Guía Australiana de Depresión

Australian and New Zealand clinical practice
guidelines for the treatment of depression

Royal Australian and New Zealand College of Psychiatrists Clinical Practice
Guidelines Team for Depression
Background: The Royal Australian and New Zealand College of Psychiatrists (RANZCP) is
co-ordinating the development of clinical practice guidelines (CPGs) in psychiatry, funded
under the National Mental Health Strategy (Australia) and the New Zealand Ministry of
Health.
Method: The CPG team reviewed the treatment outcome literature, consulted with practitioners and patients and conducted meta-analyses of outcome research.
Treatment recommendations: Establish an effective therapeutic relationship; provide the
patient with information about the condition, the rationale for treatment, the likelihood of a
positive response and the expected timeframe; consider the patients strengths, life stresses
and supports. Treatment choice depends on the clinicians skills and the patients circumstances and preferences, and should be guided but not determined by these guidelines. In
moderately severe depression, all recognized antidepressants, cognitive behavioural therapy
(CBT) and interpersonal psychotherapy (IPT) are equally effective; clinicians should consider
treatment burdens as well as benefits, including side-effects and toxicity. In severe depression, antidepressant treatment should precede psychological therapy. For depression with
psychosis, electroconvulsive therapy (ECT) or a tricyclic combined with an antipsychotic are
equally helpful. Treatments for other subtypes are discussed. Caution is necessary in
people on other medication or with medical conditions. If response to an adequate trial of a
first-line treatment is poor, another evidence-based treatment should be used. Second
opinions are useful. Depression has a high rate of recurrence and efforts to reduce this are
crucial.
Key words: depression, evidence-based review, treatment guideline.
Australian and New Zealand Journal of Psychiatry 2004; 38:389407
These guidelines focus on moderate to severe depression in adults treated by mental health professionals.
Specialist clinicians should consider, but not be limited
to, the treatments recommended. The extensive literature
includes systematic reviews of randomised controlled
trials (RCTs). Where knowledge is sparse, lower orders
of evidence have been used. Other guidelines are available for the treatment of depression in primary care
settings [1,2] and for children [3].
Treatment should be a partnership between patient,

general practitioner (GP) and mental health professional.
Engaging with the person is crucial for effective treatment. Even when depression is severe and complicated,
specialist services are involved only during the acute
phase, with the GP co-ordinating the longer-term treatment plan.
Peter Ellis, Chair (Correspondence)
While transient lowering of mood is common, persistence is qualitatively different. Clinical depression is
common, serious and treatable. Untreated, it can result in
disability and even death. It tends to be episodic and of
CPG Team for Treatment of Depression, Wellington School of Medicine

and Health Sciences, University of Otago, Wellington, New Zealand.
Email: ellis@wnmeds.ac.nz
Received 13 February 2004; accepted 30 March 2004.
Denitions
390
CPGS FOR TREATMENT OF DEPRESSION
varying severity. Many depressed people have concurrent physical and other mental health disorders.
Prevalence and severity
Depression is common. In the Australian Mental
Health Survey, 4% of adults had a depressive disorder
in the past month [4]. Compared with other mental illnesses, depressed people had higher levels of disability,
including severe disability, and used health services
more (70% had consulted a health practitioner in the
previous month) [5]. Some 43% of those with depression
suffer severe disability (< 30% on the Medical Outcomes Study short form 12) [personal communication
Gavin Andrews, Wellington, 2001]. A similar pattern is
likely in New Zealand.
Moderate to severe depression is as disabling as
congestive heart failure [6,7], and its relapsing nature
accounts for one of the highest levels of disease burden
of any condition [8].
Some 7% of people who consult a GP, and 40% of
those concerned about their mental health, have clinical
depression, often in conjunction with an anxiety or substance abuse disorder. Most experience disrupted lives
[5]. Depression is common in secondary specialist
services. A third of those presenting to psychiatric community clinics with depression are severely depressed
and need extended treatment; the remainder need
specialist advice to assist their primary healthcare
professionals [4].
Depression (and substance abuse) is the most likely
condition to be comorbid with other physical and psychiatric disorders, but is often unrecognized by primary
healthcare workers [9] and secondary physicians [10].
Course and prognosis
Depression does occur in children but more often in
teenagers. It affects boys and girls equally until age 15,
after which it is more common in girls [11]. From ages
1118 the rate increases from 0.5% to 3.4% for a major
depressive episode and from 0.9% to 3.2% for dysthymic disorder [11,12]. Most major depression begins
in the late 20s [13].
Symptoms develop over days to weeks, though there
may be anxiety, panic, fearfulness and lowered mood
over preceding months. Sudden onset is usually associated with major stress. Untreated moderate episodes last
up to 9 months. A third of those with moderate depression recover with placebo treatments, while half respond
to 68 weeks of active treatment [14]. An episode may
be the harbinger of bipolar disorder or an exacerbation of
dysthymic disorder.
The likelihood of recovery in the next month decreases

after 6 months, from 15% for months 79 to 12% up
to 5 years [15,16], at which time 12% have not recovered [16].
Remission is partial for 2030% of people with
depression, who experience continuing symptoms and
social and occupational impairment [15].
Recurrence
Emphasis on good prognosis for major depression in
primary care is appropriate. But as depression recurs
in 40% of people within a year [17], monitoring and
intervention are necessary to prevent relapse. A 12-years
follow-up of people treated for an index episode, found
depressive symptoms present for 60% of this period and
a full depressive episode for 15% [18]. People with three
or more episodes have an 80% chance of recurrence over
the next 3 years [19].
Long-term studies show even higher rates of recurrence. A 25-years follow-up of Australians hospitalized
with depression found only 1 in 8 remained depressionfree, with an average of three episodes. However, a
quarter improved in the last decade of follow-up, including 80% of those chronically depressed over the first
15 years [20]. Those with psychotic depression have
worse outcomes [17].
Complications
If untreated, depression increases risk of suicide and
other violent acts. Some 6% of people diagnosed at some
time during their lives with major depression will suicide
[21], as will 1015% of those ever admitted to hospital
a rate 30 times that of the general population
[17,22,23]. Of those with a current major depression
2550% will attempt suicide [24]. Treatment halves the
risk of suicide, especially for men under 30 [2528].
However, unemployment, isolation, impulsivity and
misuse of alcohol and drugs increase risk [29,30].
Depression, especially when recurrent or chronic,
distresses family and friends [31]. It may affect a persons capacity as a parent, and is often associated with
occupational dysfunction [32].
Aetiology and risk factors
Many factors protect against, predispose to, or precipitate depression: genes, childhood experience, previous
trauma, social and cultural supports, physical factors
(including drugs) and stress [3338]. Depression occurs
more commonly in the young [39,40] and in women, at
RANZCP CPG TEAM FOR TREATMENT OF DEPRESSION
least in Western society [5,39,41,42], and the latter is not

attributable to postnatal depression alone.
Depression affects 510% of those with medical
illness attending primary care and 614% of medical and
surgical inpatients [43]. Rates of 50% are associated
with some conditions, for example HIV-AIDS [18,44],
in which prevalence correlates with severity [18], progression [45], older age [46] and less social support [47].
It is commonly associated with Parkinsons disease [48],
migraine and chronic pain [49]. Varying rates for specific
conditions reflect differences in socio-demographics,
severity and chronicity. Increased rates may be a direct
effect of physical illness (e.g. hypothyroidism, Cushings disease and certain cerebral tumours), a side-effect
of treatment (e.g. steroids and some antihypertensives)
or a reaction to illness.
Method
Key features in developing these clinical practice
guidelines are: (i) a review of literature; (ii) metaanalyses of RCTs; (iii) evidence tables; (iv) drafting by
a group with clinical, research and consumer expertise; (v) consultation with patients, cultural consultants
and professionals with specific knowledge in sparsely
researched areas; and (vi) redrafting after wider consultation.
Searches of MEDLINE and PsycLIT (1996July 2002)
using depression, major depression, major depressive disorder, RCT, meta-analysis and review,
were supplemented by a manual search. Studies prior to
1996 were identified from the major meta-analysis of
the Agency for Health Care Policy Research [14], more
recent meta-analyses, and references identified in the
search. Key texts, review articles and existing guidelines
were examined.
Randomized controlled trials were included in the
meta-analysis if medication was prescribed in adequate
doses for adequate periods, and if information was available to calculate an intention-to-treat outcome for a
greater than 50% reduction in severity score (e.g.
Hamilton Rating Scale for Depression, HAM-D). The
minimum HAM-D score [50] was 12 for mild depression, 17 for moderate and 24 for severe. Numbers
needed to treat (NNT) and absolute risk reduction
(ARR) were calculated and summarized using metaanalyses. Confidence intervals for NNTs were calculated iteratively using STATSDIRECT [51].
The working partys cultural advisor consulted at
every stage with Maori and the Victorian Transcultural
Psychiatry Unit in Melbourne. The Section of Psychotherapy, RANZCP identified publications on dynamic
psychotherapy.
391
These guidelines are for clinicians in specialist

mental health services. They mainly focus on people
who do not recover from a first episode or have a
partial remission, and look to the long-term management of the 45% at risk of recurrence. A third of those
with depression have a single episode only, and can be
adequately treated in primary care settings, with occasional specialist support. However, specialist practice
must acknowledge the need for longer-term follow-up
and relapse prevention.
Assessment
Assessment includes the type, severity and duration of
the depression and any coexisting psychiatric or physical
disorders. It establishes both contributing stresses and
the individuals supports, resources and coping style.
Crucially, it considers the risk of suicide or risk to
others, either through an act of violence or through
neglect (e.g. in postpartum depression).
Heightened clinical suspicion is essential to effective
diagnosis. Atypical presentations are common: teenagers are not always morose, nor are the elderly always
sad. Sadness is neither a necessary nor a sufficient
criterion. Symptoms are often vague, and physical
complaints may be prominent. Women, especially postpartum, and people under 40 are the most susceptible. In
atypical depression the neurovegetative symptoms are
the reverse of those usually encountered.
Dysthymia must be distinguished from residual symptoms of major depression, with diagnosis following at
least 6 months after full remission of a major depressive
episode. If dysthymia precedes major depression (socalled double depression), poor outcome is more
likely.
Treatment decisions will reflect the key psychological,
social and cultural issues contributing to the illness, as
well as its subtype, severity and duration.
Severity and depression subtypes

Both severity and subtype are important in selecting
treatment (Table 1) [13]. Each category needs differential diagnosis and specific treatment. For most, the risk
of recurrence is higher than for uncomplicated depression and continuing treatment is indicated.
Formal assessment of severity (e.g. using the HAM-D
[50], the Center for Epidemiological Studies Depression
Scale [CES-D] [52], or similar) allows selection of
evidence-based treatments and provides a baseline to
monitor effectiveness.
392
Table 1.
Severity and subtypes of depression
Severity of major depression (DSM-IV)

