Mood and anxiety disorders are the most common psychiatric disorders in the community and in primary care settings.
This educational review is designed to be an evidence-based reference
for primary care clinicians using psychiatric medication to treat
patients with these conditions. The algorithms included here cover the
major mood and anxiety disorders, namely major depressive disorder
(MDD), generalized anxiety disorder (GAD), obsessive-compulsive disorder
(OCD), panic disorder, posttraumatic stress disorder (PTSD), and
social anxiety disorder.
There are good reasons for formulating evidence-based approaches in medicine and psychiatry.2
Given the ever increasing volume of data and with multiple randomized
controlled trials (RCTs) being undertaken annually, clinical practice
guidelines that incorporate evidence on efficacy, safety, and
effectiveness3 potentially allow integration of information and facilitate decision making.4
Nevertheless, current evidence-based approaches also have
limitations. First, such approaches are only as good as the evidence
base, which is often limited. In addition, many expert consensus
guidelines are too complex to be appealing to clinicians and remain
unread. The algorithms in this review provide a concise, logical, and
user-friendly guideline to the pharmacotherapy of psychiatric
disorders in the primary care context.
A medical algorithm is a step-by-step approach to
describing diagnosis or treatment. The psychopharmacology algorithms
presented invariably begin with diagnosis as step 1, an initial
medication as step 2, and then proceed to step 7 for patients that
prove particularly refractory to standard treatment approaches. Before
proceeding to the algorithms themselves, some of their pros and cons
are briefly considered.
Pros and Cons of Evidence-Based Algorithms
Why Evidence-Based Algorithms?
There are many good reasons for the recent
proliferation of evidence-based guidelines for psychiatric disorders.
First, the complexity of decision making in psychiatry has steadily
increased in recent years as a result of the introduction of new
medications, the completion of hundreds of clinical trials, and the
growth in systematic and anecdotal information about the management of
treatment-resistant conditions.4 Guidelines and algorithms
may provide a concise and logical “scaffolding” with which to
approach the practice of evidence-based medicine.
Second, there is increasing emphasis by government
and private funding of health care on resource allocation and cost
effectiveness in the practice of medicine. The field of
pharmacoeconomics has grown rapidly and increasingly plays a role in
the development of clinical practice guidelines.5 Once
again, guidelines and algorithms provide a way of summarizing currently
available information and specifying appropriate clinical options to
minimize wasteful and suboptimal practices. They may be able to
provide a pithy, step-by-step approach to cost-effective practices.
Third, the development of computer-based decision
tools for psychiatric assessment and treatment encourages the
formulation of algorithms. Many such programs are based on logical
rules and these are often most usefully articulated with the aid of
flow charts or algorithms.6 Guidelines can in turn be used
not only to encourage best clinical practices, but also as a teaching
tool and as a pointer to future research. As new clinical data is
gathered, such rules should be revised in a timely way.
Limitations of Evidence-Based Algorithms
There are important limitations to evidence-based medicine that need to be borne in mind.6,7
First, evidence-based guidelines and algorithms are only as good as
the evidence. Despite the important advances in the past several
decades in medicine in general and psychiatry in particular, there are
many important gaps in our knowledge about both treatment efficacy
and effectiveness.8
Second, the application of guidelines and algorithms
is dependent on the skills of the treating clinician. Thus, for
example, accurate diagnosis is often required before a treatment
guideline can be applied; inaccurate diagnosis will lead to the use of
the wrong guideline. Guidelines are intended to provide a
“scaffolding,” rather than to automate the practice of medicine.
Third, guideline and algorithm formulation is not the same as guideline and algorithm dissemination and application.9-11
There is, however, growing awareness of the factors that facilitate
the closing of the gap between development and application.12-15
Not the least of these may be the complexity and unwieldliness of
specialized clinical practice guidelines, particularly from the
perspective of users in a primary care setting.
Applying Algorithms in the Clinic
Development of evidence-based approaches encourages a
rigorous review of the literature. For example, the development of an
algorithm requires the clinician to carefully justify clinical
decisions in terms of the existing data. Furthermore, algorithms point
to the future. The development of an algorithm provides an important
focus on those areas where clinical practice, even when expert, is not
supported by research and where further investigation is required.
Ideally, such algorithms have several
characteristics, including reliability, flexibility, clarity, and
multidisciplinary input.16 The algorithms here are not
based on formal expert consenses or systematic meta-analyses, but
rather on a summary of the previous literature. Their strength lies not
so much in consensus and complexity, but rather, in their concision,
logic, and user-friendliness.
The development of algorithms and their revision
after critical assessment and after the gathering of new data is
arguably a useful didactic and research tool. Nevertheless, all
algorithms need to be applied with good clinical judgement. While
algorithms can provide a useful overview, they may also run the risk
of oversimplification. Simple algorithms may, for example, be
irrelevant in patients with complex comorbid psychiatric and medical
conditions. Algorithms are intended to provide a “scaffolding,” rather
than to regulate or automate the practice of medicine. Certainly,
algorithms will never replace the individual clinician; only an
experienced and competent decision-maker is able to apply an algorithm
in the clinic.
Major Depressive Disorder
An algorithm for the pharmacotherapy of depression is
presented in Algorithm 1. Each line of the algorithm is briefly
explained below. However, it is crucial to state at the outset that
psychotherapy is often a useful treatment of depression, either alone
in less severe cases or in conjunction with medication.17,18 Similarly, psychoeducation about depression may be an important adjunct to both pharmacotherapy and psychotherapy.19
Organizational strategies within primary care settings can also
contribute to the improved diagnosis and treatment of depression.20
The algorithm here focuses on major depression.
Nevertheless, there is increasing recognition that dysthymia also
responds to standard antidepressant treatments.21,22 This
disorder, which is characterized by chronic depressive symptoms, has
significant associated morbidity when left untreated. It therefore
deserves additional attention from both clinicians and researchers.
The algorithm here also assumes that the patient is
an adult. The tricyclic antidepressants (TCAs) may offer some benefit
for adolescents but are ineffective and often unsafe in children,23 and some of the newer antidepressants (eg paroxetine, venlafaxine) should be used only with a great deal of caution.24
In addition, differences in dosing and risk-benefit determination
need to be considered (eg, clinicians are less likely to use untested
augmentation strategies in children than in adults).25,26 Indeed, specialist consultation would seem advisable in younger patients.
Step 1
Depression should be diagnosed using specific diagnostic criteria, such as those outlined in the Diagnostic and Statisical Manual of Mental Disorders, Fourth Edition, Text-Revision, (DSM-IV-TR)
(Table 1). A range of practical questionnaires that incorporate these
criteria are available to help clinicians identify and diagnose
patients with major depression.27,28 Particular attention
should be paid to symptoms that are chosen as targets for
pharmacotherapy, which include mood symptoms, associated symptoms
(such as pain), and disability. It should be stressed that current
evidence indicates that depression remains significantly underrecognized
in primary care practice.29
By definition, the diagnosis of MDD is not made when
there is a history of manic or hypomanic episodes. Rather, such
patients are diagnosed with a bipolar disorder. For example,
postpartum depressions are often in the bipolar spectrum. It is
particularly important to exclude a history of mania or hypomania in
patients with a family history of bipolar disorder. The treatment of
depression in bipolar disorder is not discussed further here, but it can
be noted that mood-stabilizing agents (rather than antidepressants
alone) are the essential ingredients of its treatment.30,31
The differential diagnosis of depression includes not
only other psychiatric disorders, but also mood disorders due to
general medical conditions and substance-induced mood disorders. Most
of these disorders can readily be excluded by means of a thorough
medical history, physical examination, and routine blood and urine
tests.32 At the same time, it is important to be aware of
the comorbidity between depression and general medical disorders, with
increasing evidence that depression contributes to the morbidity and
mortality of illnesses such as diabetes and heart disease.33
Step 2
Depression may be complicated in several ways,
impacting decisions about pharmacotherapy and other interventions.
Brief explanations of these various complicating features and their
implications for pharmacotherapy follow.
Melancholia
Melancholic features of depression include loss of
pleasure in activities, lack of reactivity to pleasurable stimuli, and
various neurovegetative symptoms such as exacerbation of depression
in the morning, early-morning awakening, and significant weight loss.
There is some evidence that TCAs and venlafaxine may be more effective
than selective serotonin reuptake inhibitors (SSRIs) in patients with
depression accompanied by melancholic features34 and in possibly related subgroups, such as in-patients with depression,35,36 although not all data is consistent.37 Certainly the presence of melancholic features in depression predicts a poor response to nonsomatic interventions.
