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Clinical features
Common clinical
subtypes
Assessment and
management
Treatmentresistant
depression
The authors
DR HELEN SCHULTZ,
senior registrar, St Vincent’s
Health, Fitzroy, Victoria.
MS NGA TRAN,
senior mental health
pharmacist, St Vincent’s Health,
Fitzroy, Victoria.
DEPRESSION in adults
PROFESSOR DAVID CASTLE,
chair of psychiatry, St Vincent’s
Health, Fitzroy; and the University of Melbourne, Victoria.
Background
DEPRESSION is the fourth most
common disorder identified and
treated in general practice in Australia. It has a significant impact on
the lives of those who experience its
symptoms. The incidence of depressive illness is increasing across all
demographic areas and, despite new
evidence-based management modalities, depression continues to be a
major public health issue for patients,
their carers and their families.
The Australian Mental Health
Survey estimates that 4% of adults
have had a depressive disorder in
1
the past month. Other studies
show that 7% of patients who consult a GP have clinical depression,
which may coexist with an anxiety or substance abuse disorder.
Depression affects 5-10% of those
with a medical condition attending
a GP.
With the advent of new mental
health strategies for GPs, and
improved access to allied health pro-
fessionals (such as psychologists)
under Federal Government schemes,
primary care has experienced an
improved ability to manage patients
with clinical depression.
In addition, patients who are
referred to specialist services and private psychiatrists often require ongoing management of the depressive illness by a GP to avoid relapse and
to manage comorbidities. Hence, the
role of the GP, who often has a longterm relationship with the patient, is
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unique and of great therapeutic
value.
Given the advent of new antidepressant treatments and new measures for adjunctive care of patients
with depression, it is timely to examine the diagnosis and management
of this condition. This article also
discusses how to assess patients with
depression, how to choose an appropriate antidepressant, and what else
to consider if patients do not
respond to therapy.
10 October 2008 | Australian Doctor |
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How to treat – depression
Clinical features of
depression
THE core of depression is depressed mood. Loss of pleasure from previously pleasurable activities is a common
accompaniment. Indeed, at least one of these features is
required to meet DSM-IV-TR criteria for major depressive disorder.
These features can be volunteered by the patient or
observed by others; it is as though they have lost their vitality. The features should be present most days for most of the
day, although sometimes patients can brighten up for a
short period if something pleasurable occurs. This is sometimes referred to as a reactive mood.
Symptoms need to be present for two weeks for a diagnosis of a major depressive episode, according to the DSM-IVTR classification.
Patients with depression can also exhibit symptoms of
anxiety, and these may have a negative flavour, such as
worrying excessively about the future, finances or physical
health. Irritability and a ‘short fuse’ are also common.
Patients may complain of loss of energy or motivation to
perform tasks, which is often worse in the morning and
improves throughout the day. Patients can become obviously physically ‘slowed up’ (psychomotor slowing), while
others appear agitated and restless.
Sleep is often disturbed, with initial, middle and terminal
insomnia all possible. Some patients resort to alcohol to get
to sleep, but sleep is then usually restless and unrefreshing.
Waking habitually 2-3 hours before the usual time and not
being able to get back to sleep (early morning waking) is a
particular feature of severe ‘melancholic’ depression. In
contrast, some patients feel tired all the time and sleep
excessively.
Appetite is usually impaired, with a loss of interest in
food, which may seem bland and tasteless. Loss of weight
can occur, and in very severe depression food and fluid
intake is so restricted as to be life threatening. In other
cases, patients may ‘comfort eat’ and can actually gain
weight.
Patients often complain of loss of concentration, becoming
unable, for example, to read a newspaper or watch a television program. Attention is often drawn to melancholic introspection, with the world and the future perceived as bleak.
Guilt is a common theme and can become delusional,
such as believing one is an evil person, that one deserves
punishment, and so on. Negative thinking might become
so severe that life seems to be not worth living, and patients
wish they would simply not wake up in the morning. Some
become so desperate they believe suicide is the only way
out, often believing their loved ones will be better off without them.
26
| Australian Doctor | 10 October 2008
Patients with
depression can
also exhibit
symptoms of
anxiety, such as
worrying
excessively about
the future,
finances or
physical health.
Common clinical subtypes of depression
Exogenous versus
endogenous depression
IN the past, depression was
perceived as having either an
endogenous or exogenous
cause. Exogenous depression
was also referred to as reactive depression. Endogenous
depression was seen as arising from within the body as
a consequence of genetic
make-up.
Exogenous or reactive
depression was thought to
be a consequence of some
unpleasant or sad event.
Patients who experienced
symptoms of depression
after the loss of a loved one,
for example, were thought
to show no benefit from
antidepressant medication.
Those with recurrent
episodes of depression with
no clear precipitant were
often placed on antidepressant medication, with little
psychological or social input.
As our knowledge of the
genetic and physiological
basis of depression has
grown, so too has our
understanding that it is the
complex interplay between
these causal factors, along
with external or environmental precipitants, that
causes an episode of depression. Hence, the traditional
categories of endogenous
and exogenous depression
are no longer helpful or relevant.
Typical versus atypical
depression
The term ‘typical’ is used to
describe a set of symptoms
that neatly fit within the criteria of major depressive disorder (as outlined in table 1).
The key defining features of
typical depression are weight
loss and insomnia.
In contrast, atypical
depression defines a set of
symptoms in which hypersomnia and weight gain are
common features. This presentation is more common
in women than men and is
the more common presentation in patients with seasonal
affective disorder.
Melancholic depression
Many clinicians believe that
melancholic depression is a
separate disease entity,
known as ‘melancholia’ and
characterised by:
■ A genetic component.
■ Particular biological abnormalities such as constipation.
■ Better response to pharmacological agents.
■ Fewer exogenous factors
such as unpleasant life
events.
■ Less evidence of a personality dysfunction.