An episode of major depression may be classied as mild, moderate or severe:
Mild episodes: Few symptoms beyond the minimum required to make the diagnosis. Mild disability or the capacity to function normally
but with substantial and unusual effort.
Moderate episodes: More than minimum criteria met. Greater functional impairment.
Severe episodes: Most criteria present. Marked interference with social and/or occupational functioning, producing clear-cut,
observable disability (e.g. inability to work or to care for children). In the extreme, aficted people may be totally unable to function
socially or occupationally, or even to feed or clothe themselves or to maintain minimal personal hygiene.
The nature of symptoms (e.g. suicidal ideation and behaviour) should also be considered in assessing severity.
Melancholia
Distinguished by characteristic somatic symptoms and psychomotor changes. Essential feature in DSM-IV is the loss of pleasure in
all, or almost all, activities or a lack of response to usually pleasurable stimuli. ICD-10 does not use the term melancholic but calls
a similar symptom cluster depression with somatic features. Some argue for the utility of a more restrictively dened melancholia,
with greater emphasis on physical, especially motor, symptoms of depression [119]. Considered to be particularly responsive to
medication and electroconvulsive therapy.
Major depression with psychotic features
Depression accompanied by hallucinations and/or delusions that are usually, but not always, mood congruent. It is very important to
distinguish between the enduring nature of psychotic phenomena in major depression and the transient paranoid ideation/
experiences seen in the mood instability of borderline personality disorder.
Atypical depression
Characterized by mood reactivity and two or more of: signicant weight gain or increased appetite; hypersomnia; leaden paralysis;
and a long-standing pattern of sensitivity to interpersonal rejection (preceding mood disorder), causing signicant social or
occupational impairment. While a long-established concept, its essential features are still debated [120].
With postpartum onset (postpartum depression)
Onset must be within 4 weeks of the birth.
With seasonal pattern (seasonal affective disorder)
The onset and remission of major depressive episodes occurs at characteristic times of the year, typically beginning in autumn or
winter and remitting in spring.
Reference: [13].
Suicide risk
Investigations and concurrent disorders
Risk assessment, to self and others, is a key task at first

examination and throughout treatment. Risk to others
may arise through paranoid ideation as part of psychotic
depression. Risk through neglect is of concern during
postpartum depression, for the infant or older siblings.
Risk may increase during recovery from a retarded
depression (e.g. during early response to ECT), when
intense suicidal ideation persists after recovery of motor
activity, allowing the person to act on their ruminations.
Evidence that suicide attempts are more common in the
early morning (when ward staffing levels are lowest) is
not consistent and differs between age groups [5355].
Management strategies vary with the degree of risk to
self or others. As change can be rapid, review of risk and
appropriate support is necessary.
Suicide risk assessment is covered in the RANZCP
clinical practice guideline on deliberate self-harm (in
press) <http://www.ranzcp.org>.
Since concurrent physical or other psychiatric illnesses

are common, investigations are considered at initial
assessment, particularly if presentation is atypical or
precipitating factors absent, and are reconsidered if
response is poor.
Current treatment evidence
Benecial interventions
Good outcomes require sound alliance between professional and patient, adequate duration of treatment,
and co-ordination of treatment (Fig. 1).
An evidence-based treatment is selected in discussion
with the patient, and an effective dose (or number of
therapy sessions) is monitored by measuring severity
of symptoms. Antidepressants are most effective for the
most severe depression [56]. If initial response is poor,
393
and resume if:
T
A
E
Figure 1.
Outline of treatment for depression.
continue treatment or consider switching to a second or

third-line option [57] (Fig. 1). All antidepressants, and to
a lesser extent the psychological treatments, have a high
relapse rate following early discontinuation.
Relevant psychological, social and cultural issues are
explicitly considered and befriending programs may
assist outcome [58,59].
Behavioural measures are preferable to additional
medication for relieving some symptoms. For insomnia,
sleep hygiene may help (caffeine restriction/avoidance,
alcohol avoidance, adequate exercise, avoiding late
meals, etc.).
Mild depression
No treatment is more effective than supportive clinical
care with psycho-education, supplemented by teaching
problem-solving skills [60,61] or by supportive counselling [62,63].
Moderate depression
Almost all antidepressants, CBT and IPT are equally
effective (and of similar absolute cost in the medium
term, although direct costs to patients vary). Of greatest
benefit is the therapeutic relationship, which enables
agreement on treatment selection and continuation.
Regular monitoring for side-effects and encouragement
to persist (or change treatment) are helpful.
Table 2 compares antidepressants with placebo, and
Table 3 with other antidepressants. All antidepressants
and CBT are superior to placebo (standard clinical treatment without a specific active pharmacological agent),
with NNTs of 4.15.5 (20% reduction of average
absolute risk over placebo).
The findings in Table 3 are both more relevant and
more robust, due to more and bigger studies. The much
larger NNTs reflect the similarity in effectiveness of
most antidepressants, though venlafaxine has a small
394
Table 2.
Antidepressant treatment compared to placebo for moderate depression
Moderate depression
All TCAs
All SSRIs
SNRI (venlafaxine)
NARI (reboxetine)
NaSSA (mirtazapine)
Serotonin (5HT2 ) antagonists (nefazadone)
CBT
Number of patients
(number of studies)
NNT
ARR
2908 (16)
3442 (18)
1050 (5)
254 (1)
200 (2)
572 (4)
347 (4)
4.7
5.5
4.8
4.7
4.1
5.4
5.4
21.2
18.2
21.0
21.1
24.2
18.5
18.7
All these treatments are signicantly more effective than placebo; NNT, number needed to treat; ARR, absolute risk reduction;
references: [121136], [121123,125127,131,137147], [148152], [146], [132,153], [128,130,134,154], [79,80,124,155].
Table 3.
Comparisons between active treatments for severe and moderate depression

Number of patients
(number of studies)
NNT
ARR
526 (5)
87 (1)
130 (2)
101 (1)
39
14.5
8.8
45.2
2.6%
6.9%
11.4%
2.2%
7411 (33)
415 (3)
1510 (6)
707 (2)
722 (5)
570 (4)
340 (4)
833 (5)
167 (2)
107
15.0*
10.1
15.5
40.1
25.3
22
43.8
55
Severe depression
TCA cf. SSRIs
TCA cf. moclobemide
Venlafaxine cf. SSRI
Nefazadone cf. SSRI
Moderate depression
All TCA cf. SSRI
Venlafaxine cf. TCA
Venlafaxine cf. SSRI
Reboxetine cf. other antidepressants
NaSSA (mitazapine) cf. TCA
Nefazadone cf. other antidepressants
RIMA (moclobemide) cf. SSRI
CBT cf. antidepressants
IPT cf. TCA
0.9%
6.4%*
9.9%
5.7%
2.5%
4%
4.5%
2.3%
1.8%
*Venlafaxine is signicantly more benecial at the 95% level than SSRIs as a group; NNT, number needed to treat; ARR, absolute risk
reduction; references: [156160], [161], [162,163], [164], [121123,125,127,156,158,165189], [129,135,190], [152,191195],
[146,186], [132,153,196198], [128,130,134,199], [55,200202], [66,68,80,124,203], [80,124].
advantage over SSRIs. (A large NNT indicates that

many people would be treated before one extra person
responded favourably to the slightly more effective treatment.) Selection requires a balancing of benefits and
risks, including side-effects and toxicity. The relative
merits of older and newer medications remain controversial and require study.
Both tables show the effectiveness of CBT and IPT.
Whereas research requires structured treatment, often
using a treatment manual, in practice the approach is
more eclectic and reflects the therapists expertise.
There is as yet no evidence that dynamic psychotherapy
is effective. However, depression is often associated
with trauma and personality difficulties, which are commonly treated by psychodynamic therapy. Furthermore,
the literature emphasizes the shared features of effective
therapy (therapeutic alliance, motivation, hopeful expectancy and ability to work with the therapeutic framework)
and the limited benefits of one model over another.
Severe depression without psychosis
Initial treatment uses an antidepressant in the context
of a therapeutic relationship. Psychological therapy for
residual symptoms or risk of relapse may be appropriate
later.
395
There are four satisfactory placebo-controlled trials.

While the NNT compares to that in moderate depression,
it does not reach statistical significance. None of the
comparative studies of newer and older antidepressants
(Table 3) is statistically significant.
and, as studies are often uncontrolled, the risk of bias

increases. There is significant evidence of benefit for
lithium, and some for tri-iodothyronine. Pindolol, which
is not licensed as an antidepressant in Australasia,
hastens response to treatment.
Severe and complicated depression
Electroconvulsive therapy (ECT)
Trials are rare. Accurate diagnosis, consultation with

colleagues, adequate dose, support and monitoring all
contribute to response, and maintenance is critical.
While the algorithm indicates that under usual circumstances ECT is the fourth option, it may be selected
earlier for individual patients. Randomized controlled
trials recruit people with less severe illness than is
common in practice, and in deciding whether to use ECT
for severe, unresponsive depression, the specialists best
guide is experience rather than the limited literature.
The primary indication is major depression, especially
with melancholia, psychotic features and/or suicidal
risk. Raised intracranial pressure is the only absolute
contraindication, but situations of risk requiring careful
evaluation include hypertension, recent myocardial
infarction, bradyarrhythmias, cardiac pacemakers, intracranial pathology, aneurysms, epilepsy, osteoporosis,
skull defect, retinal detachment and concurrent medical
illnesses.
Electroconvulsive therapy is administered by trained
staff under medical supervision. While unilateral treatment of the non-dominant hemisphere is associated
with less severe cognitive side-effects than bilateral
treatment, its benefit remains controversial. Current
recommendations are to start with unilateral treatment,
unless the patients prior treatment response or urgency
dictate otherwise. A stimulus dosing approach with
EEG monitoring is recommended. Details are available
in RANZCP Clinical Memorandum #12 at <http://
www.ranzcp.org>.
Electroconvulsive therapys benefits are short-term and
should be followed by maintenance medication. Initiation
of medication during treatment is controversial [7072].
Unsatisfactory response to initial treatment

The first step is to reconsider the diagnosis, determine
whether the patient has followed the treatment plan,
including regular medication, and review perpetuating
psychosocial factors.
If reviewing dose, note that TCAs and venlafaxine
have a wider dose responsiveness (a flatter dose
response curve) than SSRIs [64]. Greater scope to
increase dose (subject to tolerance and toxicity) enables
TCAs and venlafaxine to be considered if SSRIs are
unsuccessful. TCAs are more effective for melancholic
depression [65].
Antidepressant plus structured psychotherapy
Cognitive behavioural therapy (or, to a lesser extent,
IPT) plus medication gives better results than either
treatment alone [6668] for depression or for comorbid
anxiety and depressive disorders [69].
Augmentation strategies
Table 4 summarizes augmentation of antidepressants
with other agents when initial treatment is unsuccessful.
Limited funding has restricted the number of subjects
Table 4.
Augmentation strategies for treating depression
TCA/SSRI + lithium cf. same TCA/SSRI alone

TCA + T3 cf. TCA + placebo
Addition of pindolol (7.5 mg/day) cf. placebo at 12 weeks
Addition of pindolol (7.5 mg/day) cf. placebo at 56 weeks
Addition of pindolol (7.5 mg/day) cf. placebo at 56 weeks: for severe,
treatment-resistant or psychotic depression
Number of people
(number of studies)
114 (3)
119 (5)
391 (7)
587 (9)
150 (2)
NNT
ARR
3.3 (38)
6.3
9.9 (687)
6.3 (513)
75
30.4 (1346%)
5.9
0.1 (119%)
5.9 (824%)
0.3
The 95% condence intervals for NNT and ARR are in square brackets where the effect is signicantly benecial compared to the
control treatment (i.e. placebo); NNT, number needed to treat; ARR, absolute risk reduction; references: [204206], [207211],
[212218], [214,215,217,219224], [212,223].
396
Long-term maintenance ECT is not of proven benefit.