Psychotic Features
Clinicians should be alert for psychotic symptoms in
depression, as these are sometimes subtle. Depression with psychotic
features is associated with increased risk for suicide and recurrent
depression. Most authorities hold that it is important to use an
antipsychotic agent in addition to an antidepressant in order to
achieve a response.38 New-generation antipsychotics have a
superior side-effect profile and are therefore a good choice in this
context. Electroconvulsive treatment (ECT) is highly effective, and may
also be considered as a first-line treatment for depressed patients
with psychotic features.39
Atypical Features
Atypical features of depression include mood
reactivity, as well as neurovegetative symptoms of reversed polarity
(ie, increased rather than decreased sleep and appetite), severe lack
of energy or leaden feelings in the limbs (leaden paralysis), and
pathologic sensitivity to interpersonal rejection. Patients may
present with only some of these symptoms. Classical monoamine oxidase
inhibitors (MAOIs) are more effective than TCAs in atypical
depression.40 However, in view of the inconvenience caused by
dietary and other restrictions when using these MAOIs, SSRIs may be
considered a first-line class of medication41 (despite the fact that not all studies of these agents in this subgroup have been positive).
Seasonal Affective Disorder
Seasonal affective disorder (SAD) is a subtype of
depression where there is a regular temporal relationship between
season (usually autumn/winter) and depression, which cannot be
accounted for by seasonal stressors. SAD has been shown to respond to
light therapy. Symptoms of depression are often atypical rather than
typical and SSRIs may also be considered as a first-line treatment for
SAD.42,43
Comorbid Anxiety or Anxiety Disorders
Comorbidity of depression and anxiety is extremely
common. Given that short-term augmentation of an antidepressant with a
benzodiazepine may reduce suffering and increase compliance,44,45
this combination seems reasonable to consider in depressed patients
with high levels of anxiety. In patients with depression and comorbid
panic disorder, it is often useful to begin at much lower doses of
antidepressants than usual because anxiety symptoms are often
initially exacerbated at ordinary doses. In patients with depression
and comorbid OCD, it is advisable to use a serotonergic medication
(ie, clomipramine or an SSRI). In patients with depression and comorbid
social anxiety disorder, SSRIs and venlafaxine, rather than TCAs,
would be favored as first-line agents.
Alcohol and/or Substance Use
A detailed history of substance abuse is essential in
patients with depression because of the frequent comorbidity of these
disorders. Depressed patients with comorbid substance use disorders
are more likely to require hospitalization, more likely to attempt
suicide, and less likely to comply with treatment. However, abstinence
may itself lead to improvement in symptoms of depression. It may
therefore be advisable to detoxify patients prior to beginning
antidepressant treatment. On the other hand, a positive family history
of depression, a history of depression preceding alcohol or other
substance use, or a history of major depression during periods of
sobriety raises the possibility that early intervention with
antidepressants may be useful. There is some evidence that the SSRIs in
particular may be useful as a primary treatment of alcohol dependence.46
Suicide
In patients with suicidal ideation, it is important
to consider whether pharmacotherapy should be initiated in hospital or
under supervision. The risk of suicide in some patients recovering
from depression may increase transiently as they develop the energy
and capacity to act on self-destructive plans made earlier in the
course of their illness. If suicidal patients are treated as
outpatients, it may be advisable to favor medications that are safe in
overdose (such as the SSRIs). If TCAs are used in this setting, it may
be advisable to prescribe only limited amounts of medication.
Pregnancy, Lactation, Menopause
Depression during pregnancy should be treated with
nonpharmacotherapeutic interventions when possible. Where clinical
considerations outweigh the risk of medication,47 one of the SSRIs or perhaps one of the TCAs may be considered48
in consultation with a specialist. In particular, there is a growing
literature pointing toward relative safety of fluoxetine in pregnancy.
ECT may be used in selected cases, or in patients in whom depression
is complicated by psychotic features, as it is both safe and effective
in depression during pregnancy. There is some evidence for the
efficacy of antidepressants in postpartum depression49—they
are often used prophylactically in patients with a history of
postpartum depression, despite conflicting data on their value.48
Depression during lactation should be treated with
nonpharmacotherapeutic interventions when possible. There is some
evidence for the safety of SSRIs during lactation,50
although there is some passage of drug and metabolites to the
breastfeeding infant. Sertraline has the lowest relative dose passed
on to the infant, but expert recommendation is that the same SSRI to
which the patient has responded should be continued.48
Specialist consultation should again be sought prior to using
medication in this context. Depression may be exacerbated in
susceptible patients during menopause and hormone replacement therapy
may be considered as an adjunct to standard pharmacotherapy.48,51
Comorbid Medical Disorders and Medications
Antidepressants are effective in a wide range of general medical disorders with comorbid MDD.52 However, clinicians need to be aware of the multiple interactions between antidepressants and other medications.53 In addition, specific medical disorders in patients with depression may impact choice of antidepressant medication.
Cardiac Disease. TCAs are
contraindicated in several cardiac conditions including
ventricular arrhythmia, subclinical sinus node dysfunction, conduction
defects (including asymptomatic conduction defects), prolonged QT
intervals, and a recent history of myocardial infarction.54
Several SSRIs and ECT appear to be safe for patients with
pre-existing and existing cardiac disease. A depressed patient
with a history of any cardiac disorder should be monitored for the
emergence of cardiac symptoms, electrocardiogram (EG) changes,
and orthostatic blood-pressure decrements. Consultation with a
cardiologist before and during antidepressant treatment may be
advisable.
Stroke. It has been
suggested that in the acute stroke period depression is associated
with left-frontal and left-basal lesions, while in the subacute period
depression is associated with right-frontal and right-parietal
lesions.55 There is also some evidence that the TCA nortriptyline may be superior to an SSRI in poststroke depression.55
Epilepsy. Many
antidepressants lower the seizure threshold and theoretically exert an
adverse effect on seizure control in depressed patients with epilepsy.
Although TCAs can still be used in such patients, the initial dosages
should be lower than usual and subsequent dosage increases should be
gradual. Epilepsy is not a contraindication to ECT.
Glaucoma, Obstructive Uropathy, etc. Anticholinergic
effects of the TCAs are undesirable in a number of settings. TCAs
may, for example, precipitate acute narrow-angle glaucoma in
susceptible individuals (ie, those with shallow anterior
chambers). Prostatism and other forms of bladder outlet
obstruction are relative contraindications to the use of TCAs.
Anticholinergic antidepressants may also exacerbate memory
problems in patients with central nervous disorders such as
Parkinson’s disease or dementia.56,57
Step 3
Any one of the different antidepressants can be used
as a first-line treatment in uncomplicated patients with MDD. There is
a good deal of experience not only with older medications, such as
the TCAs and SSRIs, but also with newer agents, such as the serotonin
norepinephrine reuptake inhibitors (SNRIs) and noradrenergic and
specific serotonergic antidepressants (NaSSAs). Despite some
suggestive findings from meta-analyses of depression trials,58 it is probably premature to conclude that any of the currently available antidepressants has a more rapid onset of action59 or is more effective.60 Thus, for now, the choice between antidepressants is primarily made on the basis of tolerability and side effects.
SSRIs are particularly useful as a first-line
treatment in view of their established efficacy and tolerable
side-effect profile.61 Prescription of therapeutic dosages
is typically straightforward and most SSRIs appear relatively safe in
overdose. Although some of the SSRIs remain more expensive than many
of the TCAs, enhanced compliance resulting from ease of use and
increased tolerability may in fact translate into greater cost
effectiveness. SSRIs may be particularly helpful in younger patients62 and perhaps the elderly, where side effects of older antidepressants can be problematic.25
Venlafaxine (an SNRI), reboxetine (a noradrenergic
reuptake inhibitor [NARI] not currently available in the US), and
mirtazapine (a NaSSA) are also useful first-line options for the
treatment of MDD. Venlafaxine is a predominant serotonin reuptake
blocker at lower doses and a combined serotonin norepinephrine
reuptake blocker at higher doses; this profile may contribute to its
apparently pronounced effect on remission of symptoms.
Mirtazapine is an α2-noradrenergic antagonist (increasing noradrenergic and serotonergic transmission) and a 5-HT2 and 5-HT3
antagonist. This unique mode of action is associated with a useful
range of clinical effects and side effects (eg, increased sedation,
few sexual side effects). Bupropion, a norepinephrine and dopamine
reuptake inhibitor (NDRI), is an antidepressant that is also marketed
for decreasing the craving associated with smoking cessation and that
is relatively free of sexual side effects.