Others believe it is just
one presentation of clinical
depression found at the
severe end of the clinical
spectrum. Either way it is
important to assess for features of melancholia and
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manage accordingly, in particular paying attention to
antidepressant medication.
Psychotic depression
When a patient presents with
features of severe depression
it is important to elucidate
whether psychotic features are
present. Common in the
elderly, the classic presentations are of nihilistic delusions, when patients report
that parts of their body have
died or rotted away, or delusions of guilt and poverty,
which may result in them
living in squalor or deprived
social means because of this
fixed belief.
In most cases, patients with
psychotic depression do not
wish to have treatment, or are
unable to consent to it, and
require specialised treatment
in an inpatient setting, often
responding to modalities such
as ECT. Nevertheless, the role
of the GP is crucial in assessing that the depression is
severe and warrants specialised input.
Depression and
suicidality
The presence of suicidal
thoughts or plans must be
ascertained in any depressed
patient. Suitable probing
questions are outlined in
table 2.
It is important to note that
there is no good evidence
that a person’s risk of suicide can be increased by discussing the risks in an open
manner. Indeed, most
patients feel relief at being
able to talk through such
issues. Patients are often
reassured that the presence
of suicidal thoughts is
common, especially in severe
depression, as they may feel
guilty or ashamed for feeling this way.
Additional risk factors for
the development of suicidal
ideation include:
■ Being male.
■ Being older.
■ Being unemployed.
■ Being divorced or separated.
■ Being socially isolated.
Having a chronic medical
illness.
■ Using alcohol or illicit substances.
A previous history of suicide attempts, active planning for suicide, final acts
such as making a will and
saying goodbyes, and access
to a dangerous means (eg, a
firearm) should be regarded
as indicating extreme risk. In
these cases, appropriate
safety measures need to be
instigated. Adolescents are
also at elevated risk, especially of impulsivity and suicidality, and alcohol and
drug use is an important
additional risk factor.
■
If it is not depression,
what else could it be?
Depressed mood may be
seen in a variety of contexts,
and before a diagnosis of a
primary depressive process is
embraced, a number of precipitating and perpetuating
causes should be considered.
Grief
Grief is a fairly ubiquitous
response to loss, and usually
follows a predictable pattern
of shock, numbness, denial,
anger, and finally some type
of acceptance. Sometimes
grief may become prolonged
and ‘complicated’, and in
some cases evolves into a
true depressive process.
In uncomplicated grief the
sadness is usually related
specifically to the loss, and
if guilt occurs it is usually
related to what might putatively have been ‘done better’
to assist the lost person in
their final life phase. Selfworth is usually preserved
and suicidality is rare in
uncomplicated grief.
Premenstrual dysphoric
disorder
Premenstrual dysphoric disorder refers to low mood in
the late luteal phase of most
menstrual cycles. There is
often associated physical
symptomatology such as
bloating and breast tenderness, and symptoms usually
resolve with the onset of
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Table 1: The FAST approach to assessing depression
Features
Assessing the depressed
patient
What are the current clinical features that support a diagnosis of depression?
■
Mood changes and anhedonia
■
Sleep and appetite disturbance
■
Irritability
■
Memory and concentration difficulties
What other features are present?
■
Anxiety symptoms
■
Comorbid substance misuse
What are the features to confirm or exclude?
■
Past history of mania
■
Presence of atypical or psychotic features
Agencies
■
Has the patient been referred to a counsellor in the past?
involved
■
Does the patient see a private psychiatrist?
■
Does the patient have a case manager?
■
Does the patient admit to suicidal thoughts and/or intent to act on them?
■
Does the patient have a clear plan for suicide?
■
Does the patient have a past history of suicidal ideation and attempts?
■
Does the patient have protective factors and supports in their life, such as
family or friends?
■
If the patient has children, are they safe?
■
Is the patient at risk of psychosocial decline, such as loss of job or difficulty
with finances?
■
Is the patient currently taking medication? Are they compliant with the
medication? Does the medication dose need to be increased?
■
If the patient is not currently taking medication, do they have a past history of
treatment success with a certain medication?
■
Is there a family history of depression and, if so, do they know which
antidepressant medication the family member responded to (family members
often show similar responses to a medication)?
■
Does the choice of medication (sedating, activating, propensity for weight
gain) align with the symptom profile?
Safety
menstruation. Serotonergic
antidepressants have an
established therapeutic role.
Physical causes
Physical causes of depressed
mood should always be considered. These include physical illnesses such as hypothyroidism, and alcohol and
illicit substance use. In clinical practice it can be difficult to establish primacy of
mood disturbance versus an
organic contributor, but
physical health issues should
always be assessed and
treated in their own right.
Other psychiatric disorders
Depression may occur in the
context of other psychiatric
disorders. Again, primacy
can be difficult to ascertain.
Depressed mood in acute
schizophrenia often resolves
with treatment of the psychosis, but it may persist and
then requires treatment in its
Treatment
own right. Post-psychotic
depression is of particular
concern, as it carries a high
risk of suicide.
Bipolar depression
Bipolar depression is a very
important differential diagnosis, as there are profound
treatment implications, not
least of which is that expo-
sure to antidepressants might
precipitate mania and/or
cause cycle acceleration.
Features that should alert
the clinician to the possibility
of bipolarity include the
abrupt onset ‘out of the blue’
of a severe depression, especially in a young person. A
family history of bipolar disorder should also be excluded.
WHEN assessing a patient
with depression, developing
rapport and providing a therapeutic environment are critical
to the process. In reality, time
and workload constraints
make this a difficult task for
the busy GP.
Also, patients may not disclose symptoms of depression
as a primary complaint, given
their feelings of vulnerability
and perceived concerns about
stigma. Hence they may mention depressed mood or trouble sleeping as a side issue or
at the end of the consultation.