Formal review and explicit consent are recommended.
Combined antidepressant treatments
Combination treatment is experimental and requires
informed consent, preferably after a second opinion or
discussion with a mood disorder clinic.
TCA and SSRI: This combination was common in the
1990s but not evidence-based. Venlafaxine is similarly
effective, with less risk of severe side-effects.
TCA and MAOI: This combination can be fatal. It was
not effective in placebo-controlled trials [73] and its
major hazard necessitates a second opinion and informed
consent.
Psychosurgery
Reserved for a tiny group with highly treatmentresistant and severe depression [74], psychosurgery is
restricted in Australia to highly experienced services.
Continuation of treatment
Continuing treatment lowers the risk of relapse and
improves psychosocial outcomes [75]. The few longterm studies have not identified when treatment can be
withdrawn, although the benefits of continuing increase
with the number of previous episodes [76]. As numbers
in these trials decrease over time, confidence intervals
widen. Subjects willing to take medication in such a trial
may be atypical of clinical populations.
Shorter-term follow-up studies support continuation
of treatment for 12 months following a first episode
(Table 5). Expert consensus supports treatment for
3 years or more after recurrent episodes, following discussion of the potential benefits and burden of treatment.
Intermittent treatment risks side-effects due to withdrawal, particularly with shorter-acting SSRIs [77].
Table 5.
Atypical depression
Trials of newer antidepressants are lacking, and earlier
studies are few and methodologically limited. The latter
found phenelzine the most effective (NNT = 2.2,
ARR = 45%) [78] followed by CBT (NNT = 3.4,
ARR = 29.4%) [79,80] and imipramine (NNT = 5.0,
ARR = 20%) [78,8082]. But concerns about sideeffects and interactions with tyramine-containing foods
prevail, and newer drugs are used first.
Depression with psychosis
Electroconvulsive therapy alone, or a TCA plus an
antipsychotic, are much superior to TCA alone: (TCAs
plus an antipsychotic vs. TCA: 6 studies [8388] 181
patients, NNT = 2, ARR = 51%; ECT vs. TCA: 8 studies
[8386,8992], 445 patients, NNT = 2.1, ARR = 48%).
Indications for treatment away from home
These include suicidality, self-neglect, stressful context, need for psychological support in severe distress.
Depending on needs and facilities, such care may
involve friends and family, respite accommodation or
inpatient hospital care.
Prevention of relapse
A sound therapeutic relationship is crucial to reducing
relapse. It will provide psycho-education (identifying
warning signs and how to respond), consider unresolved
psychosocial issues, and seek to enhance support networks and maintain effective antidepressant treatment
for an appropriate period, mindful of the number of
previous episodes and of individual factors. Continued
CBT is useful after primary treatment [93]. Such active
relapse prevention is effective in primary care [94].
Continuation compared to early discontinuation in treating depression
Treatment
Continuation of an SSRI at 6 months
Continuation of an SSRI at 12 months
Continuation with CBT (following primary treatment) cf.
placebo or no treatment at 2 years
Continuation with CBT (following primary treatment) cf. TCA
or Standard treatment at 2 years
Number of patients
(number of studies)
545 (3)
495 (3)
337 (4)
202 (2)
NNT
ARR
6.0 (512)
3.8 (36)
4.5 (310)
16.6% (924%)
26.5% (1835%)
22.3% (1034%)
7.7
NS
13.1%
NS
NNT, number needed to treat; ARR, absolute risk reduction; NS, not signicant; references: [225227], [225,228,229], [230233],
[233,234].
Enduring resistance to treatment

Some people do not respond adequately to a range
of treatments. Options then include obtaining second
opinions, discussion in a peer review group and referral
to a mood disorder service. The psychiatrist maintains
hope, provides support and ameliorates symptoms as
far as possible until the depression remits and recovery
ensues.
Discontinuing treatment
Duration of treatment takes into account its benefits
and burdens, including risk of relapse. Treatment is
discontinued gradually. Withdrawal reactions are common
with shorter-acting SSRIs and halving the dose each
week is one option. Abrupt cessation of TCAs may
precipitate an anticholinergic withdrawal reaction (flulike illness, myalgia and abdominal cramps). Gradual
withdrawal may prevent this.
Treatment of special clinical groups
Pregnant and breastfeeding women
While the teratogenic potential of most antidepressants,
apart from mood stabilisers, appears low, few studies
include information on child development [95]. Psychological treatments offer an alternative for pregnant
women who are reluctant to take medication.
Studies of antidepressants and breastfeeding are often
small and rarely measure concurrent maternal and infant
blood levels. Most find transmission in breast milk to be
limited, but there is considerable individual variation
and immaturity of infant hepatic metabolic systems
should be considered, particularly in the premature or ill
[96,97].
397
(Number Needed to Harm, here defined as treatmentdropout rate in excess of placebo) [100].
The risks and benefits of treatment must be weighed.
The substantial risks of untreated depression include
suicide, the burden of disease and its impact on other
conditions. For example, depression increases morbidity
and mortality for those with coronary artery disease,
with or without recent myocardial infarction. Postinfarction, the risk is similar to that for post-infarction
left ventricular failure [101].
Psychological strategies include group or individual
CBT in multiple sclerosis and HIV-AIDS [102], but this
is controversial in cancer [103].
When prescribing, consider whether mood results
from the medical condition or from concurrent treatment, whether the antidepressant exacerbates or causes
medical symptoms, and whether drug interactions could
affect plasma drug levels.
Drug-induced alteration in mood
Prednisone may destabilize mood, particularly at
higher doses (one in five people without previous
psychiatric illness in the first week at daily doses over
80 mg) [104]. Carbamazepine, valproate and lamotrigine
have a positive effect on mood, and phenobarbitone and
vigabatrin an adverse effect. Propranolol and other lipid
soluble beta-blockers, and occasionally less lipid soluble
beta-blockers, can cause depression, as can alphamethyldopa. Rarely, oral contraceptives affect mood.
Specic conditions
Most studies are small, with limited power to detect rare
adverse events. Consider the individuals overall health
and consult with liaison psychiatrists or physicians.
Cardiac disease
The frail elderly

As there are few studies of antidepressants in the frail
elderly (unlike older people more generally [98]), start
with a low dose and increase gradually. The elderly
taking SSRIs are vulnerable to hyponatraemia.
Those with physical illnesses
The International Consensus Group on Depression and
Anxiety felt unable to present guidelines for depression
in cancer [99], due to limited evidence. However, the
Cochrane Collaboration concluded that antidepressants
improved depression in patients with a range of physical
diseases, with an overall NNT of 4.2 and an NNH of 9.8
Depression increases the risk of cardiac mortality

threefold [105]. Consider specialist advice, since most
antidepressants have contraindications. Tricyclic antidepressants should never be the first choice in cardiac,
especially ischaemic, disease [106] as they are class 1A
anti-arrhythmics and may induce arrhythmias. SSRIs
and buproprion are safer, but large, long-term RCTs are
needed to confirm their safety [101] and their place
following myocardial infarction (e.g. [107]).
Lithium at therapeutic levels can cause sinus node
dysfunction or sinoatrial block sufficient to alter consciousness. There is increased risk with ECT for those
with cardiac disease, although its extent is debated.
MAOIs may induce orthostatic hypotension. Trazodone
398
can cause ventricular arrhythmias but appears safe for

most patients [108]. Venlafaxine has not been studied in
patients with cardiac disease.
Antihypertensives, especially diuretics, increase the
likelihood that TCAs, trazodone or MAOIs will induce
orthostatic hypotension.
Interactions between cardiac and antidepressant medications are described below.
potential; fluoxetine and fluvoxamine relatively high.

Carbamazepine appears to reduce warfarins effects [111].
Cardiac medications
SSRIs and nefazodone interact with cardiac medications through cytochrome P450 and may induce adverse
effects. MAOIs interact adversely with alpha- and betablockers and ACE inhibitors.
Epilepsy
HIV-AIDS
Standard treatments for depression (including ECT)
are safe and effective for people with seizure disorders.
However, maprotiline, amoxapine, bupropion and clomipramine, particularly in higher doses, are best avoided due
to increased risk of seizures [109]. Carbamazepine, valproate and lamotrigine have a positive effect on mood,
while phenobarbitone and vigabatrin have adverse effects.
Glaucoma
Anticholinergic drugs, such as TCAs and MAOIs, may
precipitate acute narrow-angle glaucoma in susceptible
individuals [110]. Antidepressants lacking anticholinergic activity (bupropion, sertraline, fluoxetine, trazodone)
appear safe, but intra-ocular pressure should be carefully
monitored.
Antidepressants and protease inhibitors and nonnucleoside reverse transcriptase inhibitors are metabolized by similar cytochrome P450 enzymes. As this
increases drug levels, doses need adjusting.
Migraine
Fluoxetine and sumatriptan may interact and should be
combined with caution [112].
Nonsteroidal anti-inammatory drugs (NSAIDs)
Lithium levels may increase with both unselective and
selective COX inhibitor NSAIDs (e.g. rofecoxib) [113].
Interventions of unproven efcacy
Prostatism and obstructive uropathy
St Johns wort
Antidepressants with antimuscarinic effects (e.g. most

TCAs, trazodone and MAOIs) are contraindicated.
Medications with the least propensity for this effect are
fluoxetine, sertraline, bupropion and desipramine.
While initially supported by trials in mild to moderate

depression, more recent studies of better design, with
patient HAM-D scores of >20, found that St Johns wort
is not superior to placebo (NNT = 23). Table 6 summarizes studies that use standard antidepressant doses.
There are no studies in severe depression.
Commercially available St Johns wort contains varying
amounts of the putative active compound hypericum and
it is not clear whether there are other active compounds.
The rate of side-effects is low, but significant drug
interactions are consistent with St Johns wort having
both SSRI- and MAOI-like activity.
Drug interactions
Psychotropics may lead to a range of drug interactions.
Some are described below and others can be predicted or
suspected on the basis of cytochrome P450 based interactions, mindful that most psychotropics are metabolized in multiple pathways. A number of useful websites
include <http://medicine.iupui.edu/flockhart/>. Any interaction involving a new drug, or any life-threatening
reaction with an established one, should be reported to
the Medicines Adverse Reaction Committee (MARC) in
New Zealand or the Adverse Drug Reaction Assessment
Committee (ADRAC) in Australia.
Transcranial magnetic stimulation (TMS)

There is scant evidence of benefit, but research
samples have been small [114].
Omega-3 fatty acids
Anticoagulants
Warfarin interacts with many drugs. Citalopram,
nefazodone and sertraline have relatively low interaction
While omega-3 fatty acid levels are low in depression,

there is no evidence that they improve depression.
Further research is warranted [115].
Table 6.
Placebo
SSRIs
TCAs
399
St Johns wort compared with placebo, SSRIs and TCAs
Number of patients (number of studies)

1708 (10)
240 (2)
851 (5)
NNT
6.9 (611)
20.3
29.4
ARR
14.5% (9.919%)
4.9%
3.5%
NNT, number needed to treat; ARR, absolute risk reduction; references: [136,235243], [243,244], [136,239,245247].
Figure 2. Principal evidence-based treatments for uncomplicated, melancholic or atypical depression (mild to high severity).
Tryptophan and 5-hydroxytryptophan
Complementary and self-help treatments
Only two of the 108 trials are of adequate quality.