TCAs have long been used in the treatment of
depression. They work as quickly and are as effective as any of the
more recently introduced antidepressants. Clinicians often prescribe
subtherapeutic dosages of these agents, partly because of less
tolerable side-effects at higher doses.63 The TCAs are also unsafe in overdose. On the other hand, low doses can be therapeutic for some patients64 and some TCAs (eg, the secondary tricyclics) have relatively favorable side-effect profiles,35,65 so that these agents remain an option even in the elderly.66,67
St. John’s wort may be a useful option in patients
who refuse conventional medication, particularly when depression levels
are only mild to moderate.68 A range of other herbals or
nutriceuticals (eg, tryptophan, 5-hydroxytryptophan) have some
evidence for efficacy, but cannot be recommended as first-line agents.69 The older, irreversible MAOIs, which require specific dietary restrictions, are no longer used as first-line agents.
Several factors not mentioned thus far may also
influence choice of agent. Of course, agents that have been proven
effective and tolerable in a particular individual in the past should
be favored in the present, and vice versa. Similarly, a family history
of response to a particular antidepressant may favor the choice of
that agent.70 Patient preference for a particular agent is often a deciding factor.
An interesting area of current research focuses on
interventions to decrease the response time of antidepressants. There
are theoretical reasons for suggesting that certain combinations of
agents, by combined receptor action, may be able to achieve this
result. To date, however, such work has not translated into clinical
recommendations.59
Important aspects of psychoeducation regarding the
antidepressants include the facts that antidepressants are not
addictive, side effects are typically transient, therapeutic response
is relatively slow in onset, and if one agent does not work another
should be tried.
Step 4
To determine response to medication, it is important
to ask about changes in those symptoms initially targeted for
treatment. Side effects of the medication should also be determined,
with particular attention to those that patients may be reluctant to
disclose (eg, sexual dysfunction). It may be useful to have the
patient complete a rating scale of depression (Table 2) to help
quantify response to medication. In addition to monitoring depression
symptoms, it is important to ascertain overall change in objective
disability and subject well-being (ie, quality of life).
Patients who are intolerant of a particular
medication can of course be switched to another agent. When TCA side
effects prove intolerable, it may well be useful to switch to an SSRI.
Within the SSRIs, adverse effects may not be seen when an alternative
SSRI is used. For example, some studies have found fluvoxamine to
have a lower risk of sexual side effects.71 Mirtazapine and bupropion may be useful for patients who have specific SSRI side effects such as sexual dysfunction.
When there is a poor response to medication, it is
important to optimize dosage and duration of the antidepressant. For
many of the antidepressants, there is a linear relationship between
dose and response and between dose and side effects. The steepness of
the dose-curve relationship varies from drug to drug (it is relatively
more flat for the SSRIs) and in some cases there is a therapeutic
window beyond which increased doses are less effective (eg,
nortriptyline). However, in general, optimal dosage is as close to
maximum recommended doses that the patient can tolerate. Elderly
patients generally require lower doses than younger adults.
As noted earlier, clinicians often prescribe
suboptimal doses of antidepressants. This is particularly so in the
case of the TCAs, where medications such as imipramine and
amitriptyline are not typically raised to suggested average doses of
150–200 mg/day. Even in the case of the SSRIs, some patients may fail
to respond to the standard initial starting dose, but do well at
higher doses.72
Furthermore, there is increased awareness that some
patients may be rapid metabolizers of medication and therefore require
significantly higher doses than usual.73 Thus, for
example, when patients on TCAs have little response and few
anticholinergic side effects on average doses of medication (eg,
imipramine 150–200 mg), it may be useful to further increase dosage
while monitoring EG and perhaps drug levels. Response to medication
may take 6–8 weeks or longer.25,74,75
While there is some evidence that patients who do not
begin to respond within the first 3–4 weeks of treatment are more
likely to have a relatively poor outcome at 8 weeks, it is important
to give each patient a trial of medication that is of adequate
duration.76
Step 5
Patients should be reassessed at the end of a
clinical trial of optimal dosage and duration. Increasingly, the
literature is emphasizing not only significant reduction in depressive
symptoms, but also the value of aiming for near-complete remission of
symptoms. Patients with reduced but not remitted symptoms continue to
experience significant disability and are at increased risk for
relapse.
When the patient has a good response to medication,
it is important to reinforce the necessity for continuing the
medication at the therapeutic dose despite this improvement.
Guidelines for maintenance therapy of depression have become
increasingly conservative, favoring longer courses of medication, in
view of the safety of modern antidepressants and the likelihood of
additional episodes of depression in patients with repeated episodes.77,78
It is reasonable to continue medication for at least 1 year before
gradual tapering, and to continue for even longer in patients with a
risk of recurrence. Risk factors for recurrence include history of
multiple episodes, persistent dysthymic symptoms after recovery from
MDD, and comorbid psychiatric and medical disorders. There is also
increased awareness of the potential long-term adverse effects of
antidepressants (ie, insomnia, weight gain, sexual problems), and these
require careful monitoring. A combination of pharmacotherapy and
psychotherapy may the most effective form of maintenance therapy.79
When there is a partial response despite an optimum
trial of medication, it may be useful to consider an augmenting agent.
Even among responders, residual symptoms of depression are common,
and, as noted earlier, are associated with greater likelihood of
relapse. There are few controlled studies directly comparing
augmentation strategies with switching medications,80 although both seem effective in approximately 50% of cases.81,82
Augmentation offers the advantage of retaining any possible gains
from the first agent, but the potential disadvantages of polypharmacy
(more side effects, drug interactions).81
There is good evidence from controlled trials that
lithium (at serum levels >0.4 mEq/L) and triiodothyronine (T3) up
to 50 μg/day are effective in enhancing the response of TCAs,83 although there is less evidence for augmentation of other antidepressants including the SSRIs.84
Improvement tends to occur within 3–4 weeks, and, when successful,
the augmenting agent is usually continued for 6–9 months before an
attempt is made at a gradual taper. Augmentation with estrogen and
atypical antipsychotics may be considered in certain
treatment-refractory patients. Other agents (buspirone, pindolol,
dopamine agonists and pyschostimulants, anticonvulsants, inositol,
opiates, dehydroepiandosterone, folate S-adenosyl-methionine [SAMe], and
omega-3 fatty acids) have also been suggested, but the data to date
remains anecdotal or conflicting.81,85
In recent years there has also been a trend for
specialists to combine antidepressants that affect different
neurotransmitters sytems; for example, combing an SSRI with a
noradrenergic agent.86 There are, however, few controlled
studies that support augmentation of an antidepressant with a second
antidepressant agent, and practitioners should be aware of the
significant drug interactions that may ensue from such combinations.81 There is some controlled evidence, however, for adding mirtazapine to an SSRI.
Step 6
When MDD does not respond to a clinical trial of optimal dose and duration, it is useful to reassess a number of factors.87 The presence of certain features may impact the choice of the subsequent intervention.
Severity
In patients with a severe MDD, the need for
hospitalization should be carefully monitored on a continuous basis.
In addition, in such patients the need for ECT should be considered.
Referral to a specialist may be advisable.
Compliance
It is not unlikely that clinicians often overestimate
the compliance of their patients. Many patients worry that medication
is addictive or is “a crutch.” It is well worth checking with the
patient and family whether medication is in fact being taken on a
daily basis regularly.
Comorbid Substance Use
In patients who fail to respond to pharmacotherapy of
MDD, the possibility of comorbid substance use should be considered.
There may be a need to detoxify the patient before tackling the
depression.
Comorbid Personality Disorders
Although antidepressants may be useful,88
additional interventions, such as psychotherapy, may be crucial in
patients with depression and comorbid personality disorders. While
improvement in depressive symptoms may reduce maladaptive behavior in
patients with comorbid personality disorder, there are other patients
(eg, those with borderline personality disorder) in whom the
personality disorder itself may need to be a major target of treatment.
Underlying Medical Disorder
Depressed patients who fail to respond to medication
should be thoroughly reassessed for an underlying medical disorder.
Apathy has been reported as an adverse event of some antidepressants,
and may masquerade as depression.
Pharmacokinetic Issues
Drug-drug interactions may result in a subtherapeutic dose of the prescribed antidepressant.
Psychosocial Issues
Psychosocial circumstances that continue to
complicate the course of a depression need to be assessed, as these
may necessitate appropriate intervention.89
Step 7
After the failure of an adequate clinical trial of
medication in a patient where reassessment sheds no light on any
further unresolved factors, a different antidepressant should be used.