When these situations arise
it may be prudent to offer
another consultation, perhaps
for a longer duration, to
gather the information in an
unhurried manner. Given the
time constraints and the need
for prioritisation of information, the ‘FAST’ approach
(table 1) may be a useful
reminder of the most important issues to consider when
assessing for depression and
forming a management plan.
Table 2: Questions to
elicit suicidality
■
Have things sometimes
seemed so bad that you
feel it is simply not worth
living?
■
Do you ever wish you
would simply not wake up
in the morning?
■
Do you ever think your
family and friends would
be better off without you?
■
Have you ever thought of
harming yourself or trying
to end your life?
If YES, ask:
— How powerful are those
thoughts?
— Can you resist them?
— Do you have any
specific plan about how
you might do it?
— Do you have access to
means such as a
firearm? (consider in
rural areas in particular)
Time is ticking for high-risk CV patients
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How to treat – depression
Guidelines for managing depression
General principles
THERE is never any substitute for good clinical care,
and in depression this is
arguably expressly important.
Depressed patients often feel
at a loss as to why they are
feeling the way they are, and
may present with somatic
symptoms or resort to ‘selfmedication’ with alcohol and
other substances.
Furthermore, patients often
feel that they are a burden on
others, and this can include
the doctor. The GP has a
vital role to play in establishing trust, providing a supportive and listening environment, and giving hope.
Providing information about
depression and its treatment
is very important.
Patients often do not ‘take
in’ much of what is said
during a consultation, so
repeating key points and providing written information,
videos or DVDs, or directing
the patient to useful web
sites, can assist. Suggest the
patient’s spouse or partner
also familiarise themself with
this material, and offer a joint
appointment where appropriate.
The GP is also uniquely
placed to provide longitudinal ongoing care, and to
understand the patient’s particular context, not least their
domestic environment and
the impact of the illness on
loved ones. Monitoring medication efficacy and side
effects and ensuring safety are
also key roles.
Figure 1: Classes of antidepressants.
Amine
uptake
blockers
Enzyme
inhibitors
MAOI
Irreversible
Phenelzine
Tranylcypromine
Receptoracting
drugs
TCA
α2-adrenoceptor
antagonist
Mianserin
5HT2C selective
Reversible
Moclobemide
NDRI
Bupropion*
NRI
Reboxetine
NA selective
SNRI
Venlafaxine
Duloxetine
SSRI
Sertraline
Fluoxetine
Paroxetine
Citalopram
Fluvoxamine
Escitalopram
*Australia: indication for short-term adjunctive therapy for nicotine dependence only
MAOI: monoamine oxidase inhibitor; TCA: tricyclic antidepressant; NDRI: noradrenaline and dopamine reuptake inhibitor; NRI: noradrenaline reuptake
inhibitor; SNRI: serotonin and noradrenaline reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; NaSSA: noradrenergic and specific serotonergic agent
Psychological treatments
Figure 2: Side effects and benefits of antidepressants: time course.
■
Side effects
■
Benefits
■
■
Pharmacological
treatments
■
Antidepressants
Although pharmacological
and psychological interventions are effective for the
treatment of depression, in
primary and secondary care
settings antidepressant drugs
remain the mainstay of treatment. Careful monitoring of
symptoms, side effects and
suicide risk should be routinely undertaken, especially
when initiating therapy.
Patient preference and past
experience of treatment
should inform the choice of
agent (figure 1).
All patients prescribed
antidepressants should be
informed about the time
course of treatment, the
delayed onset of effect and
the potential side effects, particularly during the first two
weeks of therapy (figure 2).
It is also important to
emphasise the problems associated with abruptly stopping
medication or reducing the
dose. These include nausea,
dizziness, paraesthesia, anxiety and headache. These
effects are potentially more
severe with drugs that have
a short half-life, such as
paroxetine, venlafaxine and
fluvoxamine. Tapering doses
rather than stopping altogether may prevent or allevi-
28
NaSSA
Mirtazapine
Week
1
Although
pharmacological
and psychological
interventions are
effective, in
primary and
secondary care
antidepressants
are the mainstay
of treatment.
| Australian Doctor | 10 October 2008
Week
2
Week
3
Week
4
ate these symptoms.
Results from various metaanalyses suggest that all antidepressants differ with
respect to their side-effect
profile but have similar efficacy in treating depression.
However, recent studies have
suggested that serotonergicnoradrenergic antidepressant
drugs, such as venlafaxine,
mirtazapine and duloxetine,
seem to have greater efficacy
in depression compared with
SSRIs.
In addition, the tricyclic
antidepressants are less
favourable, not because they
are less effective than the
newer agents, but because
they are more dangerous in
overdose and less well tolerated.
It is important to consider
the side-effect profile as well
as the efficacy data when
choosing an antidepressant.
Often the side-effect profile
can be advantageous if it
addresses some of the symptoms of depression. For
example, a sedating agent is
useful if the patient is experi-
ports its use for the treatment
of mild to moderate depression, caution should be taken
when advising a trial, as
there is ongoing uncertainty
about:
■ The appropriate dose.
■ Variations in the potencies
of the preparations available.
■ Potential serious drug
interactions with agents
such as anticoagulants,
anticonvulsants and oral
contraceptives.
St John’s wort can cause
switching to hypomania in
patients with bipolar disorder.
There is evidence to suggest that tryptophan and 5hydroxytryptophan are
better than placebo at alleviating depression. Further
studies are needed to evaluate the efficacy and safety of
these agents before their
widespread use can be recommended. The potential
association between these
substances and the potentially fatal eosinophilia-myalgia syndrome has not been
elucidated.
Taking an SSRI with/after food will
assist in GI discomfort. Consider
antacids or H2 blockers if
necessary.
Most side effects are early onset
and time limited (about 1-2 weeks).
Benzodiazepines may be useful for
short-term treatment (1-2 weeks) for
pronounced insomnia or anxiety.