Antidepressant activity, and association with the potentially fatal eosinophiliamyalgia syndrome, remain inconclusive [116].
A recent review concluded that none is well supported

by evidence but some warrant further investigation
[117].
400
Figure 3.
Principal evidence-based treatments for psychotic depression.
Conclusion
The principal treatments have similar benefit.
Compliance with a particular treatment depends more
on the relationship between therapist and patient and
on sustained support [118]. If treatment continues for
at least 12 months, outcome is better than if stopped
prematurely.
The principal recommendations are shown in Figs 2
and 3, with levels of evidence for depression with psychosis (Fig. 3) being less robust than those in Fig. 2. The
place of ECT depends on the urgency of the situation
and the patients preference. Maintenance reduces the
high risk of relapse or recurrence.
In summary, the evidence supports provision of the
treatments specified above as part of an overall clinical
management plan. Everyone with depression faces unique
circumstances, and the clinician considers the extent to

which evidence is pertinent. The aim of treatment is
to achieve and maintain remission. Depression is a
recurrent disorder, especially for those in secondary care
settings. An active focus on prevention is tailored to the
persons specific needs and strengths.
Acknowledgements
This paper was written by Pete M. Ellis, Ian Hickie
and Don A.R. Smith.
CPG team:
Pete M. Ellis (Wellington School of Medicine and
Health Sciences, University of Otago), Ian Hickie (University of Sydney), John Bushnell (Wellington School of
Medicine and Health Sciences, University of Otago), Paul
Hirini (School of Maori Studies, Massey University,
Palmerston North), Suzy Stevens (Mental Health Foundation, Auckland: consumer consultant), Don A. R.
Smith (Wellington School of Medicine and Health
Sciences, University of Otago: project manager).
Consultant reviewers
Phillip Boyce (psychiatrist), Sunny Collings (psychiatrist), Sue Fitchett (clinical psychologist), David Guthrie
(consumer), Peter Joyce (psychiatrist), Phil Mitchell
(psychiatrist), Malcolm Stewart (clinical psychologist),
Grant Taylor (clinical psychologist), John Thorburn
(clinical psychologist).
Editorial consultant
We thank Sidney Bloch for his editorial assistance.
Statement of competing interests
Peter Ellis receives research funds from Eli Lilly for a
study of antipsychotic drugs and has a managed share
portfolio that contains some pharmaceutical company
shares. Ian Hickie has received grants for research or
sponsorship for educational activities, particularly related
to treatment of depression by general practitioners, from
a variety of pharmaceutical companies including Pfizer,
Eli-Lilly, Bristol Myers Squibb and Wyeth. Additionally
he has chaired advisory groups for the Australian
Federal Government Department of Health and Ageing,
related to the management of depression and other
common mental disorders by general practitioners.
References
1. Ellis PM, Smith DAR. Treating depression: the beyondblue
guidelines for treating depression in primary care. Not so much
what you do but that you keep doing it. Medical Journal of
Australia 2002; 176(Suppl.):S77S83.
2. National Health Committee. Guidelines for the treatment and
management of depression by primary healthcare professionals.
Wellington: Ministry of Health, 1996.
3. National Health and Medical Research Council. Getting up from
feeling down: young people and depression. Canberra: National
Health and Medical Research Council, 1997.
4. Andrews G. Brief report provided to the New Zealand Treasury
on the prevalence and disability of DSM-IV disorders from the
1997 Australian National Survey of Mental Health and
Well-being. Wellington: New Zealand Treasury, 2000.
5. McLennan W. Mental health and wellbeing: profile of adults,
Australia 1997. Canberra: Australian Bureau of Statistics, 1998.
6. Wells K, Stewart A, Hays RD et al. The functioning and
well-being of depressed patients: results from the Medical
Outcomes Study. Journal of the American Medical Association
1989; 262:914919.
7. Hays RD, Well KB, Sherbourne CD, Rodgers W, Spritzer K.
Functioning and well-being outcomes of patients with depression
compared with chronic general medical illnesses. Archives of
General Psychiatry 1995; 52:1119.
401
8. Murray CJL, Lopez AD (eds.) The global burden of disease:

a comprehensive assessment of mortality and disability from
disease, injuries and risk factors in 1990 and projected to 2020.
Cambridge MA: Harvard University Press, 1996.
9. Goldberg D. The recognition of psychiatric illness by
non-psychiatrists. Australian and New Zealand Journal of
Psychiatry 1984; 18:128133.
10. Keller MB. Under-recognition and under-treatment by
psychiatrists and other healthcare professionals. Archives of
Internal Medicine 1990; 150:946948.
11. McGee R, Feehan M, Williams S, Anderson J. DSM-III
disorders from age 1115 years. Journal of the American
Academy of Child and Adolescent Psychiatry 1992; 31:5059.
12. Feehan M, McGee R, Raja SN, Willimas SM. DSM-III disorders
in New Zealand 18 year olds. Australian and New Zealand
Journal of Psychiatry 1994; 28:8799.
13. American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV), 4th edn. Washington,
DC: American Psychiatric Press, 1994.
14. Mulrow CD, Williams JW, Trivedi M, Chiquette E, Aguilar C,
Cornell JE. Treatment of depression: Newer pharmacotherapies:
AHCPR. Rockville, MD: Agency for Healthcare Policy and
Research, 1999.
15. Keller MB, Lavori PW. Double depressive disorder, major
depressive disorder and dysthymic disorder. Distinct entities or
different phases of a single disorder? Psychopharmacology
Bulletin 1984; 20:399402.
16. Keller MB, Lavori PW, Mueller TI et al. Time to recovery,
chronicity and levels of psychopathology in major depression.
Archives of General Psychiatry 1992; 49:809816.
17. Lee AS, Murray RM. The long-term outcome of Maudsley
depressives. British Journal of Psychiatry 1998; 153:741751.
18. Judd LL, Hagop SA, Maser JD et al. A prospective 12 year study
of subsyndromal and syndromal depressive symptoms in
unipolar major depressive disorders. Archives of General
Psychiatry 1998; 55:694700.
19. Thase ME, Sullivan LR. Relapse and recurrence of depression: a
practical approach for prevention. CNS Drugs 1995; 4:261277.
20. Brodaty H, Luscombe G, Peisah C, Anstey K, Andrews G.
A 25 year longitudinal, comparison study of the outcome of
depression. Psychological Medicine 2001; 31:13471359.
21. Inskip H, Harris C, Barraclough B. Lifetime risk of suicide for
affective disorder, alcoholism and schizophrenia. British Journal
of Psychiatry 1998; 172:3537.
22. Black DW, Winokur G, Nasralla A. Effects of psychosis
on suicide risk in 1,593 patients with unipolar and bipolar
affective disorders. American Journal of Psychiatry 1988;
145:849852.
23. Hyman S, Arana GW. Suicide and affective disorder. In:
Jacobs DBH (ed.) Sucide: understanding and responding.
Madison: International University Press, 1990; 171181.
24. Jamison KR. Suicide and bipolar disorder. Annals of the New
York Academy of Science 1986; 487:301315.
25. Rutz W, von Knorring L, Walinder J. Frequency of suicide on
Gotland after systematic postgraduate education of general
practitioners. Acta Psychiatrica Scandinavica 1989; 80:151154.
26. Isacsson G, Gergman U, Rich CL. Epidemiological data suggest
antidepressants reduce suicide risk among depressives. Journal
of Affective Disorders 1996; 41:18.
27. Isacsson G, Holmgren P, Druid H, Bergman U. Psychotropics
and suicide prevention: Implications from toxicological
screening of 5281 suicides in Sweden 199294. British Journal
of Psychiatry 1999; 174:259265.
28. Oquendo M, Malone K, Ellis SP, Sackeim HA, Mann JJ.
Inadequacy of antidepressant treatment for patients with major
depression who are at risk for suicidal behavior. American
402
29. Appleby L, Cooper J, Amos T, Faragher B. Psychological

autopsy study of suicides by people under 35. British Journal of
Psychiatry 1999; 175:168174.
30. Mann J, Waternaux C, Hass GL, Malone KM. Toward a clinical
model of suicidal behavior in psychiatric patients. American
31. Keitner G, Ryan C, Miller IW, Kohn R, Bishop DS, Epstein NB.
Role of the family in recovery and major depression. American
32. Weich S, Lewis G. Poverty, unemployment and common mental
disorders: population based cohort study. British Medical
Journal 1998; 317:115119.
33. Kendler KS, Kessler RC, Neale MC, Heath AC, Eaves LJ. The
prediction of Major Depression in women: Towards an
integrated aetiological model. American Journal of Psychiatry
1993; 150:863870.
34. Romans SE, Walton VA, McNoe B, Herbison GP, Mullen PE.
Otago womens health survey 30 month follow-up I: Onset
patterns of non-psychotic psychiatric disorder. British Journal of
Psychiatry 1993; 163:733738.
35. Romans SE, Walton VA, McNoe B, Herbison GP, Mullen PE.
Otago womens health survey 30 month follow-up II. Remission
patterns of non-psychotic psychiatric disorder. British Journal of
Psychiatry 1993; 163:739746.
36. Brown GW, Moran P. Clinical and psychosocial origins of
chronic depressive episodes: a community survey. British
37. Brown GW, Harris TO, Hepworth C, Robinson R. Clinical and
psychosocial origins of chronic depressive episodes. II: A patient
enquiry. British Journal of Psychiatry 1994; 165:457465.
38. Thase ME. Treatment of severe depression. Journal of Clinical
Psychiatry 2000; 61(Suppl.1):1725.
39. Bebbington P, Katz R, McGuffin P et al. The risk of minor
depression before the age of 65: results from a community
survey. Psychological Medicine 1989; 24:707718.
40. Weissmann MM, Leaf DJ, Tischler GL et al. Affective disorders
in five United States communities. Psychological Medicine
1988; 18:141153.
41. Joyce PR, Oakley-Browne MA, Wells JE, Bushnell JA,
Hornblow AR. Birth cohort trends in major depression:
increasing rates and earlier onset in New Zealand. Journal of
Affective Disorders 1990; 18:8389.
42. Klerman GL, Weissmann MM. Increasing rates of depression.
Journal of the American Medical Association 1989;
261:22292235.
43. Katon W, Ciechanowski P. Impact of major depression on
chronic medical illness. Journal of Psychosomatic Medicine
2002; 53:859863.
44. Fairfield KM, Libman H, Davis RB, Eisenberg DM, Beckett A,
Phillips RS. Brief communication: detecting depression:
providing high quality primary care for HIV-infected patients.
American Journal of Medical Quality 2001; 16:7174.
45. Zorrilla EP, McKay JR, Luborsky L, Schmidt K. Relation
of stressors and depressive symptoms to clinical progression of
viral illness [Comment]. American Journal of Psychiatry 1996;
154:718.
46. Singh N, Squier C, Sivek C, Wagener MM, Yu VL.
Psychological stress and depression in older patients with
intravenous drug use and human immunodeficiency virus
infection: implications for intervention. International Journal of
STD and AIDS 1997; 8:251255.
47. McClure JB, Catz SL, Prejean J, Brantley PJ, Jones GN.
Factors associated with depression in a heterogeneous
HIV-infected sample. Journal of Psychosomatic Research 1996;
40:407415.
48. Rampello L, Chiechio S, Raffaele R, Vecchio I, Nicoletti F. The
SSRI, citalopram, improves bradykinesia in patients with
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
Parkinsons disease treated with 1-dopa. Clinical