Switching between classes of antidepressants has long been considered
a useful strategy in nonresponders, and there is controlled data to
support this idea for certain agents.82,90 There is also some evidence that switching from one SSRI to another may be useful.80
In most cases cross-tapering is possible, but half-life (eg,
fluoxetine has the longest half-life of the SSRIs) and
drug-interactions (eg, MAOIs should not be overlapped with other
antidepressants) should be kept in mind.
Some medications may be particularly useful in cases
of depression that do not respond to one or more antidepressants.
Although some clinicians no longer use TCAs due to their side-effect
profile, these agents continue to have a role, perhaps particularly in
patients with melancholic features34 and in possibly related subgroups, such as in-patients with depression,35,36 although not all evidence is consistent.37
High doses of the SNRI venlafaxine (up to 375 mg) have been
demonstrated to be effective in patients with treatment-resistant
depression.91 Furthermore, the classic MAOIs remain a useful
resource for patients that have not responded to other more commonly
used classes of medication.92 ECT can be considered, and in
the future other nonpharmacologic somatic interventions (transcranial
magnetic resonance imaging, vagus-nerve stimulation) may also have a
role.93,94
Estrogen augmentation may have a role in perimenopausal/postmenopausal treatment-refractory depression95,96 and in postpartum depression.96,97 The role of the atypical antipsychotics as augmenting agents in refractory depression also appears promising.98
Indeed, as response to augmentation may not be related to the degree
of nonresponse to the preceeding monotherapy trial, augmentation
strategies can sometimes be useful in patients who have not responded
to multiple single agents.99
Generalized Anxiety Disorder
Recently, there have been important advances in the
nosology and treatment of GAD. In particular, there is increasing
evidence that patients with GAD and mixed anxiety-depression
frequently present in primary care settings,100 and the DSM-IV-TR now provides fairly user-friendly criteria for the diagnosis of GAD (Table 3).
A few simple points can perhaps be made to help
conceptualize GAD. In primary care practice, GAD can perhaps be viewed
as a “tension disorder.” This is a useful term insofar as it crosses
the boundary between psychic symptoms (worries, feeling keyed up,
irritability) and somatic complaints (muscle tension, restlessness,
insomnia). While GAD patients may not present with “worries,” they
often describe themselves as “worriers”: worry may represent an
avoidance behavior that is used to diminish tension (analogous to the
way that agoraphobia may develop after panic attacks).
The algorithm presented here (Algorithm 2) provides a
step-by-step approach to the pharmacotherapy of GAD, based on reading
the research literature. It is important to mention at the outset,
however, that psychotherapy approaches may be a first-line
intervention in some GAD patients and should be considered in all
patients with this disorder. In addition, psychoeducation is of the
utmost importance, particularly in the initial stages of treatment, and
should address the direct effects of anxiety on the life of the
patient, as well as possible effects on family members.
Step 1
GAD is characterized by chronic, uncontrollable, and
excessive worry, accompanied by a range of somatic symptoms. Making
the correct diagnosis is essential. Given that GAD often presents with
somatic symptoms and comorbid psychiatric disorders, the diagnosis is
frequently overlooked. On the other hand, improvements in the
nosology and treatment of GAD now make it useful to establish whether
diagnostic criteria for this disorder are met.
Particular attention should be paid to the evaluation
of symptoms that are chosen as targets for pharmacotherapy and to
symptoms that may point to the presence of other psychiatric
disorders. It is also useful to determine the severity of GAD symptoms
using a scale, such as the Hamilton Rating Scale for Anxiety. It is
possible that the situation in GAD mirrors that in depression, where
less severe forms of the disorder respond equally well to
pharmacotherapy and to psychotherapy.
It is also necessary to rule out the presence of
comorbid psychiatric and medical disorders. Mood disorders, such as
depression and dysthymia, and other anxiety disorders are common in
patients with GAD. In addition, attention should be paid to the
possibility of comorbid somatization disorder or substance abuse,
dependence, or withdrawal. In particular, excessive alcohol or caffeine
use may contribute to chronic anxiety symptoms and should be excluded.
Children with pervasive anxiety likely deserve evaluation by a
specialist before a diagnosis of GAD is made.
Step 2
Several factors may complicate GAD, thus impacting
decisions about pharmacotherapy and other interventions. The most
important of these factors, along with their treatment implications,
are listed below.
Geriatric Patients
Research indicates that GAD in the elderly is not uncommon and is often accompanied by depression.101
Given the possibility of accumulation of the drug and consequent
adverse effects, such as motor vehicle accidents, falls, and
fractures, benzodiazepines (particularly in high doses or those with
long half-lives) should be prescribed only with great caution in this
population. In addition, dosages of many other psychotropics require
adjustment in the elderly.
Alcohol and/or Substance Use
When the diagnosis of GAD predates the onset of
substance abuse, treatment may be initiated relatively soon after
abstinence. However, when symptoms of anxiety have their onset during
substance abuse or withdrawal, it is likely that a longer period of
abstinence is indicated prior to re-evaluation of the need for
treatment. In addition, given the risk of dependence, benzodiazepines
should be used with caution in patients with a history of substance
abuse.102
Other Comorbid Disorders
As noted earlier, there is a high rate of comorbidity
among GAD, other anxiety disorders, and mood disorders. GAD will
often respond to the antidepressants that are used as first-line
medication in these disorders and these agents should therefore be
initially prescribed. Similarly, in patients with chronic anxiety and
comorbid personality disorder (eg, borderline personality disorder),
antidepressants may be particularly useful.
Pregnancy, Lactation, Menopause
Pharmacotherapy should ideally be avoided during
pregnancy and lactation. Nevertheless, where clinical considerations
outweigh the risk of medication, such intervention should be
considered after consultation with a specialist. In particular, there
is a growing literature pointing toward relative safety of fluoxetine
in pregnancy.103 Certain benzodiazepines (eg,
chlordiazepoxide) may be safer, while others (eg, alprazolam) should be
avoided during pregnancy and lactation; the lowest effective dose
should be prescribed for the shortest possible duration, and high-peak
concentrations should be avoided by dividing the daily dosage into
two or three doses.104 Anxiety symptoms may be exacerbated
in susceptible patients during menopause, and hormone replacement
therapy may be considered as an adjunct to standard pharmacotherapy.
Comorbid Medical Disorders and Medications
Clinicians need to be aware of the multiple
interactions between medications used in the treatment of GAD and the
treatment of other disorders, as well as of the impact of the
medication’s adverse effects on medical disorders.
Step 3
The first-line treatment of uncomplicated GAD is
somewhat controversial. At this point, given the substantial
comorbidity of GAD with depression and other disorders for which
antidepressants are effective, expert consensus favors the use of one
of these agents (specifically, TCAs, venlafaxine, or SSRIs).105,106 However, a number of other agents may also be useful in patients with GAD.106-108
The TCAs have been shown effective in GAD in several
controlled trials, although many of these agents have troublesome
side-effect profiles. Venlafaxine is an SNRI that is effective in both
short- and long-term studies of GAD and depression. There is growing
evidence that the SSRIs are useful in the treatment of GAD, and a
number of these agents (ie, escitalopram and paroxetine) are approved
by the Food and Drug Administration for this indication. Other classes
of antidepressants, such as the classic MAOIs (eg, phenelzine), may
also be effective in the treatment of GAD, although relatively less has
been published on their use in this disorder.109
There is a good deal of evidence for the efficacy of
the benzodiazepines in GAD as well as for their safety during
long-term use, and other authors have recommended them as first-line
agents. Nevertheless, the high comorbidity of symptoms of depression
in GAD, and the significant difficulties experienced by many patients
during benzodiazepine withdrawal, constitute a strong argument against
their use.
Benzodiazepines with longer half-lives or
slow-release preparations may, however, be associated with fewer
withdrawal problems. Furthermore, hydroxyzine, a tranquilizer that is
an antagonist at both the H1 and the 5-HT2
receptor, has long been available, and has recently received renewed
attention with studies demonstrating not only efficacy in GAD, but
also a lack of withdrawal symptoms after discontinuation.110
Buspirone, a 5-HT1A agonist, takes 2–4
weeks or longer to begin working, and appears to be experienced as
less helpful in patients recently treated with benzodiazepines.111
Its advantages lie in its benign side-effect profile, the lack of
dependence, and its proven efficacy in GAD. Disadvantages include a
lack of efficacy against the depressive symptoms often found in GAD
and a lack of efficacy in some trials. Whereas some SSRIs have been
shown useful in children and adolescents with GAD, a controlled study
of buspirone in this population was negative.