Recent data suggest SSRIs may
increase GI bleeding.
Monitor for evidence of
hyponatraemia, especially in the
elderly. This may cause delirium and
confuse the clinical picture.
encing insomnia. However,
there may also be contraindications to particular antidepressants. The following two
examples highlight these two
issues.
Mirtazapine is an agent
that increases both noradrenergic and serotonergic
(5-HT) transmission through
a unique mechanism. The
potent antagonism of 5-HT2
and 5-HT3 receptors serves
to decrease anxiety, relieve
insomnia and stimulate
appetite. In addition, mirtazapine has an antihistaminergic effect, which is
useful for patients with
insomnia. As it also tends to
increase appetite, mirtazapine is a good choice for
depressed patients with
melancholic features such as
insomnia, weight loss and
agitation.
Venlafaxine and duloxetine inhibit the reuptake of
serotonin and noradrenaline,
hence they are referred to as
SNRI agents. Although this
effect may offer greater efficacy, these agents should not
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be prescribed to patients
with severe or uncontrolled
hypertension. Blood pressure
should be checked initially
and regularly during treatment, particularly during
dosage titration. For patients
who experience a sustained
increase in blood pressure,
the dose should be reduced
or the drug discontinued.
In some cases, mirtazapine
has been combined with an
SSRI agent to augment the
antidepressant response or to
counteract serotonergic side
effects of these drugs, particularly nausea, agitation and
insomnia. Mirtazapine has no
significant pharmacokinetic
interaction with other antidepressants.
Table 3 lists features of
commonly prescribed antidepressants.
Complementary agents
St John’s wort (Hypericum
perforatum) has been studied
in a series of randomised controlled trials in patients with
major depression. Even
though the best evidence sup-
Over and above supportive
psychotherapy, several specific psychological techniques have proven efficacy
in depression. These techniques have proven efficacy
alone for milder forms of
depression and can also be
a useful adjunct to medication for more severe depression. They may also be associated with better relapse
prevention.
Some of these techniques
can be effectively delivered
by trained GPs, with the
support of written and/or
online material (see Online
resources, page 31). However, specialist input from a
clinical psychologist might
be required. Patients who
respond to medication may
be in a better position to
engage in psychotherapy, as
they experience an improvement in motivation and concentration.
Problem-solving therapy
Problem-solving therapy is a
validated therapeutic option
that works on simple principles relating to how the
patient approaches life problems and how they might
plan better for challenges in
everyday life.
For example, the patient
might be advised to make a
list of the really important
things that need to be
achieved on any given day
and concentrate on those
rather than becoming overwhelmed by the seeming
enormity of life’s everyday
challenges.
Cognitive behaviour therapy
CBT addresses two main
issues relating to depression
— the behavioural conse-
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Table 3: Common antidepressants and their features*
quences and the cognitive
perpetuating factors. Thus it
is recognised that depression
results in a general avoidance of activity, which in
itself feeds the depression.
Structured activities, with an
emphasis on good sleep
hygiene, regular meals and
exercise, and re-engagement
in avoided activities such as
socialising, are key.
Addressing cognitive
impediments to such activities is also important. This
can include questioning the
thought patterns that perpetuate avoidance: for example, the thought “I won’t
enjoy it” can be countered
by “How do you know: are
you a fortune teller? What
can you lose by just giving
it a go?”
More broadly, the cognitive component includes
challenging negative thinking, enabling the patient to
recognise and question their
own negative thinking patterns, and drilling deeper to
explore underlying negative
schemata. Negative automatic thoughts are monitored and challenged, with
recourse to a ‘check list’ that
encompasses the veracity
and usefulness of the negative thinking pattern for the
individual. This list might
include:
■ Does this way of thinking
fit all the facts?
■ Are there other ways of
looking at this situation?
■ Am I falling into thinking
traps such as all-or-nothing thinking (eg, “Unless I
do this perfectly I am
totally hopeless”)?
■ Is this way of thinking
useful for me?
cont’d next page
Antidepressant
Usual clinical
dose (mg/day)
Positive attributes
Potential negative attributes and cautions
Citalopram
20-40
Fewer drug interactions via the cytochrome
P450 system
Helpful for anxiety disorders, or if anxiety a prominent
feature of depression
Nausea, dry mouth, diarrhoea
Escitalopram
10-20
More potent than the racemic compound found in
citalopram, so lower dose required
Nausea, dry mouth, diarrhoea
Fluoxetine
20-80
Long half-life so may be beneficial for patients who
have poor adherence or miss doses
Longer time to reach steady-state
concentrations
Can be stimulating in some patients
High incidence of sexual dysfunction
Drug interactions via its effect on the
cytochrome P450 system
Wait at least five weeks if switching from
fluoxetine to a monoamine oxidase inhibitor
Fluvoxamine
100-200
Approved for the treatment of obsessive-compulsive
disorder
High incidence of GI symptoms
Drug interactions via its effect on the
cytochrome P450 system
Use care when combining with clozapine,
olanzapine, methadone or warfarin
Paroxetine
20-60
Useful in anxiety disorders
Can cause sedation
Anticholinergic side effects, such dry mouth
mouth and blurred vision, may be more
marked than with other agents
Discontinuation syndrome is common
Drug interactions via its effect on the
cytochrome P450 system
High incidence of sexual dysfunction
Sertraline
50-200
Approved for use in anxiety disorders
Safety data in patients who have experienced an MI
GI side effects
Can cause hyponatraemia, particularly in the
elderly
Mirtazapine
15-45
Few drug interactions
Less or no sexual dysfunction
Less sedation at higher doses
May stimulate appetite
Sedation
Appetite stimulation may lead to weight gain
Venlafaxine
75-300
Fewer drug interactions via the cytochrome P450 system
May increase blood pressure
High incidence of GI distress and sexual
dysfunction
Troublesome withdrawal effect
Duloxetine
60
May offer a more balanced dual inhibition of serotonin
and noradrenaline
May increase blood pressure
High incidence of GI upset
Moderate inhibitor of the cytochrome P450
system
Reboxetine
4-12
Can be stimulating
Can cause insomnia, sweating, constipation
and dry mouth
*This table should be used as a guide when tailoring an antidepressant for a particular patient. Always refer to the full prescribing information for a comprehensive description of side effects for
each medication.
