider the potential phase-specific benefits of individual therapies (see Fig. 5), noting, however, that, as yet,
the evidence is incomplete and the findings from many studies are inconclusive. Further, to date, insufficient studies have been conducted to determine the specific benefits of
psychological monotherapy vs. combination with medication. However, as regards IPT and CBT in combination with antidepressants, in addition to efficacy in the acute phase
of treatment, these psychological interventions have been shown to facilitate remission and recovery and diminish the subsequent likelihood of relapse and recurrence (110–
113).

duration of pharmacotherapy and the relative

Managing partial or no response to treatment
importance of psychological and pharmacological
The terms Ôtreatment resistantÕ, Ônon-responseÕ or strategies (143–145).
Ôpartial response to treatmentÕ lack clear definition In practice, partial or non-response to treat-
because varying criteria have been applied both ment is experienced by the individual as ongoing
clinically and in depression research to define depressive symptoms and a lack of functional
degrees of response (142). recovery.
In general, these terms are used to describe an Generally, with each treatment failure the
inadequate response to appropriate therapeutic likelihood of a subsequent response decreases
measures for depression that can include medica- and the chance of eventual remission and recov-
tions and ⁄ or psychological interventions and ⁄ or ery diminishes (109). A discernible improvement
physical treatments. The difficulty in operational- in response to medication usually becomes evi-
izing these definitions is immediately evident. dent within the first 2 weeks of treatment (95–97)
Deciding on what is an appropriate therapy, and and a measurable change within this time frame
the context within which it should be adminis- is more likely to result in a sustained response
tered, requires a much better understanding of (146, 147). However, a lack of continuing
treatment response in depression. Expert consen- improvement beyond the first few weeks of
sus has also not been achievable because of treatment is likely to result in longer term non-
disagreement as to the adequacy of dose and response (148, 149).

17
Malhi et al.

Therefore, the practical treatment of partial or integration of clinical management skills and
no treatment response requires experience and therapeutic strategies. The key elements of these
careful consideration. Specifically, this entails the are outlined in Box 8.

Box 8. Managing partial or no treatment response

Review
adherence & Clinical Optimise
dose
Management

Seek
ECT
consultation
Therapeutic
Re-evaluate Re-assess for Strategies Augment/
Substitute
diagnosis comorbidities Combine

Fig. 6. Managing partial or no treatment response.

Clinical management
Review adherence and dosage. Ensure adherence to and satisfaction with treatment plan. If taking an antidepressant review dosage (Fig. 6).
Re-evaluate diagnosis. Consider maintaining factors of depression, such as psychosocial stressors. Re-evaluate substance abuse or personality issues and re-consider
alternative causes (e.g. bipolar disorder and thyroid dysregulation).
Re-assess comorbidities. Especially anxiety, drug and alcohol, or personality disorders. Assess for medical comorbidities.
Refer and consult. Consultation with colleagues or referral to a specialist or specialist clinic should be considered in complex cases, or where there has been partial or no
response to multiple treatment trials. Advice should also be sought when prescribing novel treatments.
In conjunction with clinical management, structured rating scales (see ÔAssessmentÕ) can assist in quantifying treatment response and determining change in clinical
profile.

Therapeutic strategies
Optimize
• Optimize existing treatments.
• If taking an antidepressant, optimize dose (where possible, e.g. TCAs, check levels).
• TCAs, venlafaxine and escitalopram generally have antidepressant activity across a broader dose range (150–152).
Augment and ⁄ or combine
• Add psychological treatment (CBT) or antidepressant medication as indicated ⁄ necessary.
• Pharmacological augmentation strategies: lithium (level I) (153, 154), atypical antipsychotics (level I) (olanzapine, risperidone, quetiapine) (155), short-term
benzodiazepine use (level I) (156) or thyroid hormone (157, 158). Note, lithium is used widely as an augmentation agent and can be administered in conjunction
with all antidepressants.
• Combining antidepressants: there is little controlled evidence to support this approach, but clinically it is occasionally used to treat non-response. Logical
combinations include combining serotonergic and noradrenergic acting drugs (159–161).
• Caution: when employing augmentation strategies or if combining antidepressants, monitor carefully for side-effects and potential toxicity.
Substitute
Includes changing between antidepressants and psychological treatments, or substituting class of antidepressant.