Although β-blockers are often prescribed by general
practitioners for anxiety symptoms, there is not sufficient evidence
to include them as a first-line medication for GAD. Kava extract is an
herbal that showed some promise for the treatment of anxiety,112
but it has not been studied rigorously enough in GAD and its safety
remains unclear. Similarly, given their disadvantageous side-effect
profiles (including tardive dyskinesia), one should be extremely
cautious about the use of low-dose antipsychotic medications in the
treatment of chronic anxiety, despite the anecdotal impression of many
clinicians that these agents can be useful for this indication.
Step 4
The next step is to determine response to the
medication. This is achieved by careful evaluation of change in
symptoms initially targeted for treatment. These are typically the
excessive worry, various somatic symptoms, and the consequent
functional impairment. Determining the side effects of the medication
is also important, as these may influence compliance. Gathering
collateral information from the family of the patient may be useful in
making these evaluations.
Patients who are intolerant of a particular
medication can be switched to another agent or to another class of
agents. For example, when TCA side effects prove intolerable, it may
well be useful to switch to an SSRI. Within the SSRIs, adverse effects
may not be seen when an alternative SSRI is used.
When there is a poor response to medication, the
first course of action is to optimize dose and duration of the
treatment. For many of the antidepressants, there is a linear
relationship between dose and response and between dose and side
effects. Thus, optimal dosage is as close to maximum recommended doses
that the patient can tolerate. Elderly patients generally require
lower doses than younger adults. Particularly in the case of the TCAs,
clinicians often prescribe suboptimal doses, rather than using doses of
150 mg or more of medications such as imipramine. Even in the case of
the SSRIs, some patients may fail to respond to the standard initial
starting dose, but do well at higher doses.
Furthermore, there is increasing awareness that some
patients may be rapid metabolizers of antidepressant medication and,
therefore, require significantly higher doses than usual. Thus, for
example, when patients on TCAs have little response and few
anticholinergic side effects on average doses of medication (eg,
imipramine 150 mg), it may be useful to further increase dosage while
monitoring EG and perhaps drug levels. In addition, response to
antidepressant medication may take 6–8 weeks or longer.
Buspirone treatment usually begins at 5 mg TID. This
dose may be increased by 5 mg every 2–3 days. Therapeutic doses of
buspirone range from 30–60 mg QD, typically given in divided doses.
Buspirone has at least a 2–4 week time lag from initiation to clinical
onset; optimum duration of a trial of treatment should thus be no
less.
Although benzodiazepines are not suggested as a
first-line treatment, should these be used, it is important to
administer them in an optimal fashion. In particular, it may be useful
to replace short-acting agents with slow-release compounds or
long-acting agents. All too frequently, patients on short-acting
compounds have intermittent increases of anxiety before the next dose
of medication is to be taken.
Step 5
At the end of a clinical trial of optimal dose and
duration, patients should be thoroughly reassessed. There is growing
recognition of the importance of residual anxiety symptoms in causing
disability and predicting relapse, and of the consequent necessity of
aiming for remission of symptoms as the endpoint of treatment.113
When the patient has a good response to medication,
it is important to reinforce the necessity for continuing the
medication at the therapeutic dose despite this improvement.114
It has been said that more than half of anxious patients treated for
<6 months with buspirone or benzodiazepines relapse at the end of 1
year. Indeed, guidelines for maintenance therapy of GAD emphasize the
safety of modern agents, the likelihood of additional episodes of
illness in patients with repeated past episodes, and the theoretical
possibility that appropriate treatment may prevent the onset of
secondary disorders.106 Such guidelines have become increasingly conservative, favoring longer courses of medication.
Neither augmentation nor switching strategies in GAD
have been well researched. Augmentation offers the advantage of
retaining any possible gains from the first agent, but the potential
disadvantages of polypharmacy (more side effects and drug
interactions).81 Given the literature on combining SSRIs
with buspirone in the treatment of refractory depression, this
strategy perhaps deserves consideration in GAD patients with partial
response.
Step 6
When GAD does not respond to a clinical trial of
adequate dose and duration, it may be useful to reassess a number of
important factors that may influence choice of further interventions.
Comorbidity
It is important to establish whether comorbid mood or
other anxiety disorders are present. For example, comorbid dysthymia
may not respond to buspirone alone, comorbid social anxiety disorder
is unlikely to respond to a TCA (other than clomipramine), and
comorbid hypochondriasis may require high doses of serotonin reuptake
inhibitors. Excluding important comorbid psychiatric disorders is
perhaps the most important step in the evaluation and management of
refractory GAD.
Compliance
Many patients with GAD suffer from extreme anxiety
and are in fact compliant with their medication. Nevertheless, there
is perhaps a tendency for clinicians to overestimate patient
compliance. Patients are particularly likely to be concerned about
physical or psychological dependence on medication. It is well worth
checking not only with the patient, but also with the family, whether
medication is in fact taken as prescribed.
Comorbid Substance Use
In the presence of active alcohol or substance use,
it may be necessary to shift the emphasis of treatment toward a
substance use disorder as the primary diagnosis, with the anxiety as a
secondary problem. Detoxification is typically a first step in the
management of these patients.115,116
Comorbid Personality Disorders
Although antidepressants may be useful, additional
interventions, such as psychotherapy, may be helpful in patients with
chronic anxiety and comorbid personality disorder. While improvement
in anxiety symptoms may reduce maladaptive behavior in patients with
comorbid personality disorder, there are other patients (eg, those
with borderline personality disorder) in whom the personality disorder
itself may need to be a major target of treatment.
Underlying Medical Disorder
Patients with GAD who fail to show any noticeable
response to treatment should be thoroughly reassessed for the
possibility of an underlying medical condition. A range of different
medical disorders may lead to chronic anxiety, including endocrine
disorders (eg, hyperthyroidism), respiratory disorders (eg, chronic
obstructive pulmonary disorders), cardiac disorders (eg, congestive
heart failure) and others. If present, such disorders naturally require
specific intervention. Note that when using a benzodiazepine in
patients with liver dysfunction, consider using those metabolized only
by conjugation (eg, lorazepam, oxazepam).
Pharmacokinetic Issues
Drug-drug interactions may result in a subtherapeutic dose of the prescribed antidepressant.
Psychosocial Issues
In some cases, a diagnosis of an adjustment disorder
with anxious features may be more accurate than that of GAD, and a
psychotherapeutic approach therefore indicated. (This factor may
partially explain high rates of placebo response in some clinical
trials in GAD). In other cases of chronic anxiety, psychosocial
factors may be enduring and therefore continuously complicate
treatment of GAD until given independent attention.
Step 7
Following failure of an adequate clinical trial of
medication, and in the event of a thorough reassessment providing no
further important clues, the medication should be changed. The
research literature on approaches to resistant GAD is unfortunately
extremely scant.117 Referral to a specialist should be considered.
In such cases, following some of the strategies that
have proven useful in the treatment of resistant depression is
suggested. In particular, switching to a different class of
antidepressants is recommended. Venlafaxine should be considered if it
has not already been employed. In particularly resistant cases, one
should consider the classical MAOIs.
One study has argued that GAD patients with more
cognitive symptoms respond better to antidepressants, while those with
more somatic symptoms respond better to a benzodiazepine. A minority
of patients may, indeed, ultimately require long-term treatment with
benzodiazepines after consideration of their benefits and risks.
Panic Disorder, Social Anxiety Disorder, and PTSD
Panic disorder, social anxiety disorder (social
phobia), and PTSD are all anxiety disorders and are among the most
common of the psychiatric disorders.1 Each is characterized
by panic attacks or hyperarousal and by underdiagnosis or
misdiagnosis as physical illness in primary care settings. In
addition, each may be associated with significant morbidity and
functional impairment. Indeed, it has been estimated that anxiety
disorders account for one third of the costs of all mental illness.118
The role of psychotherapy in the treatment of panic disorder, social anxiety disorder, and PTSD must be emphasized.119
Cognitive-behavioral therapy can augment the anxiolytic effects of
medication, is essential in reducing avoidance behaviors (eg,
agoraphobia, avoidance of social situations), and may be important in
ultimately allowing medication discontinuation. In addition,
psychoeducation of both patient and family is crucial in the treatment
of anxiety disorders.
Algorithm 3 assumes that the patient is an adult.