The chances of a major event (heart
attack, stroke or CV death) or hospitalisation
within 12 months are 1 in 7 for patients
with a history of CAD1*
*CAD refers to coronary artery disease.
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How to treat – depression
from previous page
Interpersonal therapy
Interpersonal therapy is another
well-validated psychological therapy. It emphasises the ‘here and
now’ and specifically targets interpersonal issues pertinent to depression, ie:
■ Unresolved grief.
■ Relationship problems.
■ Role transition issues (eg, retire-
■
ment, divorce).
Social isolation.
Cognitive behavioural-analysis
system of psychotherapy
More recently the cognitive behav-
ioural-analysis system of psychotherapy has been developed
particularly for people with
chronic depression. It incorporates
elements of CBT and psychodynamic psychotherapy and uses
so-called ‘situational analysis’ to
help the patient identify the effects
of their behaviours on those
around them, and then teaches
strategies to change behaviours
that are unhelpful.
Table 4: Current recommendations for pharmacological treatment of major
depressive disorder*
Therapeutic
choice
Recommendations
Evidence
First
SSRIs, SNRIs, mirtazapine
Higher rates of remission have been reported with venlafaxine,
and particularly in severe depression with escitalopram
Level I
Level I
Second
TCAs: amitriptyline and clomipramine have greater efficacy
than SSRIs in hospitalised depressed patients (safety and
tolerability need to be considered).
Level II
Third
Other TCAs and MAOIs (lower recommendation because of
safety and tolerability issues)
Level II
2
*Source: Kennedy SH, et al., 2007
Levels of evidence
I: Meta-analysis or replicated randomized controlled trial (RCT) that includes a placebo condition
II: At least one RCT with placebo or active comparison condition
III: Uncontrolled trial with 10 or more subjects
IV: Anecdotal case reports
SSRI: selective serotonin reuptake inhibitor
SNRI: serotonin and noradrenaline reuptake inhibitor
TCA: tricyclic antidepressant
MAOI: monoamine oxidase inhibitor
What to do when patients do not get better
Switching
In consultation with their
patient, a practitioner may
consider switching to another
agent in the case of intolerable side effects, or if there
has been no improvement
after one month of therapy.
If there has been a partial
response, the decision to
switch may be delayed until
six weeks.
Practical points to consider
when switching include:
■ It may be an option to
switch between two different SSRI agents and
achieve a different response
or alleviate troublesome
side effects.
■ If
switching from an
MAOI, immediate switching is contraindicated and
the patient must wait two
weeks before starting
another agent. The time to
wait between stopping an
SSRI or other antidepressant and starting an MAOI
30
Table 5: General
strategies for
approaching the
patient with treatmentresistant depression
Review the diagnosis,
including past history
(notably of any hypomanic
or manic episodes), past
treatments and treatment
responses
■ Review treatments and
ensure the patient has
been adherent
■ Explore comorbidities,
including anxiety disorder,
personality disorder,
substance use and
physical comorbidities
■ Explore current
psychosocial issues that
might be impeding
recovery; these include
‘secondary gain’ and the
benefits to the patient of
being in the sick role
Figure 3: Cross tapering antidepressant medication.
■
depends upon the respective agent. In general, the
literature recommends a
one- to two-week gap.
However, due to persistent
norfluoxetine in the blood,
allow at least five weeks
after stopping fluoxetine
before starting an MAOI.
■ Cross-tapering (figure 3) is
usually the preferred
option for switching medications. All antidepressants have the potential to
cause withdrawal phenomena if the patient has been
on therapy for longer than
six weeks.
■ The speed of cross-tapering is best judged by
patient tolerability.
Combination therapy
Numerous combinations
have been advocated in clinical practice; however, there
have been very few well-con-
| Australian Doctor | 10 October 2008
Previous
medication
New
medication
Dose
SO-CALLED ‘treatmentresistant depression’ is generally defined as a failure of
response to at least two antidepressants at therapeutic dose
for at least four weeks. General strategies in dealing with
this clinical scenario are
shown in table 5.
Psychotherapeutic options,
as outlined above, should be
explored. For example, a
course of CBT by an expert
clinical psychologist can be
enormously helpful in getting
the patient on the right track.
In terms of medication
options, there are three main
strategies:
■ Switching to another antidepressant.
■ Combining two antidepressants.
■ Augmenting with another
agent.
Time 2-6 weeks
trolled, evidence-based trials
available for evaluation. In
most cases the combination
of two antidepressants with
different modes of action
can be initiated to enhance
antidepressant effect in
treatment-resistant patients.
The combination may also
allow one agent to offset the
intolerable side effects of the
other, thereby increasing
remission rate and improving adherence.
Augmentation
Augmentation involves adding
either another medication or
second antidepressant at subtherapeutic doses to the
existing antidepressant. Most
evidence to support augmentation involves lithium and
olanzapine. Augmentation
with mood stabiliser agents
is often initiated in the secondary care setting.
Medication adherence
In many cases in which there
is a poor response to treatment, or a relapse when a
patient initially reported a
good response, partial or
non-adherence may be the
cause. Patients will frequently
volunteer that they often
forget doses or simply
stopped taking their medication when they felt better.
However, in some cases
patients reduce or stop medication because of side effects
or the stigma of taking an
antidepressant agent (perceived fear they may be
viewed as ‘crazy’). Despite
reassurance, many patients
feel medication is ‘addictive’
and should not be relied on.
These concerns should be
probed for and discussed in
an open manner, to ensure
adherence is optimal.