Neuropharmacology 2002; 25:2124.
Ruoff GE. Depression in the patient with chronic pain. Journal
of Family Practice 1996; 43(Suppl.): S25S33.
Hamilton M. A rating scale for depression. Journal of
Neurology, Neurosurgery and Psychiatry 1960; 23:5662.
Mietinnen O, Nurminnen M. Comparative analysis of two rates.
Statistics in Medicine 1985; 17:873890.
Radloff LS. The CES-D scale: a self report Major Depressive
Disorder scale for research in the general population. Applied
Psychological Measurement 1977; 1:385401.
Doganay Z, Sunter AT, Guz H et al. Climatic and diurnal
variation in suicide attempts in the ED. American Journal of
Emergency Medicine 2003; 21:271275.
Preti A, Miotto P. Diurnal variation in suicide by age and gender
in Italy. Journal of Affective Disorders 2001; 65:253261.
Williams R, Edwards RA, Newburn GM et al. A double-blind
comparison of moclobemide and fluoxetine in the treatment of
depressive disorders. International Clinical
Psychopharmacology 1993; 7:155158.
Khan A, Leventhal R, Khan SR, Brown WA. Severity of
depression and response to antidepressants and placebo: An
analysis of the food and drug administration database. Journal of
Clinical Psychopharmacology 2002; 22:4045.
Thase ME, Rush AJ, Howland RH et al. Double-blind switch
study of imipramine or sertraline treatment of anti-depressant
chronic depression. Archives of General Psychiatry 2002;
59:233239.
Harris T, Brown GW, Robinson R. Befriending as an
intervention for chronic depression among women in an inner
city. 1: Randomized controlled trial. British Journal of
Psychiatry 1999; 174:219224.
Harris T, Brown GW, Robinson R. Befriending as an
intervention for chronic depression among women in an inner
city. 2: Role of fresh-start experiences and baseline psychosocial
factors in remission from depression. British Journal of
Psychiatry 1999; 174:225232.
Mynors-Wallis LM, Gath DH, Lloyd-Thomas AR et al.
Randomised controlled trial comparing problem solving
treatment with amitriptyline and placebo for major depression in
primary care. British Medical Journal 1995; 310:441445.
Mynors-Wallis LM, Gath DH et al. Randomised controlled trial
of problem solving treatment antidepressant medication and
combined treatment for major depression in primary care. British
Medical Journal 2000; 320:2630.
Barkham M, Hardy GE. Counselling and interpersonal therapies
for depression: towards an evidence base. British Medical
Bulletin 2001; 57:115132.
King M, Sibbald B, Ward E et al. Executive summary.
Randomised controlled trial of non-directive counselling,
cognitive-behaviour therapy and usual general practitioner care
in the management of depression as well as mixed anxiety and
depression in primary care. Health Technology Assessment 2000;
4:183.
Corruble E, Guelfi JD. Does increasing dose improve efficacy
with poor antidepressant response: a review. Acta Psychiatrica
Scandinavica 2000; 101:343348.
Parker G. New and old antidepressants. all equal in the eyes
of the lore? British Journal of Psychiatry 2001; 179:9596.
Murphy GE, Simons AD, Wetzel RD et al. Cognitive therapy
and pharmacotherapy. Singly and together in the treatment of
depression. Archives of General Psychiatry 1984; 41:3341.
Kellor MB, McCullough JP, Klein DN et al. A comparison of
nefazadone, the cognitive behavioral-analysis system of
psychotherapy and their combination for the treatment of chronic
depression. New England Journal of Medicine 2000;
342:14621470.
68. Hollon SD, DeRubeis RJ, Evans MD et al. Cognitive therapy

and pharmacotherapy for depression. Singly and in combination.
69. Ninan PT, Rush J, Crits-Christoph P et al. Symptomatic and
syndromal anxiety in chronic forms of major depression: effects
of nefazodone, cognitive behavioral anaylsis system of
psychotherapy, and their combination. Journal of Clinical
Psychiatry 2002; 63:434441.
70. American Psychiatric Association. The practice of
electroconvulsive therapy: Recommendations for treatment,
training and privileging. Washington, DC: American Psychiatric
Press, 1990.
71. Freeman CP. The ECT handbook. (Council report CR39).
London: Gaskell, 1995.
72. Mayur PM, Gangadhar BN, Subbakrishna DK, Janakiramaiah N.
Discontinuation of antidepressant drugs during electroconvulsive
therapy: a controlled study. Journal of Affective Disorders 2000;
58:3741.
73. Pare CM. The present status of monoamine oxidase inhibitors.
British Journal of Psychiatry 1985; 146:576584.
74. Marino JR, Cosgrove GR. Neurosurgical treatment for
neuropsychiatric illness. Psychiatric Clinics of North America
1997; 20:933943.
75. Kocsis JH, Schatzberg A, Rush AJ et al. Psychosocial outcomes
following long-term, double-blind treatment of chronic
depression with sertraline vs placebo. Archives of General
Psychiatry 2002; 59:723728.
76. Viguera AC, Baldessarini RJ, Friedberg J. Discontinuing
antidepressant treatment in major depression. Harvard Review of
Psychiatry 1998; 5:293306.
77. Michelson D, Fava M, Amsterdam J et al. Interuption of
selective serotonin reuptake inhibitor treatment. British Journal
of Psychiatry 2000; 176:363368.
78. Liebowitz MR, Quitkin FM, Stewart JW et al. Antidepressant
specificity in atypical depression. Archives of General
Psychiatry 1988; 45:129137.
79. Jarrett RB, Schaffer M, McIntire D et al. Treatment of atypical
depression with cognitive therapy or phenelzine: a double-blind,
placebo-controlled trial. Archives of General Psychiatry 1999;
56:431437.
80. Stewart J, Garfinkel R, Nunes EV, Donovan S, Klein DF.
Atypical features and treatment response in the National Institute
of Mental Health Treatment of Depression Collaborative
Research Program. Journal of Clinical Psychopharmacology
1998; 18:429434.
81. Quitkin FM, Stewart JW, McGrath PJ et al. Phenelzine
versus imipramine in the treatment of probable atypical
depression: defining syndrome boundaries of selective
MAOI responders. American Journal of Psychiatry 1988;
145:306311.
82. Quitkin FM, McGrath PJ, Stewart JW et al. Atypical depression,
panic attacks, and response to imipramine and phenelzine:
a replication. Archives of General Psychiatry 1990; 47:935941.
83. Kaskey GB, Nasr S, Meltzer HY. Drug treatment in delusional
depression. Psychiatry Research 1980; 1:267277.
84. Charney DS, Nelson JC. Delusional and non-delusional and
unipolar depression: further evidence of distinct sub-types.
American Journal of Psychiatry 1981; 138:328333.
85. Brown R, Frances A, Kocsis JH, Mann JJ. Psychotic vs
non-psychotic depression: Comparison of treatment response.
Journal of Nervous and Mental Disease 1982; 170:635637.
86. Minter RE, Mandel MR. The treatment of psychotic major
depressive disorder with drugs and electroconvulsive therapy.
Journal of Nervous and Mental Disease 1979; 167:726733.
87. Spiker DG, Hanin I, Perel JM, Cofsky JE, Rossi AJ, Sorisio D.
Pharmacological treatment of delusional depressives.
Psychopharmacology Bulletin 1982; 18:184186.
403
88. Spiker DG, Weiss JC, Dealy RS et al. The pharmacological