• Before altering any treatment, allow a trial of appropriate duration, usually 2–6 weeks, at adequate dosage for pharmacological or psychological treatments
(sometimes longer) (162, 163) (see also Box 6).
• When substituting antidepressants, alter antidepressant class unless reason for substitution is poor tolerability, which has prevented an adequate trial.
• Consider dual-acting agents (e.g. venlafaxine and duloxetine) (164), TCAs (165) or MAOI (e.g. phenelzine) if adverse effects and dietary restrictions can be tolerated
(109).

ECT (level II)

• ECT is an effective alternative treatment option in cases of marked severity, risk or ongoing non-response to medication or psychological treatments (80–82).

TCA, tricyclic antidepressant; CBT, cognitive behavioural therapy; MAOI, monamine oxidase inhibitor; ECT, electroconvulsive therapy.

porate both clinical experience and evidence-based

Discussion
findings. The importance of the individual and the
The management of depression, even that which is need to form a therapeutic alliance have been
uncomplicated by comorbidity, is a sophisticated emphasized throughout and psychological
process. Throughout the Depression CPR, man- approaches have been given primacy. While the
agement advice has been balanced so as to incor- focus of the Depression CPR is to guide the

18
 Depression CPR

management of depression in adults, clinical
depression arises in other populations and often
in conjunction with other illnesses. These specific
circumstances, along with antidepressant side-
effects and novel ⁄ emerging treatments, are briefly
addressed.
use the Depression CPR in conjunction with
publications that outline the evidence for managing
depression with comorbid anxiety (173), substance
misuse (174, 175), personality disorders (176),
schizophrenia (177) and medical problems (178,
179).

Special populations and comorbidities Antidepressant side-effects and novel treatments

The Depression CPR target the management of
depression in adults because this is the population
that provides the majority of the evidence base.
The recommendations have therefore not reviewed
the evidence for special populations. However, the
reader is directed to existing publications that
provide specific guidance in managing depression
in young people (166, 167), the elderly (168, 169)
and during the perinatal period (170–172).
In practice, depression is often accompanied by
other disorders and this necessarily complicates its
management. However, because of insufficient
evidence it is not yet possible to develop recom-
mendations that address the many varied presen-
tations of clinical depression. To deal with such
complex presentations the reader is encouraged to
Antidepressants can produce a vast range of side-
effects and for specific information recognized
pharmaceutical data sources and the product
information of an individual agent should be
consulted. Class effects are summarized in Fig. 7,
but a detailed description is beyond the scope of
the Depression CPR.
Similarly, it has not been possible to accommo-
date in the Depression CPR detailed discussion of
the many novel treatments for depression for
which there is accumulating evidence. For exam-
ple, St JohnÕs wort (180), meditation (181), exercise
(182), innovative pharmacological agents [e.g. ag-
omelatine (183)] and a range of physical interven-
tions [for example, vagal nerve stimulation,
transcranial magnetic stimulation, deep brain stim-

Side effects associated with the principle antidepressant classes

Fig. 7. Side-effects associated with the principle antidepressant classes. Source: adapted from Refs (191–193).  MAOIs require dietary
restrictions to prevent hypertensive crisis, some combinations with other drugs can be fatal. +, uncommon; ++, common; +++,
very common; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; SNRI, serotonin and noradrenaline re-
uptake inhibitor; NARI, noradrenaline reuptake inhibitor; NaSSA, noradrenaline and specific serotonergic antidepressant; MAOI,
monoamine oxidase inhibitor; RIMA, reversible inhibitor of monoamine oxidase. Antidepressants are generally well-tolerated and are
not addictive, but non-compliance or discontinuation because of adverse effects remains a significant problem in clinical settings and
research trials. The figure outlines the main adverse effects experienced, according to each antidepressant class. Compared with other
antidepressants, SSRIs tend to be safer and better tolerated by patients, with a more favourable adverse effect profile, even at high
doses (68). Many of the adverse effects of SSRIs, such as gastrointestinal symptoms, tend to be transient and cease within a few days or
weeks after commencing treatment (194). Tricyclic antidepressants have higher discontinuation rates than SSRIs (191), are associated
with greater rates of anticholinergic side-effects, hypotensive and sedation effects and can also be toxic in overdose (194). The side-
effect and safety profile of TCAs limits their use as a first-line treatment option. Similarly, MAOIs are not favoured as initial treatment
options because of the risk of hypertensive crisis if strict dietary requirements are not maintained (195). The blood levels of some
antidepressants (e.g. TCAs) can be monitored, but this is not usually necessary and is not routinely advocated.