Many antidepressant med-
www.australiandoctor.com.au
ications cause sexual side
effects, particularly anorgasmia
in women. Patients may not
voluntarily divulge this to
their doctor and may simply
choose to reduce the prescribed dose or stop taking
the medication altogether.
When to refer patients
The decision to refer a patient
to specialist care often arises
out of issues regarding safety
and failure to respond to firstline therapy. Secondary consultation may be useful for
diagnostic clarification or in
cases of complicated presentations, such as comorbidities.
When present, crisis, assessment and treatment teams are
available at all hours and
respond to concerns of safety
and vulnerability. If safety is
of concern, a GP should not
hesitate to consult specialised
services for advice or referral.
Conclusion
THERE have been recent
improvements to the way
GPs can respond to the
needs of patients with
mental illnesses such as
depression. Newer agents
will continue to provide
treatment choices, and as
the evidence base continues
to grow regarding
psychological treatments,
GPs are well placed to offer
management in the primary
care setting.
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Authors’ case study
References
Comment
HENRY, 53 and married, has been visiting
your practice for several years. He has hypertension controlled by an antihypertensive, is
moderately overweight and admits to drinking
3-4 standard drinks a night to ‘wind down’.
On this occasion Henry makes an appointment to see you because he has been having
trouble sleeping, finding he is waking in the
early hours of the morning and is unable to get
back to sleep. He requests some sleeping
tablets. Henry attributes this problem to ongoing stress at work. His employer is experiencing financial difficulties and Henry is not sure
if his job is stable.
On further questioning, Henry admits to a
poor appetite, and you note that he has lost
weight. He has trouble concentrating at work.
At home his wife has told him he has a short
fuse, and she can’t tolerate his irritability.
Henry describes feeling overwhelmed, and
divulges he had an uncle who committed suicide when it ‘all became too much’.
In this case it does appear that Henry has
features of depression. Importantly, he
has a family history of depression and
suicide. Henry is attempting to treat his
symptoms with alcohol, which is
common, but is also attributing his problems to his poor sleep patterns. He has a
history of hypertension, which needs to
be considered when choosing an antidepressant.
Henry was assessed and did not have
thoughts or plans to commit suicide. He
was seen for a longer consultation together
with his wife, who agreed Henry was
depressed. He was started on citalopram,
which assisted in restoring his sleep patterns, and his mood and concentration
improved. After careful discussion, Henry
agreed to abstain from alcohol, and was
referred to a private psychologist for supportive psychotherapy.
GP’s contribution
Case study
DR LIZ MARLES
Redfern, NSW
JENNY, 35, first presented at 10
weeks’ gestation in her first pregnancy. She had a history of intermittent depression and anxiety
since her teenage years, against a
background of childhood emotional and physical abuse. There
was a family history of depression
(one of her parents).
In her mid-20s Jenny was admitted to a psychiatric unit for depression with anorexia nervosa features
and thoughts of self-harm, and
was started on venlafaxine.
Since then she had had no further admissions, but at different
times had experienced depressed
mood, sleep disturbance and anhedonia, coupled with anxiety symptoms and panic attacks. About 18
months earlier she had been started
on paroxetine 30mg daily, which
was successful in managing her
anxiety symptoms.
When Jenny became pregnant,
obstetric advice was to reduce her
paroxetine dose to 20mg daily.
However, she started to experience
a return of her symptoms, with
early morning waking, difficulty
concentrating, a flat mood, mild
anxiety and panic attacks.
She became quite anxious about
the pregnancy but was very concerned about coming off the medication, and relapsed into the type
of depression she had had in the
past, with suicidal thinking.
Questions for the authors
Were Jenny’s symptoms likely to
be related to hormonal changes
associated with pregnancy?
Although there may be a link
between hormonal changes and
development of these symptoms in
this case, most important is that
Jenny has a past history of depression and hence is at high risk of
further episodes. In addition, she
has a positive family history of
depression, with concomitant
social and emotional problems.
It would be wise to also consider
the context of this pregnancy, such
as whether the pregnancy was
planned and whether it is resulting in ruminations about past
family dysfunction, all of which
can be precipitants of depression.
What would be the risks associated with continuing paroxetine in
pregnancy?
There is evidence in the literature that antidepressants may be
linked to the development of fetal
malformations. However, in every
case the benefits to maternal
mental health, especially when
clear-cut symptoms of depression
are present, must be weighed up
against any potential risks.
In addition, Jenny is in her 10th
week of pregnancy, and by this
time the risk of relapse of deprescont’d next page
1. Ellis P. Australian and New Zealand clinical practice guidelines for the treatment of depression.
Australian and New Zealand Journal of Psychiatry
2004; 38:389-407.
2. Kennedy SH, et al. Treating Depression
Effectively: Applying Clinical Guidelines. London:
Informa Healthcare, 2007.
Further reading
■
Britt HC, Miller GC. The BEACH study of general
practice. Medical Journal of Australia 2000;
173:63-64.
■ Gallagher P, Porter RJ. The neuropsychology of
mood disorders. In: Joyce P, Mitchell P, editors.
Mood Disorders Recognition and Treatment.
Sydney: UNSW Press, 2004.
■ Katon W, Ciechanowski P. Impact of major
depression on chronic mental illness. Journal of
Psychosomatic Medicine 2002; 53:859-63.
■ Linde K, Berner M, et al. St John’s wort for depression: meta-analysis of randomized controlled trials.
British Journal of Psychiatry 2005; 186:99-107.
■ McLennan W. Mental Health and Wellbeing:
Profile of Adults, Australia 1997. Canberra:
Australian Bureau of Statistics, 1998.
■ National Collaborating Centre for Mental Health.
Depression: Management of Depression in
Primary and Secondary Care. London: National
Institute for Health and Clinical Excellence, 2004.