treatment of delusional depression. American Journal of
Psychiatry 1985; 142:430435.
89. Glassman AH, Kantor SJ, Shostak M. Depression, delusions and
drug response. American Journal of Psychiatry 1975;
132:462463.
90. Davidson JR, McLeod MN, Kurland AA, White HL.
Antidepressant drug therapy in psychotic depression. British
91. Avery D, Luborsky L. Depression treated with imipramine and
ECT. The DeCarolis study reconsidered. American Journal of
Psychiatry 1979; 136:559562.
92. Janakiramaiah N, Gangadhar BN, Nga Venkatesha Murthy PJ,
Harish MG, Subbakrishna DK, Vedamurthachar A.
Antidepressant efficacy of Sudarshan Kriya Yoga (SKY) in
melancholia: a randomized comparison with electroconvulsive
therapy (ECT) and imipramine. Journal of Affective Disorders
2000; 57:255259.
93. Jarrett RB, Kraft D, Doyle J et al. Preventing recurrent
depression using cognitive therapy with and without a
continuation phase: a randomized clinical trial. Archives of
94. Katon W, Rutter C, Ludman EJ et al. A randomized trial of
relapse prevention of depression in primary care. Archives
of General Psychiatry 2001; 58:241247.
95. Medicines in Pregnancy Working Party of the Australian Drug
Evaluation Committee. Prescribing medicines in pregnancy.
An Australian categorization of risk of drug use in pregnancy.
4th edn. Canberra: Therapeutic Goods Administration, 1999.
96. Dodds S, Buist A, Norman TR. Antidepressants and breast
feeding: a review of the literature. Paediatric Drugs 2000;
2:183192.
97. Anonymous. Drugs and breast feeding. Prescribe International
2002; 11:17.
98. Katona K, Livingston G. How well do antidepressants work in
older people? A systematic review of the Number Needed to
Treat. Journal of Affective Disorders 2002; 69:4752.
99. Ballenger JC, Davidson JR, Lecrubier Y et al. Consensus
statement on depression, anxiety, and oncology. Journal of
Clinical Psychiatry 2001; 62(Suppl.8):6467.
100. Gill D, Hatcher S. Database of systematic reviews (4). In:
Cochrane Database of Systematic Reviews CD001312, 2000.
101. Roose SP. Considerations for the use of antidepressants in
patients with cardiovascular disease. American Heart Journal
2000; 140(Suppl.4):8488.
102. Blanch J, Rousand A, Martinez E et al. Impact of lipodystrophy
on the quality of life of HIV-1-infected patients. Journal of
Acquired Immune Deficiency Syndromes 2002; 31:404407.
103. Sheard T, Maguire P. The effect of psychological interventions
on anxiety and depression in cancer patients: results of two
meta-analyses. British Journal of Cancer 1999; 80:17701780.
104. Brown ES, Suppes T. Mood symptoms during corticosteroid
therapy: a review. Harvard Review of Psychiatry 1998;
5:239246.
105. Penninx BWJH, Beekman ATF, Honig A et al. Depression and
cardiac mortality: Results from a community-based longitudinal
study. Archives of General Psychiatry 2001; 58:221227.
106. Glassman AH. Cardiovascular effects of antidepressant drugs:
updated. Journal of Clinical Psychiatry 1998;
59(Suppl.15):1318.
107. Swanson JR, OConnor CM, Barton D et al. Influence of
depression and effect of treatment with sertraline on quality of
life after hospitalization for acute coronary syndromes. American
Journal of Cardiology 2003; 92:12711276.
108. Seiner SJ, Mallya G. Treating depression in patients with
cardiovascular disease. Harvard Review of Psychiatry 1999;
7:8593.
404
109. Rosenstein DL, Nelson JC, Jacobs SC. Seizures associated with
antidepressants: a review. Journal of Clinical Psychiatry 1993;
54:289299.
110. Lieberman E, Stoudemire A. Use of tricyclic antidepressants in
patients with glaucoma. Psychosomatics 1987; 28:145148.
111. Sayal KS, Duncan-McConnell HW, Taylor DM. Psychotropic
interactions with warfarin. Acta Psychiatrica Scandinavica 2000;
102:250255.
112. Joffe RT, Sokolov ST. Co-administration of fluoxetine and
sumatriptan: the Canadian experience. Acta Psychiatrica
113. Lundmark J, Gunnarsson T, Bengtsson F. A possible interaction
between lithium and refecoxib. British Journal of Clinical
Pharmocology 2002; 53:403404.
114. Martin JL, Barband MJ, Schlaepfer TE et al. Transcranial
magnetic stimulation for treating depression. Cochrane
Database of Systematic Reviews CD003493 2002; 2.
115. Maidment ID. Are fish oils an effective therapy in mental illness
an analysis of the data. Acta Psychiatrica Scandinavica 2000;
102:311.
116. Shaw K, Turner J, Del Mar C. Tryptophan and
5-hydroxytryptophan for depression. Cochrane Database of
Systematic Reviews 2003; 3.
117. Jorm AF, Christensen H, Griffiths KM, Rodgers B. Effectiveness
of complementary and self-help treatments for depression.
Medical Journal of Ausstralia 2002; 176(Suppl.):S84S96.
118. Delgado PL. Approaches to the enhancement of patient
adherence to antidepressant medication treatment. Journal of
Clinical Psychiatry 2000; 61(Suppl.2):69.
119. Parker G. Classifying depression. Should paradigms lost be
regained? American Journal of Psychiatry 2000;
157:11951203.
120. Parker G, Roy K, Mitchell P, Wilhelm K, Malhi G,
Hadzi-Pavlovic D. Atypical depression: a reappraisal. American
121. Stark P, Hardison CD. A review of multicenter controlled studies
of fluoxetine vs. imipramine and placebo in outpatients with
major depressive disorder. Journal of Clinical Psychiatry 1985;
46:5358.
122. Cohn JB, Wilcox CS. Low-sedation potential of buspirone
compared with alprazolam and lorazepam in the treatment of
anxious patients: a double-blind study. Journal of Clinical
Psychiatry 1986; 47:409412.
123. Brown WA, Arato M, Shrivastava R. Pituitary-adrenocortical
hyperfunction and intolerance to fluvoxamine, a selective
serotonin uptake inhibitor. American Journal of Psychiatry 1986;
143:8890.
124. Elkin I, Shea MT, Watkins JT et al. National Institute of Mental
Health Treatment of Depression Collaborative Research
Program. General effectiveness of treatments. Archives of
125. Feighner JP, Boyer WF. Paroxetine in the treatment of
depression: a comparison with imipramine and placebo. Acta
Psychiatrica Scandinavica 1989; 350(Suppl.):125129.
126. Lydiard RB, Laird LK, Morton WA Jr. et al. Fluvoxamine,
imipramine, and placebo in the treatment of depressed
outpatients: effects on depression. Psychopharmacology Bulletin
1989; 25:6870.
127. Reimherr FW, Chouinard G, Cohn CK et al. Antidepressant
efficacy of sertraline: a double-blind, placebo- and
amitriptyline-controlled, multicenter comparison study in
outpatients with major depression. Journal of Clinical Psychiatry
1990; 51(Suppl.B):1827.
128. Fontaine R, Ontiveros A, Elie R et al. A double-blind
comparison of nefazodone, imipramine, and placebo in
major depression. Journal of Clinical Psychiatry 1994;
55:234241.
129. Schweizer E, Feighner J, Mandos LA et al. Comparison of

venlafaxine and imipramine in the acute treatment of major
depression in outpatients. Journal of Clinical Psychiatry 1994;
55:104108.
130. Rickels K, Schweizer E, Clary C et al. Nefazodone and
imipramine in major depression: a placebo-controlled trial.
British Journal of Psychiatry 1994; 164:802805.
131. Doogan DP, Langdon CJ. A double-blind, placebo-controlled
comparison of sertraline and dothiepin in the treatment of major
depression in general practice. International Clinical
132. Bremner JD. A double-blind comparison of Org 3770,
amitriptyline and placebo in major depression. Journal of
Clinical Psychiatry 1995; 56:519525.
133. Fabre L, Birkhimer LJ, Zaborny BA, Wong LF, Kapik BM.
Fluvoxamine versus imipramine and placebo: a double-blind
comparison in depressed patients. International Clinical
134. Cohn CK, Robinson DS, Roberts DL et al. Responders
to antidepressant drug treatment: a study comparing
nefazodone, imipramine, and placebo in patients with major
depression. Journal of Clinical Psychiatry 1996;
57(Suppl.2):1518.
135. Lecrubier Y, Bourin M, Moon CA et al. Efficacy of venlafaxine
in depressive illness in general practice. Acta Psychiatrica
136. Philipp M, Kohnen R, Hiller KO. Hypericum extract versus
imipramine or placebo in patients with moderate depression:
randomised multicentre study of treatment for eight weeks.
(published erratum appears in BMJ 2000; 320: 361.) British
Medical Journal 1999; 319:15348.
137. Muijen MD, Roy D, Silverstone T. A comparative clinical trial
of fluoxetine, mianserin and placebo in depressed outpatients.
Acta Psychiatrica Scandinavica 1988; 78:384390.
138. Rickels K, Amsterdam J, Clary C et al. A placebo-controlled,
double-blind, clinical trial of paroxetine in depressed outpatients.
Acta Psychiatrica Scandinavica 1989; 350(Suppl.):117123.
139. Laughren TP. The review of clinical safety data in a new drug
application. Psychopharmacology Bulletin 1989;25:58.
140. Dunlop SR, Dornseif BE, Wernicke JF et al. Pattern
analysis shows beneficial effect of fluoxetine treatment in
mild depression. Psychopharmacology Bulletin 1990;
26:173180.
141. Kiev A. A double-blind, placebo-controlled study of paroxetine
in depressed outpatients. Journal of Clinical Psychiatry 1992;
53(Suppl.):2729.
142. Smith WT, Glaudin V. A placebo-controlled trial of paroxetine
in the treatment of major depression. Journal of Clinical
Psychiatry 1992; 53:3639.
143. Claghorn JL. The safety and efficacy of paroxetine compared
with placebo in a double-blind trial of depressed outpatients.
Journal of Clinical Psychiatry 1992; 53(Suppl.):3335.
144. Heiligenstein JH, Tollefson GD, Faries DE. A double-blind trial
of fluoxetine, 20mg and placebo in outpatients with DSM-III-R
major depression and melancholia. International Clinical
145. Fabre LBL, Birkhimer LJ, Zaborny BA, Wong LF, Kapik BM.
Fluvoxamine versus imipramine and placebo: a double-blind
comparison in depressed patients. International Clinical
146. Massana J. Reboxetine versus fluoxetine. an overview of
efficacy and tolerability. Journal of Clinical Psychiatry 1998;
59(Suppl.):810.
147. Olie JP, Gunn KP, Katz E. A double-blind placebo-controlled
mulitcentre study of sertraline in the acute and continuation
treatment of major depression. European Psychiatry 1997;
12:3441.
148. Schweizer E, Feighner J, Mandos LA, Rickels K. Comparison of

venlafaxine and imipramine in the acute treatment of major
depression in outpatients. Journal of Clinical Psychiatry 1994;
55:104108.
149. Thase ME, Venlafaxine XR 207 Study Group. Efficacy and
tolerability of once-daily venlafaxine extended release (XR) in
1997; 58:393398.
150. Rudolph RL, Fabre LF, Feighner JP, Rickels K, Entsuah R,
Derivan AT. A randomised, placebo-controlled, doseresponse
trial of venlafaxine hydrochloride in the treatment of major
depression. Journal of Clinical Psychiatry 1998; 59:116122.
151. Kahn A, Upton GV, Rudolph RL, Entsuah R, Leventer SM,
Venlafaxine Investigator Study Group. The use of venlafaxine in
the treatment of major depression and major depression
associated with anxiety: A doseresponse study. Journal of
152. Rudolph RL, Feiger AD. A double-blind, randomized,
placebo-controlled trial of once-daily venlafaxine extended
release (XR) and fluoxetine for the treatment of depression.
Journal of Affective Disorders 1999; 56:171181.
153. Smith WT, Glaudin V, Panagides J et al. Mirtazapine vs.
amitriptyline vs. placebo in the treatment of major depressive
disorder. Psychopharmacology Bulletin 1990; 26:191196.
154. Feighner J, Targum SD, Bennett ME et al. A double-blind,
placebo-controlled trial of nefazodone in the treatment of
patients hospitalized for major depression. Journal of Clinical
Psychiatry 1998; 59:246253.
155. de Jong R, Treiber R, Henrich G. Effectiveness of two
psychological treatments for inpatients with severe and chronic
depression. Cognitive Therapy Research 1988; 10:645663.
156. Lydiard RB, Laird LK, Morton WA Jr. Fluvoxamine, imipramine,
and placebo in the treatment of depressed outpatients: effects on
depression. Psychopharmacology Bulletin 1989; 25:6870.
157. Tignol J, Stoker MJ, Dunbar GC. Paroxetine in the treatment of
melancholia and severe depression. International Clinical
158. Roose SP, Glassman AH, Attia E, Woodring S. Comparative
efficacy of selective serotonin reuptake inhibitors and tricyclics
in the treatment of melancholia. American Journal of Psychiatry
1994; 151:17351739.
159. Kasper S, Moller H-J, Montgomery SA, Zondag E.
Antidepressant efficacy in relation to item analysis and severity
of depression: A placebo-controlled trial of fluvoxamine versus
imipramine. International Clinical Psychopharmacology 1995;
9(Suppl.4):312.
160. Lepine JP, Goger J, Blashko C et al. A double-blind study of the
efficacy and safety of sertraline and clomipramine in outpatients
with severe major depression. International Clinical
161. Guelfi JD, Payan C, Fermanian J et al. Moclobemide versus
clomipramine in endogenous depression. A double-blind
randomised clinical trial. British Journal of Psychiatry 1992;
160:519524.
162. Clerc GE, Ruimy P, Verdeau-Palles J. A double-blind
comparison of venlafaxine and fluoxetine in patients hospitalized
for major depression and melancholia. International Journal of
163. Tzanakaki M, Guazzelli M, Nimatoudis I, Zissis NP, Smeraldi E,
Rizzo F. Increased remission rates with venlafaxine compared
with fluoxetine in hospitalized patients with major depression
and melancholia. [erratum appears in International Clinical
Psychopharmacology 2000; 15: 120.] International Clinical
164. Feiger A, Kiev A, Shrivastava RK, Wisselink PG, Wilcox CS.
Nefazadone versus sertraline in outpatients with major
depression: Focus on efficacy, tolerability and effects on sexual
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
176.
177.
178.
179.
180.
181.
182.
405
function and satisfaction. Journal of Clinical Psychiatry 1996;