Although there is less data on the treatment of children and
adolescents with these disorders, what does exist suggests that a
similar approach may be useful in some younger patients.120,121 Specialist consultation may, however, be indicated in such cases.
Step 1
The first step in any treatment algorithm involves
correct diagnosis. Panic attacks (Table 4) may be present in panic
disorder, social anxiety disorder, and PTSD, although shortness of
breath may be more common in the panic attacks of panic disorder;
blushing and stuttering may be more common in those of social anxiety
disorder; and hyperarousal including a startle response is
characteristic of PTSD.
Panic attacks in panic disorder and PTSD (Tables 5,
6) may be spontaneous or may be cued by exposure to stimuli previously
associated with a panic attack (eg, a confined space), while panic
attacks in social phobia (Table 7) are cued by feared social
situations (eg, public speaking).
The initial evaluation should include assessment of
the severity and frequency of panic attacks and hyperarousal, the
degree of avoidance behavior, and the extent of functional impairment.
Panic disorder, social anxiety disorder, and PTSD may all be
associated with other psychiatric symptoms, particularly depressive
and substance abuse symptoms, which therefore also deserve particular
attention.
Panic attacks may occur in other psychiatric
disorders, such as depression, specific phobias, OCD, and substance
use disorders. In addition, certain general medical conditions (eg,
hyperthyroidism) may present with panic attacks. Caffeine may
exacerbate panic attacks as well. A thorough medical history, physical
examination, and routine blood and urine tests, are therefore useful
in patients presenting with panic attacks.
Step 2
Panic disorder, social anxiety disorder, and PTSD may
be complicated in several ways, impacting decisions about
pharmacotherapy. Brief explanations of these complicating factors and
their implications for pharmacotherapy follow.
Severity
Patients with severe symptoms may require brief
hospitalization to help contain symptoms. The possible association
between panic disorder and increased risk of suicide, for example,
needs to be taken seriously. In addition, acute administration of
high-potency benzodiazepines (eg, alprazolam, clonazepam) may be
necessary. Slow-release preparations or benzodiazepines with longer
half-lives (eg, clonazepam) have the advantage of avoiding rebound
anxiety between doses. While high-potency benzodiazepines have been
shown to be effective in panic disorder and in social anxiety disorder
in controlled trials, in view of their dependence potential, these
agents should be reserved for acute rapid anxiety reduction in
patients with severe symptoms.122
Melancholia
Patients with anxiety disorders often have comorbid
depression, but this usually also responds to first-line anti-anxiety
treatments such as the SSRIs. However, there is some evidence (albeit
controversial) that TCAs and venlafaxine may be more effective than
SSRIs in patients with depression accompanied by melancholic features34 and in possibly related subgroups, such as in-patients with depression,35,36 although not all data is consistent.37
Interestingly, clomipramine is a TCA with properties that overlap
with the SSRIs in that it is relatively selective for the serotonin
system. Melancholic features of depression include loss of pleasure in
activities, lack of reactivity to pleasurable stimuli, and various
neurovegetative symptoms, such as exacerbation of depression in the
morning, early-morning awakening, and significant weight loss.
Alcohol and/or Substance Use
Alcohol and other substance use disorders are
associated with exacerbation of anxiety disorders. Anxiety disorders
may lead to use of alcohol and other substances in order to
self-medicate anxiety. Thus, although it is generally advisable to
detoxify patients prior to beginning pharmacotherapy, in some cases
such pharmacotherapy is an integral part of the treatment of the
secondary substance use disorder.102 There is some evidence
that the SSRIs in particular may be useful as a primary treatment of
alcohol dependence. Benzodiazepines are relatively contraindicated in
these patients.46
Pregnancy, Lactation, Menopause
Pharmacotherapy should ideally be avoided during
pregnancy and lactation. Furthermore, panic attacks may diminish
during pregnancy. Nevertheless, where clinical considerations outweigh
the risk of medication, such intervention should be considered after
consultation with a specialist. In particular, there is a growing
literature pointing toward relative safety of fluoxetine in pregnancy,103 and certain benzodiazepines may be safe if used circumspectly.104
Panic attacks may be exacerbated in susceptible patients during
menopause, and hormone replacement therapy may be considered as an
adjunct to standard pharmacotherapy.
Comorbid Medical Disorders and Medications
Clinicians need to be aware of the multiple
interactions between medications used in the treatment of the anxiety
disorders and other medications, as well as of the impact of
medication adverse effects on medical disorders. Fortunately, certain
SSRIs have relatively few interactions with other medications, and the
SSRIs as a class are well tolerated in most medical disorders.
Step 3
In Algorithm 3, SSRIs or venlafaxine are suggested as
the first-line treatment of panic disorder, social anxiety disorder,
and PTSD. There is now a great deal of evidence that SSRIs are both
well tolerated and effective in these disorders.105,123-128 More recently, venlafaxine has been shown to be useful in panic disorder and social anxiety disorder.
Panic disorder also responds to the TCAs and to
certain other antidepressants (but not all). The relatively poor
tolerability and safety profile of the TCAs and other older
antidepressants, such as the MAOIs,129 means that these
agents should not be used as first-line medications. No matter which
antidepressant is used in the treatment of panic disorder, however, it
is crucial to initiate treatment with very low doses (eg, fluoxetine 5
mg or imipramine 10 mg) in order to prevent early exacerbation of
panic attacks.
Social anxiety disorder does not respond to the TCAs
(with the possible exception of clomipramine, a predominantly
serotonergic TCA), and these agents should not be used as first-line
treatments of this disorder. When social anxiety symptoms are limited
only to specific performance situations (“performance anxiety”),
β-blockers can be prescribed on an as-needed basis. These agents
appear particularly useful for reducing “peripheral” symptoms of
anxiety such as tremor and palpitations.130 However, there
is growing data that the SSRIs are useful both in more generalized
social anxiety disorder (when symptoms extend to most social
situations), and less generalized social anxiety disorder.131
PTSD also responds to TCAs and certain other
antidepressants. The relatively poor tolerability and safety profile
of TCAs and other older antidepressants, such as the MAOIs, means that
these agents should not be used as first-line medications. Treatment
response rate is possibly lower in some combat veterans than in
civilians with PTSD, so that any pessimism about prognosis which
derives from studies of PTSD in veterans should not apply to all
patients.125
There are few studies showing that any one SSRI is
superior to another in the treatment of anxiety disorders. Of course,
agents that have been proven effective and tolerable in a particular
individual in the past should be favored in the present, and vice
versa. Similarly, despite an absence of supporting empirical data,
many clinicians suggest that family history of response to a
particular antidepressant favors the choice of that agent.
Important aspects of psychoeducation regarding the
SSRIs and SNRIs include the fact that these are not addictive, that
despite being termed antidepressants they are highly effective in
anxiety disorders, that side effects are typically transient, that
therapeutic response is relatively slow in onset, and that if one
agent does not work another should be tried.
High-potency benzodiazepines (alprazolam, clonazepam)
have also been shown to be effective in the treatment of panic
disorder and social anxiety disorder. In PTSD these agents do not
appear effective. Some authors have suggested that high-potency
benzodiazepines qualify as first-line monotherapies in panic disorder
and social anxiety disorder, but others have emphasized the potential
problems of long-term treatment. A compromise position is that
short-term augmentation of antidepressant agents with benzodiazepines
may be useful in rapidly stabilizing symptoms, and should therefore be
considered in panic disorder132 and perhaps social anxiety disorder, particularly when high levels of anxiety threaten to disrupt ongoing pharmacotherapy.
Although β-blockers are often prescribed by primary
care practitioners for anxiety symptoms, there is not sufficient
evidence to include them as a first-line medication for panic
disorder, generalized social anxiety disorder, or PTSD. Similarly, given
their disadvantageous side-effect profiles (including tardive
dyskinesia), one should be extremely cautious about the use of
low-dose antipsychotic medications in the treatment of anxiety
symptoms, despite the anecdotal impression of many clinicians that
these agents can be useful for this indication.
Step 4
To determine response to medication, it is important
to ask about change in those symptoms initially targeted for
treatment. Side effects of the medication should also be determined,
with particular attention to those that patients may be reluctant to
disclose (eg, sexual dysfunction). It may be useful to complete
symptom rating scales (Tables 8, 9) in order to help quantify response
to medication.
Patients who are intolerant of a particular
medication can of course be switched to another agent. Within the
SSRIs, adverse effects may not be seen when an alternative SSRI or
clomipramine is used.
When there is a poor response to medication, it is
important to optimize dosage and duration of the medication.