■ Papakostas GI, et al. Are antidepressant drugs that
combine serotonergic and noradrenergic mechanisms of action more effective than the selective
serotonin reuptake inhibitors in treating major
depressive disorder? A meta-analysis of studies of
newer agents. Biological Psychiatry 2007;
62:1217-27.
Online resources
■
DSM-IV-TR; American Psychiatric Association:
www.appi.org/dsm.cfx
■ beyondblue: www.beyondblue.org.au
■ SANE Australia: www.sane.org
■ GROW: www.grow.net.au
■ Black Dog Institute:
www.blackdoginstitute.org.au
■ Climate (Clinical Management and Treatment
Education): www.climate.tv
■ PANDA (Post and Antenatal Depression
Association Inc): www.panda.org.au
■ Multicultural Mental Health Australia:
www.mmha.org.au
■ RANZCP. Guidance on the use of SSRIs and venlafaxine (SNRI) in late pregnancy:
www.ranzcp.org
Plavix + aspirin gives ACS patients enhanced
†
protection against future CV events. So they can get
back to more rewarding events.1-3
†ACS refers to acute coronary syndrome: UA/NSTEMI/STEMI.
For PBS Information refer to primary advertisement.
BEFORE PRESCRIBING PLEASE REVIEW PRODUCT INFORMATION IN THE PRIMARY ADVERTISEMENT IN THIS PUBLICATION. References: 1. The Clopidogrel in Unstable Angina to Prevent
Recurrent Events (CURE) Trial Investigators. N Engl J Med 2001;345(7): 494-502. 2. Sabatine MS, et al, for the CLARITY-TIMI 28 Investigators. N Engl J Med 2005; 352:1179-1189. 3. COMMIT (Clopidogrel
and Metoprolol in Myocardial Infarction Trial) collaborative group. Lancet 2005; 366:1607-1621. 4. Plavix Approved Product Information, August 2007. sanofi-aventis australia pty ltd ABN 31 008 558 807,
Talavera Corporate Centre, Building D, 12-24 Talavera Road, Macquarie Park, NSW 2113. Plavix is a registered trademark of sanofi-aventis. AU.CL0.08.05.04 Saatchi & Saatchi Healthcare HSX0366/AD/3
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4
10 October 2008 | Australian Doctor |
31
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How to treat – depression
from previous page
sion from discontinuing
paroxetine would most likely
outweigh the potential risk of
cardiac malformation. Moreover, recurrence of depression
on discontinuing of paroxetine may expose the fetus to
the negative consequences of
untreated anxiety and depression, including suicide.
Nevertheless, there are
potential risks to the fetus
when exposed to SSRIs during
pregnancy. These are:
■ Slight increase in rate of
spontaneous miscarriages.
■ Possible increased risk of
congenital cardiac malformations, especially with fluoxetine and paroxetine.
■ Lower birth weight or premature birth.
■ Persistent pulmonary hypertension of the newborn with
use after 20 weeks’ gestation.
■ Transient neonatal adaptation symptoms.
Early exposure to paroxetine and fluoxetine during
the first trimester may result
in an increased risk of congenital cardiac malforma-
tions (ventricular septal
defects). Although paroxetine may confer increased
risk of the above defects, it
should also be recognised
that these implicated specific
defects are rare and the
absolute risks are small.
Is there a safer and more
appropriate alternative choice
of antidepressant in pregnancy?
All the SSRIs have been
implicated in a possible
increase in the risk of congenital malformations. Until
recently, sertraline has been
recommended as a better
SSRI in pregnancy; however,
emerging evidence has indicated a similar risk of cardiac defects to that of paroxetine and fluoxetine.* As a
result, several factors must
be taken into consideration
when selecting an antidepressant in pregnancy:
■ Patient preference, tolerability and prior response.
■ Risks and benefits to the
fetus/infant and the mother
— these should be discussed
with the patient and partner.
Comorbidity and concurrent
medications.
■ Early input of guidance and
monitoring systems for cardiac malformation with
high-risk agents.
In summary, selection of
psychopharmacological treatment in pregnant women with
depression will result primarily from a careful evaluation
of the degree of severity of
maternal disease against the
potential risks of prenatal
exposure to antidepressants.
■
How to Treat Quiz
2. Trudy, 23, presents with low mood and
tearfulness for the last 2-3 months. She is
not interested in socialising or doing any of
the things she used to enjoy. She is also
not sleeping well and is finding it difficult to
cope at work. Which TWO statements
about the diagnosis of depression are
correct?
a) Either depressed mood or loss of pleasure
from previously pleasurable activities is a
requirement for the diagnosis of major
depressive disorder
b) Symptoms need to be present for two
weeks for a diagnosis of a major depressive
episode according to the DSM-IV-TR
classification
c) The core features of a depressive episode
must be present every day and persistent
throughout the day
d) Depression should be subdivided into
endogenous and exogenous depression
3. Which THREE statements about clinical
subtypes of depression are correct?
a) Hypersomnia and weight gain are common
features in atypical depression
ing, a decision should be made
after analysing risks and benefits for the mother and baby,
given that very small amounts
of antidepressants may pass
†
into the breast milk.
In a case such as this, a
perinatal mental health plan
would be useful. A copy
should be kept in the patient’s
file and distributed to the
health care team. This plan
would include details on the
monitoring of the infant in the
early postpartum period. A
template is available on the
RANZCP web site (www.
ranzcp.org).
*Louik C, et al. First-trimester
use of selective serotonin reuptake inhibitors and the risk of
birth defects. New England
Journal of Medicine 2007;
356:2675-83.
†
Moses-Kolko EL, et al. Neonatal signs after late in utero exposure to serotonin reuptake
inhibitors: literature review and
implications for clinical applications. Journal of the American
Medical Association 2005;
293:2372-83.
INSTRUCTIONS
Complete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points. We no longer accept quizzes
by post or fax.