57(Suppl.2):5362.
Feighner JP. A comparative trial of fluoxetine and amitriptyline
in patients with major depressive disorder. Journal of Clinical
Psychiatry 1985; 46:369372.
Fawcett J, Zajecka JM, Kravitz HM et al. Fluoxetine versus
amitriptyline in adult outpatients with major depression. Current
Therapeutic Research 1989; 45:821831.
Guillibert E, Pelicier Y, Archambault JC et al. A double-blind,
multicentre study of paroxetine versus clomipramine in
depressed elderly patients. Acta Psychiatrica Scandinavica 1989;
350(Suppl.):132134.
Levine S, Deo R, Mahadevan K. A comparative trial of a new
antidepressant, fluoxetine. International Clinical
Psychopharmacology 1989; 4(Suppl.1):4145.
Perry PJ, Garvey MJ, Kelly MW, Cook BL, Dunner FJ,
Winokur G. A comparative trial of fluoxetine versus trazodone in
1989; 50:290294.
Danish University Antidepressant Group. Paroxetine: a selective
serotonin reuptake inhibitor showing better tolerance, but weaker
antidepressant effect than clomipramine in a controlled
multicenter study. Journal of Affective Disorders 1990;
18:289299.
Dowling B, Webb MGT, Halpin CM et al. Fluoxetine: a
comparative study with dothiepin. Irish Journal of Psychiatry
1990; Spring:37.
Keegan D, Bowen RC, Blackshaw S et al. A comparison of
fluoxetine and amitriptyline in the treatment of major depression.
International Clinical Psychopharmacology 1991; 6:117124.
Hutchinson DR, Tong S, Moon CA et al. Paroxetine in the
treatment of elderly depressed patients in general practice:
a double-blind comparison with amitriptyline. International
Clinical Psychopharmacology 1992; 6(Suppl.4):4351.
Bignamini A, Rapisarda V. A double-blind multicentre study of
paroxetine and amitriptyline in depressed outpatients. Italian
Paroxetine Study Group. International Clinical
Ohrberg S, Christiansen PE, Severin B et al. Paroxetine and
imipramine in the treatment of depressive patients in psychiatric
practice. Acta Psychiatrica Scandinavica 1992; 86:437444.
Bowden CL, Schatzberg AF, Rosenbaum A et al. Fluoxetine and
desipramine in major depressive disorder. Journal of Clinical
Beasley CM Jr, Sayler ME, Potvin JH. Fluoxetine versus
amitriptyline in the treatment of major depression: a multicenter
trial. International Clinical Psychopharmacology 1993;
8:143149.
Moller HJ, Berzewski H, Eckmann F et al. Double-blind
multicenter study of paroxetine and amitriptyline in depressed
inpatients. Pharmacopsychiatry 1993; 26:7578.
Rosenberg C, Damsbo N, Fuglum E et al. Citalopram and
imipramine in the treatment of depressive patients in general
practice. A Nordic multicentre clinical study. International
Doogan DP, Langdon CJ. A double-blind, placebo-controlled
comparison of sertraline and dothiepin in the treatment of major
depression in general practice. International Clinical
Stuppaeck CH, Geretsegger C, Whitworth AB et al. A
multicenter double-blind trial of paroxetine versus amitriptyline
in depressed inpatients. Journal of Clinical Psychopharmacology
1994; 14:241246.
Staner L, Kerkhofs M, Detroux D et al. Acute, subchronic and
withdrawal sleep EEG changes during treatment with paroxetine
and amitriptyline: a double-blind randomized trial in major
depression. Sleep 1995; 18:470477.
406
183. Ravindran AV, Judge R, Hunter BN et al. A double-blind,

multicenter study in primary care comparing paroxetine and
clomipramine in patients with depression and associated anxiety.
Paroxetine Study Group. Journal of Clinical Psychiatry 1997;
58:112118.
184. Fournier JP, Lane RM, Chouinard DB et al. A double-blind
comparison of sertraline and imipramine in outpatients with
major depression. Human Psychopharmacology 1997;
12:203215.
185. Taragano FE, Lyketsos CG, Mangone CA, Allegri RF,
Comesana-Diaz E. A double-blind, randomized, fixed-dose trial
of fluoxetine vs. amitriptyline in the treatment of major
depression complicating Alzheimers disease. Psychosomatics
1997; 38:246252.
186. Berzewski H, Van Moffaert M, Gagiano CA. Efficacy and
tolerability of reboxetine compared with imipramine in a
double-blind study in patients suffering from major depressive
offsodes. European Neuropsychopharmacology 1997;
7(Suppl.1):s37s47.
187. Keller MB, Gelenberg AJ, Hirschfeld RM et al. The treatment of
chronic depression, part 2: a double-blind, randomized trial
of sertraline and imipramine. Journal of Clinical Psychiatry
1998; 59:598607.
188. Nelson JC, Kennedy JS, Pollock BG et al. Treatment of major
depression with nortriptyline and paroxetine in patients with
ischemic heart disease. American Journal of Psychiatry 1999;
156:10241028.
189. Hoehn-Saric R, Ninan P, Black DW et al. Multicenter
double-blind comparison of sertraline and desipramine for
concurrent obsessivecompulsive and major depressive
disorders. Archives of General Psychiatry 2000; 57:7682.
190. Gentil V, Kerr-Correa F, Moreno R et al. Double-blind
comparison of venlafaxine and amitriptyline in outpatients with
major depression with or without melancholia. Journal of
Psychophamacology 2000; 14:6166.
191. Dierick M, Ravizza L, Realini R et al. A double-blind
comparison of venlafaxine and fluoxetine for treatment of
major depression in outpatients. Progress in
Neuropsychopharmacology and Biological Psychiatry 1996;
20:5771.
192. Tylee A, Beaumont G, Bowden MW et al. A double-blind,
randomised, 12-week comparison study of the safety and the
efficacy of venlafaxine and fluoxetine in moderate to severe
major depression in general practice. Primary Care Psychiatry
1997; 3:5158.
193. Costa e Silva J. Randomized, double-blind comparison of
venlafaxine and fluoxetine in outpatients with major depression.
Journal of Clinical Psychiatry 1998; 59:352357.
194 Poirier MF, Boyer P. Venlafaxine and paroxetine in
treatment-resistant depression. Double-blind, randomised
comparison. British Journal of Psychiatry 1999; 175:1216.
195. Mehtonen OP, Sogaard J, Roponen P, Behnke K. Randomized,
double-blind comparison of venlafaxine and sertraline in
outpatients with major depressive disorder. Venlafaxine 631
Study Group. Journal of Clinical Psychiatry 2000; 61:95100.
196. Zivlov M, de Jongh GD. A 6-week randomised, double-blind
multicentre trial in hospitalised depressed patients. Human
197. Halikas JA. Org 3770 (mirtazapine) versus trazodone: a placebo
controlled trial in depressed elderly patients. Human
198. Richou H, Ruimy P, Charbaut J. A multicentre double-blind,
clomipramine controlled efficacy and safety study of Org 3770.
Human Psychopharmacology 1995; 10:263271.
199. Rush AJ, Armitage R, Gillin JC et al. Comparative effects of
nefazodone and fluoxetine on sleep in outpatients major
depressive disorder. Biological Psychiatry 1998; 44:314.
200. Geerts S, Bruynooghe F, De Cuyper H et al. Moclobemide

versus fluoxetine for major depressive episodes. Clinical
Neuropharmacology 1994; 17(Suppl.1):5057.
201. Ramaekers JG, Ansseau M, Muntjewerff ND et al. Considering
the P450 cytochrome system as determining combined effects of
antidepressants and benzodiazepines on actual driving
performance of depressed outpatients. International Clinical
202. Lapierre YD, Joffe R, McKenna K et al. Moclobemide versus
fluoxetine in the treatment of major depressive disorders in
adults. Journal of Psychiaty and Neuroscience 1997;
22:118126.
203. Keller MB, McCullough JP, Klein DN et al. A comparison of
nefazodone, the cognitive behavioral-analysis system of
psychotherapy, and their combination for the treatment of
chronic depression. New England Journal of Medicine 2000;
342:14621470.
204. Katona CL, Abou-Saleh MT, Harrison DA et al.
Placebo-controlled trial of lithium augmentation of fluoxetine
and lofepramine. British Journal of Psychiatry 1995; 166:8086.
205. Fava M, Rosenbaum JF, McGrath PJ, Stewart JW, Amsterdam JD,
Quitkin FM. Lithium and tricyclic augmentation of fluoxetine
treatment for resistant major depression: a double-blind,
controlled study. American Journal of Psychiatry 1994;
151:13721374.
206. Baumann P, Nil R, Souche A et al. A double-blind,
placebo-controlled study of citalopram with and without lithium
in the treatment of therapy-resistant depressive patients: a
clinical, pharmacokinetic, and pharmacogenetic investigation.
Journal of Clinical Psychopharmacology 1996; 16:307314.
207. Prange AJ Jr, Wilson IC, Rabon AM, Lipton MA. Enhancement
of imipramine antidepressant activity by thyroid hormone.
American Journal of Psychiatry 1969; 126:457469.
208. Goodwin FK, Prange AJ Jr, Post RM, Muscettola G,
Lipton MA. Potentiation of antidepressant effects by
1-triiodothyronine in tricyclic nonresponders. American Journal
of Psychiatry 1982; 139:3438.
209. Thase ME, Kupfer DJ, Frank E, Jarrett DB. Treatment of
imipramine-resistant recurrent depression. II. An open clinical
trial of lithium augmentation. Journal of Clinical Psychiatry
1989; 50:385388.
210. Steiner M, Radwan M, Elizur A, Blum I, Atsmon A, Davidson S.
Failure of 1-triiodothyronine to potentiate tricylic antidepressant
response. Current Therapeutic Research 1978; 23:655659.
211. Joffe RT, Singer W, Levitt AJ, MacDonald C. A placebocontrolled comparison of lithium and triiodothyronine
augmentation of tricyclic antidepressants in unipolar refractory
depression. Archives of General Psychiatry 1993; 50:387393.
212. Perez V, Soler J, Puigdemont D, Alvarez E, Artigas F.
A double-blind, randomized, placebo-controlled trial of pindolol
augmentation in depressive patients resistant to serotonin
reuptake inhibitors. Grup de Recerca en Trastorns Afectius.
213. Artigas F, Perez V, Alvarez E. Pindolol induces a rapid
improvement of depressed patients treated with serotonin
reuptake inhibitors. Archives of General Psychiatry 1994;
51:248251.
214. Tome MB, Isaac MT. Cost-benefit and cost-effectiveness
analysis of the rapid onset of selective serotonin reuptake
inhibitors by augmentation. International Journal of Psychiatry
in Medicine 1998; 27:377390.
215. Bordet R, Thomas P, Dupuis B. Effect of pindolol on onset of
action of paroxetine in the treatment of major depression:
intermediate analysis of a double-blind, placebo-controlled trial.
Reseau de Recherche et Dexperimentation
Psychopharmacologique. American Journal of Psychiatry 1998;
155:13461351.
216. Tome MB, Isaac MT, Harte R, Holland C. Paroxetine and