Dose-response relationship of the SSRIs has not been as well studied
in the anxiety disorders as in depression. Optimal dosage may be as
close to maximum recommended doses that the patient can tolerate
(usually 2–3 times starting dose). Certainly, the lowest effective
antidepressant dose of an SSRI may not be sufficient for some patients
with panic disorder, social anxiety disorder, and PTSD. Elderly
patients generally require lower doses than younger adults do.
Furthermore, response to SSRIs in these disorders may
take 6–8 weeks or longer. PTSD in particular may be associated with a
relatively slow response to antidepressant treatment. It is important
to give each patient a trial of medication that is of adequate
duration.
Step 5
At the end of a clinical trial of optimal dose and
duration, the patient should be thoroughly reassessed. There is
growing recognition of the importance of residual anxiety symptoms in
causing disability and predicting relapse, and of the consequent
necessity of aiming for remission of symptoms as the endpoint of
treatment.113
When the patient has a good response to medication it
is important to reinforce the necessity for continuing the medication
at the therapeutic dose despite this improvement. Guidelines for
maintenance therapy of anxiety disorders have become increasingly
conservative, favoring longer courses of medication, in view of the
safety of modern antidepressants and the likelihood of relapse in
patients with an untreated chronic illness. In panic disorder, social
anxiety disorder, and PTSD it is not unreasonable to continue medication
for at least a year before gradual tapering.126-128,133
Cognitive-behavioral therapy may be useful prior to beginning and
during medication withdrawal in order to maintain gains, although more
research on the optimal combination and sequencing of pharmacotherapy
and psychotherapy in these disorders is needed.
When there is a partial response despite an optimum
trial of medication, it may be useful to consider an augmenting agent.
Neither augmentation nor switching strategies in these conditions
have been well researched. Augmentation offers the advantage of
retaining any possible gains from the first agent, but the potential
disadvantages of polypharmacy (more side effects, drug interactions).81
Of all the augmentation strategies in the treatment of the anxiety
disorders, however, arguably the most important is augmentation of
pharmacotherapy with additional psychotherapy.134,135
In panic disorder, high-potency benzodiazepines have
been anecdotally described as useful in treatment-resistant panic
disorder,136 and these agents (particularly slow-release
agents or those with a longer half-life) may be expected to reduce
anxiety secondary to antidepressants and to combat the primary
disorder. However, the potential for dependence must be borne in mind.
The anticonvulsant gabapentin has shown some efficacy as monotherapy
in panic disorder,137 does not have dependence potential, and
is another theoretical possibility for use as an augmenting agent. An
alternative strategy noted in uncontrolled reports, is to augment an
SSRI with low doses of a predominantly noradrenergic TCA.138,139
However, such strategies demand caution as very high levels of a TCA
may result if combined with certain SSRIs. Another possibility is the
use of pindolol to augment an SSRI—a strategy found useful in a
preliminary controlled trial in panic disorder.140 Specialist consultation may be advisable when augmentation seems indicated.
In social anxiety disorder, given its efficacy as monotherapy, augmentation with clonazepam is a theoretical consideration.141
Nevertheless, this again runs the risk of benzodiazepine dependence.
Buspirone augmentation has been noted to be useful in an open-label
trial. The anticonvulsant gabapentin also showed some efficacy as
monotherapy in social anxiety disorder,142 does not have
dependence potential, and is another theoretical possibility for use
as an augmenting agent. Nevertheless, there is a paucity of research on
augmentation strategies in social anxiety disorder. Pindolol
augmentation of a SSRI was ineffective in a controlled trial of social
anxiety disorder.143
In PTSD, a range of augmentation strategies have been suggested, but few have been studied in controlled trials.144 The anticonvulsant lamotrigine showed some efficacy as monotherapy in PTSD,145
and is a theoretical possibility for use as an augmenting agent.
There is a growing literature on the use of atypical antipsychotics as
monotherapy for PTSD, and these medications therefore also have a
possible role as augmentating agents.144 Again, however,
further research in this area is needed before definitive
recommendations can be made. In the interim, specialist consultation
should be sought in such cases.
Step 6
When anxiety disorders do not respond to a clinical
trial of optimal dose and duration, it is useful to reassess a number
of factors. The presence of certain features may impact on the choice
of the subsequent intervention.
Compliance
Clinicians often overestimate the compliance of their
patients and it is often useful to check with patients and their
families whether medication is being taken as prescribed. Many
patients worry that medication is addictive or is a “crutch.”
Comorbid Substance Use
In patients who fail to respond to pharmacotherapy,
the possibility of comorbid substance use should again be considered.
Self-medication with alcohol and other substances is particularly
common in social anxiety disorder and PTSD. There may be a need to
withdraw the patient before tackling the anxiety disorder per se.115,116
Comorbid Personality Disorders
Although SSRIs may be useful, additional
interventions, such as psychotherapy, may be crucial in patients with
anxiety disorder and comorbid personality disorder. While improvement
in anxiety symptoms may reduce maladaptive behavior in comorbid
personality disorder, the personality disorder itself may need to be a
major target of treatment.
Underlying Medical Disorder
Anxious patients who fail to respond to medication should be thoroughly reassessed for an underlying medical disorder.
Pharmacokinetic Issues
Drug-drug interactions may result in a subtherapeutic dose of the prescribed antidepressant.
Psychosocial Issues
Psychosocial circumstances that continue to
complicate the course of an anxiety disorder need to be assessed, as
these may necessitate appropriate intervention. Loss or separation may
precipitate panic disorder, and this may need to be addressed.
Ongoing avoidance patterns, such as avoidance of feared social
situations in social anxiety disorder, may need to be specifically
addressed. PTSD may be associated with disruptions in interpersonal
relationships, altered perceptions of the self and others, survivor
guilt, etc, which require specific intervention.
Step 7
After the failure of an adequate clinical trial of
medication in a patient where reassessment sheds no light on any
further unresolved factors, a different agent should be used. It is
often advisable to switch classes of medication. It is also possible
that switching from one SSRI to another may be useful.
Some medications may be particularly useful in cases
of treatment-resistant anxiety disorders. Venlafaxine has been
suggested to be useful in patients with social anxiety disorder who
have failed to respond to SSRIs.146 The classical
irreversible MAOIs, despite necessitating measures, such as a
specialized diet, remain a useful resource for patients with panic
disorder, social anxiety disorder, or PTSD who have not responded to
other more commonly used classes of medication.147 Finally, augmentation strategies can sometimes be useful in patients who have not responded to multiple single agents.
If all avenues have been thoroughly explored, a
second opinion by an expert is indicated. Medication trials that ended
prematurely or that did not use optimal dosing can be repeated. It
may ultimately be necessary to revert to the regimen on which the
patient demonstrated the best response.
Obsessive-Compulsive and Related Disorders
OCD is characterized by obsessions and compulsions
and is classified as an anxiety disorder. It is interesting to note,
however, that a number of other disorders are also characterized by
repetitive thoughts and rituals, and though not classified as anxiety
disorders, they may also respond to standard OCD treatment. These
so-called OCD spectrum disorders include body dysmorphic disorder
(characterized by recurrent concerns with imagined ugliness),
hypochondriasis (characterized by recurrent concerns with imagined
illness), and trichotillomania (characterized by recurrent
hair-pulling).148
Step 1
Current evidence indicates that OCD is commonly underdiagnosed and undertreated.149
There is also the converse possibility that various disorders with
intrusive symptoms, such as PTSD or GAD, can be misdiagnosed as OCD.
Diagnostic criteria for OCD are provided in Table 10.
Most patients with OCD have both obsessions (which
increase anxiety) and compulsions (which aim to decrease anxiety),
particularly now that the DSM-IV-TR definition of compulsion
includes mental rituals. Evaluation should include assessment of
symptom pattern, severity, and functional impairment. Comorbid axis I
and II disorders, including tic disorders, as well as medical
conditions (including pregnancy) and disorders need to be accurately
identified. There is growing evidence that OCD and/or tics in some
patients, particularly children, are precipitated or exacerbated by
streptococcal throat infections.150
Evaluation of the OCD patient also requires attention
to psychosocial factors that may have precipitated or exacerbated OCD
symptoms. For example, are family members involved in the patient’s
rituals? What is the patient’s explanatory model of OCD—does he or she
regard it as a sign of weakness or as evidence of brain dysfunction?