The mark required to obtain points is 80%. Please note that some questions have more than one correct
answer.
Depression — 10 October 2008
1. Which TWO statements about the
epidemiology of depression are correct?
a) Depression is the seventh most common
disorder identified and treated in general
practice in Australia
b) The incidence of depressive illness is
increasing
c) The Australian Mental Health Survey
estimates that 4% of adults have had a
depressive disorder in the past month
d) Studies show that 3% of patients who
consult a GP have clinical depression
How should the remainder of
the pregnancy and perinatal/postnatal period be managed?
It may be beneficial to share
Jenny’s management with a
psychiatrist skilled in perinatal
psychiatry. In this case it was
the advice of the obstetrician
to reduce the paroxetine dose;
it would be useful to refer for
an expert opinion and management by a psychiatrist.
Careful consideration needs
to be made of her level of risk,
which may fluctuate. Of con-
cern is the presence of suicidal ideation, and Jenny may
require referral to a psychiatric crisis service or even an
inpatient unit to monitor her
risk and mental state more
closely.
Dose requirements frequently increase during the
second half of pregnancy to
offset increased drug turnover.
To maintain optimal pharmacotherapy, the dose should be
assessed between 20 weeks’
gestation and delivery.
There are several reports of
neonatal withdrawal syndrome in the literature as a
result of third-trimester SSRI
neonatal exposure. Symptoms
of SSRI withdrawal occur in
about 25% of cases and are
usually mild. They include:
■ Respiratory distress.
■ Temperature changes.
■ Feeding difficulty.
■ Jitteriness.
■ Irritability.
■ Fits.
■ Hypoglycaemia.
■ Jaundice.
■ Neurological changes.
With regard to breastfeed-
ONLINE ONLY
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b) Psychotic depression is uncommon in the
elderly
c) Atypical depression is more common in
women than in men
d) Early morning waking is a particular feature
of severe melancholic depression
4. You go on to take a detailed history from
Trudy. Which THREE statements about the
differential diagnosis of depression are
correct?
a) Physical illnesses as a cause of depression
need to be considered
b) Alcohol and illicit substance use as a cause
of depression need to be considered
c) If there is abrupt onset of a severe
depression, especially in a young person,
bipolar disorder should be considered
d) Family history is not of relevance to enquire
about
5. Which THREE statements about
assessing the safety of patients with
depression are correct?
a) The presence of suicidal thoughts or plans
must be ascertained in any depressed
patient
b) A person’s risk of suicide can be increased
by discussing the risks in an open manner
c) Alcohol and drug use is an important
additional risk factor for suicide
d) Factors associated with an increased risk of
suicidal ideation include being male, older,
unemployed or separated/divorced
6. After a detailed assessment of Trudy you
make a diagnosis of primary depressive
disorder. You have also established that
she has not had any suicidal ideation. You
go on to formulate a management plan.
Which TWO statements about
pharmacological therapy in patients with
depression are correct?
a) All patients prescribed antidepressants
should be informed about the delayed onset
of effect
b) It is best not to warn patients about the
possible side effects of antidepressants, as
it may deter them from taking medication
c) It is important to emphasise the problems
associated with abruptly stopping or
reducing the dose of antidepressants
d) Withdrawal phenomena are potentially more
severe with drugs that have a long half-life
7. Which THREE statements about
pharmacotherapy in patients with
depression are correct?
a) Recent studies have suggested that
serotonergic-noradrenergic antidepressant
drugs seem to have greater efficacy
compared with SSRIs in depression
b) Tricyclic antidepressants are less favourable
in treating depression, as they are less
effective than the newer agents
c) Serotonin and noradrenaline reuptake
inhibitors should not be prescribed to patients
with severe or uncontrolled hypertension
d) Recent data suggest SSRIs may increase
the risk of GI bleeding
8. Which TWO statements about
psychological therapies for depression are
correct?
a) Psychological therapy alone has not been
found to be efficacious in the treatment of
depression
b) Certain psychological therapies can be a
useful adjunct to medication in more severe
depression
c) If a patient does not engage in
psychotherapy initially, it is not worth
reconsidering psychotherapy at a later date
d) Certain psychological therapies may be
associated with better relapse prevention
9. Which THREE statements about
treatment-resistant depression are correct?
a) Treatment-resistant depression is generally
defined as a failure of response to at least
two antidepressants at therapeutic doses
for at least two weeks
b) General strategies for approaching patients
with treatment-resistant depression include
reviewing the diagnosis
c) General strategies for approaching patients
with treatment-resistant depression include
exploring comorbidities
d) General strategies for approaching
patients with treatment-resistant
depression include checking that the
patient has been compliant
10. Which TWO statements about switching
antidepressant medications are correct?
a) There is no point in switching from one
SSRI to another SSRI, as the side effects
are likely to be the same with both
b) Withdrawal phenomena are only seen with
antidepressants that affect the serotonergic
system
c) If switching from a monoamine oxidase
inhibitor (MAOI) the patient must wait two
weeks before starting another agent
d) Cross-tapering is usually the preferred
option for switching medications, with the
exception of the MAOIs
CPD QUIZ UPDATE
The RACGP now requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the 2008-10 triennium. You
can complete this online along with the quiz at www.australiandoctor.com.au. Because this is a requirement, we are no longer able to accept the quiz by post
or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online.
HOW TO TREAT Editor: Dr Wendy Morgan
Co-ordinator: Julian McAllan
Quiz: Dr Wendy Morgan
NEXT WEEK Traumatic brain injury is the most common cause of death and disability in people aged under 40 worldwide. The next How to Treat looks at the pathophysiology, assessment and
management of head injury. The author is Dr John Raftos, senior specialist in emergency medicine, St Vincent’s Hospital, Darlinghurst; Sutherland Hospital, Caringbah; and Sydney Hospital, Sydney, NSW.
32
| Australian Doctor | 10 October 2008
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