pindolol: a randomized trial of serotonergic autoreceptor
blockade in the reduction of antidepressant latency. International
217. Berman RM, Darnell AM, Miller HL, Anand A, Charney DS.
Effect of pindolol in hastening response to fluoxetine in the
treatment of major depression: a double-blind, placebocontrolled trial. American Journal of Psychiatry 1997;
154:3743.
218. Moreno FA, Gelenberg AJ, Bachar K, Delgado PL. Pindolol
augmentation of treatment-resistant depressed patients. Journal
of Clinical Psychiatry 1997; 58:437439.
219. Maes M, Vandoolaeghe E, Ranjan R et al. Increased serum
soluble CD8 or suppressor/cytotoxic antigen concentrations in
depression: suppressive effects of glucocorticoids. Biological
Psychiatry 1996; 40:12731281.
220. Sacristan JA, Gilaberte I, Boto B et al. Cost-effectiveness of
fluoxetine plus pindolol in patients with major depressive
disorder: results from a randomized, double-blind clinical trial.
221. Perez V, Gilaberte I, Faries D, Alvarez E, Artigas F.
Randomised, double-blind, placebo-controlled trial of pindolol
in combination with fluoxetine antidepressant treatment. Lancet
1997; 349:15941597.
222. Zanardi R, Artigas F, Franchini L et al. How long should
pindolol be associated with paroxetine to improve the
antidepressant response? Journal of Clinical
223. Zanardi R, Franchini L, Gasperini M, Lucca A, Smeraldi E,
Perez J. Faster onset of action of fluvoxamine in combination
with pindolol in the treatment of delusional depression: a
controlled study. Journal of Clinical Psychopharmacology 1998;
18:441446.
224. Maes M, Libbrecht I, van Hunsel F, Campens D, Meltzer HY.
Pindolol and mianserin augment the antidepressant activity of
fluoxetine in hospitalized major depressed patients, including
those with treatment resistance. Journal of Clinical
225. Montgomery SA, Dufour H, Brion S et al. The prophylactic
efficacy of fluoxetine in unipolar depression. British Journal of
Psychiatry Supplement 1988; 3:6976.
226. Montgomery SA, Rasmussen JG, Tanghoj P. A 24-week study of
20 mg citalopram, 40 mg citalopram, and placebo in the
prevention of relapse of major depression. International Clinical
227. Robert P, Montgomery SA. Citalopram in doses of 2060 mg is
effective in depression relapse prevention: a placebo-controlled
6 month study. International Clinical Psychopharmacology
1995; 10(Suppl.1):2935.
228. Montgomery SA, Dunbar G. Paroxetine is better than placebo in
relapse prevention and the prophylaxis of recurrent depression.
229. Gilaberte I, Montejo AL, de la Gandara J et al. Fluoxetine in the
prevention of depressive recurrences: a double-blind study.
Journal of Clinical Psychopharmacology 2001; 21:417424.
230. Kovacs M, Rush AJ, Beck AT, Hollon SD. Depressed
outpatients treated with cognitive therapy or pharmacotherapy.
231. Frank E, Kupfer DJ, Perel JM et al. Three-year outcomes for
maintenance therapies in recurrent depression. Archives of
407
232. Fava GA, Grandi S, Zielezny M, Canestrari R, Morphy MA.

Cognitive behavioral treatment of residual symptoms in primary
major depressive disorder. American Journal of Psychiatry 1994;
151:12951299.
233. Paykel ES, Scott J, Teasdale JD et al. Prevention of relapse in
residual depression by cognitive therapy: a controlled trial.
234. Blackburn IM, Moore RG. Controlled acute and follow-up trial
of cognitive therapy and pharmacotherapy in out-patients with
recurrent depression. British Journal of Psychiatry 1997;
171:328334.
235. Halama P. Wirksamkeit des Johanniskrautextraktes LI 160 bei
depressiver Verstimmung. Nervenheilkunde 1991; 10:250253.
236. Reh C, Laux P, Schenk N. Hypericum-Extrakt bei depressionen
eine wirksame alternative. Therapiewoche 1992;
42:15761581.
237. Hansgen KD, Vesper J, Ploch M. Multicenter double-blind study
examining the antidepressant effectiveness of the hypericum
extract LI 160. Journal of Geriatric Psychiatry and Neurology
1994; 7(Suppl.1):S15S18.
238. Laakmann G, Schule C, Baghai T, St. Kieser M. Johns wort in
mild to moderate depression: the relevance of hyperforin for the
clinical efficacy. Pharmacopsychiatry 1998; 31(Suppl.1):5459.
239. Schrader E, Meir B, Brattstrom A. Hypericum treatment of
the mild-moderate depression in a placebo-controlled study.
A prospective, bouble-blind, randomised, placebo-controlled,
multicentre study. Human Psychopharmacology 1998;
13:163169.
240. Woelk H. Comparison of St Johns wort and imipramine for
treating depression: Randomised controlled trial. British Medical
Journal 2000; 321:536539.
241. Shelton RC, Keller MB, Gelenberg A et al. Effectiveness of
St Johns Wort in major depression: a randomised controlled
trial. Journal of the American Medical Association 2001;
285:19781986.
242. Lecrubier Y, Clerc G, Didi R, Kieser M. Efficacy of St. Johns
wort extract WS 5570 in major depression: a double-blind.
placebo-controlled trial. American Journal of Psychiatry 2002;
159:13611366.
243. Hypericum Depression Trial Study Group. Effect of Hypericum
perforatum (St Johns Wort) in major depressive disorder: a
randomized controlled trial. Journal of the American Medical
Association 2002; 287:18071814.
244. Schrader E. Equivalence of St Johns wort extract (Ze 117) and
fluoxetine: a randomized, controlled study in mild-moderate
depression. International Clinical Psychopharmacology 2000;
15:6168.
245. Harrer G, Hubner WD, Podzuweit H. Effectiveness and tolerance
of the hypericum extract LI 160 compared to maprotiline: a
multicenter double-blind study. Journal of Geriatric Psychiatry
and Neurology 1994; 7(Suppl.1):S24S28.
246. Wheatley D. LI 160, an extract of St. Johns wort, versus
amitriptyline in mildly to moderately depressed outpatients a
controlled 6-week clinical trial. Pharmacopsychiatry 1997;
30(Suppl.2):7780.
247. Vorbach EU, Arnoldt KH, Hubner WD. Efficacy and tolerability
of St. Johns wort extract LI 160 versus imipramine in patients
with severe depressive episodes according to ICD-10.
Pharmacopsychiatry 1997; 30(Suppl.2):8185.

Guía Australiana de Depresión

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Guía Australiana de Depresión

Uploaded by

Copyright:

Available Formats

Australian and New Zealand clinical practice

guidelines for the treatment of depression

Treatment should be a partnership between patient,

Peter Ellis, Chair (Correspondence)

CPG Team for Treatment of Depression, Wellington School of Medicine

CPGS FOR TREATMENT OF DEPRESSION

The likelihood of recovery in the next month decreases

RANZCP CPG TEAM FOR TREATMENT OF DEPRESSION

least in Western society [5,39,41,42], and the latter is not

These guidelines are for clinicians in specialist

Severity and depression subtypes

CPGS FOR TREATMENT OF DEPRESSION

Severity and subtypes of depression

Severity of major depression (DSM-IV)

Investigations and concurrent disorders

Risk assessment, to self and others, is a key task at first

Since concurrent physical or other psychiatric illnesses

RANZCP CPG TEAM FOR TREATMENT OF DEPRESSION

and resume if:

Outline of treatment for depression.

continue treatment or consider switching to a second or

CPGS FOR TREATMENT OF DEPRESSION

Antidepressant treatment compared to placebo for moderate depression

Comparisons between active treatments for severe and moderate depression

[146,186], [132,153,196198], [128,130,134,199], [55,200202], [66,68,80,124,203], [80,124].

advantage over SSRIs. (A large NNT indicates that

RANZCP CPG TEAM FOR TREATMENT OF DEPRESSION

There are four satisfactory placebo-controlled trials.

and, as studies are often uncontrolled, the risk of bias

Severe and complicated depression

Electroconvulsive therapy (ECT)

Trials are rare. Accurate diagnosis, consultation with

Unsatisfactory response to initial treatment

Augmentation strategies for treating depression

TCA/SSRI + lithium cf. same TCA/SSRI alone

[212218], [214,215,217,219224], [212,223].

CPGS FOR TREATMENT OF DEPRESSION

Long-term maintenance ECT is not of proven benefit.

Continuation compared to early discontinuation in treating depression

RANZCP CPG TEAM FOR TREATMENT OF DEPRESSION

Enduring resistance to treatment

The frail elderly

Depression increases the risk of cardiac mortality

CPGS FOR TREATMENT OF DEPRESSION

can cause ventricular arrhythmias but appears safe for

potential; fluoxetine and fluvoxamine relatively high.

Prostatism and obstructive uropathy

Antidepressants with antimuscarinic effects (e.g. most

While initially supported by trials in mild to moderate

Transcranial magnetic stimulation (TMS)

While omega-3 fatty acid levels are low in depression,

RANZCP CPG TEAM FOR TREATMENT OF DEPRESSION

St Johns wort compared with placebo, SSRIs and TCAs

Number of patients (number of studies)

Tryptophan and 5-hydroxytryptophan

Complementary and self-help treatments

Only two of the 108 trials are of adequate quality.

A recent review concluded that none is well supported

CPGS FOR TREATMENT OF DEPRESSION

Principal evidence-based treatments for psychotic depression.

circumstances, and the clinician considers the extent to

RANZCP CPG TEAM FOR TREATMENT OF DEPRESSION

8. Murray CJL, Lopez AD (eds.) The global burden of disease:

CPGS FOR TREATMENT OF DEPRESSION