19
Malhi et al.
ulation (184–187) and light therapy (188–190)], all
of which are increasingly used worldwide in the
treatment of mood disorders.
To conclude, the imprecision with which depres-
sion has been defined has limited research and
understanding of the disorder and thereby con-
stricted the sophistication with which it is routinely
managed.
The Depression CPR have been developed to
provide basic practical guidance as to the manage-
ment of depression and are a combination of data-
driven evidence and clinical experience. They
cannot take into account the myriad of clinical
variables that are invariably present, and are thus
not prescriptive, and need to be used flexibly.
Recommendations, like guidelines, are practical
clinical tools, derived from an incomplete and
evolving database. They need to be interpreted
taking into account the personÕs clinical circum-
stances, sociocultural context, comorbidities and
local health resources. Therefore, they do not
represent a reference standard of care in medico-
legal proceedings. The recommendations have been
constructed so as to provide a useful framework
for the clinical management of depression and
should ideally be used in conjunction with other
recognized sources of information (72, 191, 192,
196) and the application of clinical wisdom.
Acknowledgements
This paper was part of a larger project, Mood Matters,
which represented a collaboration between the Northern
Sydney Central Coast Mental Health Drug & Alcohol
(NSCCMHDA), NSW Health Clinical Redesign Program
and the CADE Clinic, University of Sydney. The authors
sincerely acknowledge contributions by Dr Nick Kowalenko,
Dr Glenys Dore, Dr Kevin Vaughan, Rosa Portus, Dr Peter
Short and Vicki Campbell. The authors also acknowledge all
staff and consumers of NSCCMHDA who actively partici-
pated in this project and particularly the members of the
multidisciplinary advisory panel who participated in the
development process of these practice recommendations. Prof
Gin Malhi acknowledges the NHMRC Program Grant
(510135) for essential financial support.
This publication has been made possible through infra-
structure support from NSCCMHDA and the University of
Sydney CADE Clinic and an unrestricted educational grant
from Servier.
The icons used in this article have been sourced from Clip
Art, Microsoft Office Online (http://office.microsoft.com/en-
au/clipart/default.aspx) and used in accordance with the
Microsoft Service Agreement. The media elements are intended
to enhance the existing content and are not considered to be the
primary value of the recommendations.
Declaration of interest
In the past 3 years, Professor Gin Malhi has served on a
number of international and national pharmaceutical advi-
20
sory boards, received funding for research and has been in
receipt of honoraria for talks at sponsored meetings world-
wide involving the following companies: AstraZeneca, Eli
Lilly, Jansen-Cilag, Organon, Pfizer and Wyeth. Professor
Garry Walter has received educational grants from Eli Lilly,
Janssen-Cilag and Pfizer, a research grant from AstraZeneca,
and travel assistance and an honorarium for a talk from Eli
Lilly. Dr Lisa Lampe has received honoraria for lectures,
workshops, advisory boards and educational material in the
past 5 years from the following companies: Wyeth, Lund-
beck, Pfizer, Sanofi, Janssen Cilag and AstraZeneca. She has
received travel assistance from Wyeth and sits on the Pristiq
Advisory Board (Wyeth). In the last 5 years Professor
Richard Porter has received honoraria for speaking engage-
ments from Janssen-Cilag and Sanofi-Aventis. During the
past 3 years, Professor Roger Mulder received honoraria for
speaking and travel assistance from Douglas Pharmaceuti-
cals, Janssen-Cilag and AstraZeneca. Professor Michael Berk
has received funding for research from Stanley Medical
Research Foundation, MBF, NHMRC, Beyond Blue, Gee-
long Medical Research Foundation, Bristol Myers Squibb,
Eli Lilly, GlaxoSmithKline, Organon, Novartis, Mayne
Pharma, Servier, AstraZeneca, has received honoraria for
speaking engagements from AstraZeneca, Bristol Myers
Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lund-
beck, Organon, Pfizer, Sanofi Synthelabo, Solvay, Wyeth and
served as a consultant to AstraZeneca, Bristol Myers Squibb,
Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck and
Pfizer.
Danielle Adams, Andrea Taylor, Dr Nick OÕConnor, Dr
Michael Paton, Dr Liz Newton and Dr Ann Wignall have no
competing interests.
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