Certainly, psychoeducation as part of the management of OCD is
crucial. Similarly, cognitive-behavioral techniques are an important
aspect of OCD treatment, whether used alone or in combination with
medication.151
In the discussion here, we assume that the patient is
an adult. Nevertheless, there is increasing data on the
pharmacotherapy of OCD in children.152,153 Indeed,
Algorithm 4 here can readily be adapted for children, bearing in mind
considerations such as differences in dosing and differences in
risk-benefit determination (eg, clinicians are less likely to use
untested augmentation strategies in children). Specialist consultation
may, however, be indicated in such cases.
Step 2
Possible complications in OCD that may impact on pharmacotherapy include the following.
Severity
Patients with severe symptoms may require brief
hospitalization to help contain symptoms. In general, however, the
principles of behavior therapy suggest that patients should attempt to
continue with their ordinary daily routines where possible.
Melancholia
There is some evidence (albeit controversial) that
TCAs may be more effective than SSRIs in patients with depression
accompanied by melancholic features34 and in possibly related subgroups, such as in-patients with depression,35,36 although not all data is consistent.37
Melancholic features of depression include loss of pleasure in
activities, lack of reactivity to pleasurable stimuli, and various
neurovegetative symptoms such as exacerbation of depression in the
morning, early-morning awakening, and significant weight loss. The
only TCA that is effective in OCD is clomipramine.
Tourette’s Disorder
Tourette’s disorder (TD) is characterized by both
motor and vocal tics. Many patients with TD have comorbid OCD.
Although this OCD may respond to standard OCD treatments, additional
medication that targets the tics (eg, dopamine blockers such as
haloperidol, pimozide, or risperidone) may be necessary for resolution
of the range of symptoms that characterize the disorder.154
Pregnancy, Lactation, Menopause
Pharmacotherapy should ideally be avoided during
pregnancy and lactation. Nevertheless, where clinical considerations
outweigh the risk of medication, such intervention should be
considered after consultation with a specialist. In particular, there
is a growing literature pointing toward the relative safety of
fluoxetine in pregnancy.103
Comorbid Medical Disorders and Medications
Clinicians need to be aware of the multiple
interactions between medications used in the treatment of OCD and
other medications, as well as the impact of a medication’s adverse
effects on medical disorders. Fortunately, certain SSRIs have
relatively few interactions with other medications, and the SSRIs as a
class are well tolerated in most medical disorders.
Step 3
The first line of medication in the treatment of OCD
should comprise a serotonin reuptake inhibitor (SRI). Consistent with
growing evidence for the importance of serotonin in OCD, both
clomipramine and the SSRIs appear to be more effective than
desipramine in the treatment of OCD.155,156 Furthermore,
the efficacy and safety of clomipramine and the SSRIs in the treatment
of OCD have been well researched, with studies indicating that at
least half of patients will respond to one of these agents. The SRIs
are also useful for body dysmorphic disorder, hypochondriasis,
obsessive-compulsive symptoms in TD, and possibly in trichotillomania
(albeit with relatively less robust responses), compulsive
skin-picking and other stereotypic movements, so-called compulsive
sexual behavior, and pathological gambling.148,157
An immediate question, however, is which SRI to use
first. Given the apparent lack of differences in efficacy between the
SRIs, the side-effect profile of these agents may be an important
question in considering which agent to use first. Certainly, there are
invariably fewer side effects during treatment with the SSRIs than
during treatment with clomipramine. Thus, it seems reasonable to
suggest that treatment of OCD be initiated with a SSRI. While any SSRI
is acceptable, choice of a SSRI may be influenced by characteristic
side-effect profiles of the different SSRIs, previous individual and
familial responses to pharmacotherapy, etc. Low doses should initially
be used in patients with comorbid panic disorder.
Step 4
To determine response to medication, it is important
to ask about change in those symptoms initially targeted for
treatment. Side effects of the medication should also be determined,
with particular attention to those that patients may be reluctant to
disclose (eg, sexual dysfunction). It may be useful to complete a
symptom rating scale (Table 11) to help quantify response to
medication.
Patients who are intolerant of a particular
medication can of course be switched to another agent. Within the
SRIs, adverse effects may not be seen when an alternative SSRI or
clomipramine is used.
When there is a poor response to medication, it is
important to optimize dosage and duration of the medication. Although
some patients with OCD respond to standard doses of SRIs, others
require doses that are much higher than in depression. In adults,
clomipramine should be increased to approximately 250 mg, and the
SSRIs should be increased to maximal dosages (eg, fluoxetine 60–80
mg). Unfortunately, the likelihood of side effects increases at these
high doses. Electrocardiogram monitoring isnecessary when children and
adolescents, or patients with pre-existing heart disease, are treated
with clomipramine.
Furthermore, response to SSRIs in OCD may take rather
longer than in many other disorders—up to 12 weeks. It is obviously
important to give each patient a trial of medication that is of
adequate duration. Therefore, patients need to be educated that
response may take a significant length of time and that they need to
remain optimistic even when no change is seen at first.
Step 5
At the end of a clinical trial of optimal dose and
duration, patients should be thoroughly reassessed. There is growing
recognition of the importance of residual anxiety symptoms in causing
disability and predicting relapse, and of the consequent necessity of
aiming for remission of symptoms as the endpoint of treatment.113
Nevertheless, many OCD patients who are judged “responders” to
medication therapy may continue to experience obsessions and
compulsions, albeit with less intensity. In clinical trials, a
decrease of 25% to 35% on the Yale-Brown Obsessive-Compulsive Scale
typically corresponds to a categorical treatment response.
In patients where an SRI is effective, maintenance
pharmacotherapy should be instituted. Rapid discontinuation of these
agents risks the return of symptoms. Nevertheless, a maintenance dose
of SSRIs in OCD may be lower than the dose initially required during
acute treatment.158 At least 1 year of maintenance
pharmacotherapy is reasonable. When a decision is made to attempt
discontinuation of medication, it is advisable to taper medication off
slowly (eg, by 25% every 2 months). Concomitant behavioral treatment
during pharmacotherapy may well increase chances of being able to
discontinue medication without relapse.
Comparison of augmentation with switching strategies
in OCD has not been well researched. Augmentation offers the advantage
of retaining any possible gains from the first agent, but the
potential disadvantages of polypharmacy (more side effects, drug
interactions).81 Of all the augmentation strategies in the
treatment of OCD, perhaps the most important is augmentation of
pharmacotherapy with additional psychotherapy.159 However,
when there is a partial response despite an optimum trial of medication,
or when there are comorbid tics, it may be useful to consider an
augmenting medication. Certainly, in patients with comorbid tics,
there is good evidence that augmentation of a SRI with a dopamine
blocker can be effective.160 The introduction of the
new-generation antipsychotics has led to increased use of these agents
in the augmentation therapy of OCD, and they appear useful even
treatment-refractory patients even in the absence of comorbid tics.161 Another possible strategy is to supplement an SSRI with a low dose of clomipramine,162
although careful monitoring of adverse effects and
electrocardiographs may be warranted with such a combination. Other
augmentation strategies have been suggested, but there are few
positive controlled trials. There is also relatively little work on
augmentation strategies in OCD-related disorders, although addition of
a dopamine blocker may also be useful in some of these patients.163
Step 6
When OCD does not respond to a clinical trial of
optimal dose and duration, it is useful to reassess a number of
factors. The presence of certain features may impact on the choice of
the subsequent intervention.
Compliance
Clinicians often overestimate the compliance of their
patients and it is often useful to check with patients and their
families whether medication is being taken as prescribed. Many
patients worry that medication is addictive or is a “crutch.”
Comorbid Substance Use
In patients who fail to respond to pharmacotherapy,
the possibility of comorbid substance use should again be considered.
There may be a need to withdraw the patient before tackling the
anxiety disorder per se.115,116
Comorbid Personality Disorders
Although SSRIs may be useful, additional
interventions, such as psychotherapy, may be crucial in patients with
OCD and comorbid personality disorder. While improvement in OCD
symptoms may reduce maladaptive behavior in comorbid personality
disorder, the personality disorder itself may need to be a major
target of treatment.
Underlying Medical Disorders
Anxious patients who fail to respond to medication
should be thoroughly reassessed for an underlying medical disorder. In
OCD in children, for example, the role of streptococcal throat
infection may be of particular importance.
Pharmacokinetic Issues
Drug-drug interactions may result in a subtherapeutic dose of the prescribed antidepressant.
Psychosocial Issues
Psychosocial circumstances that continue to
complicate the course of OCD need to be assessed, as these may
necessitate appropriate intervention. In particular, the participation
of friends and family in rituals may serve to derail treatment.
Step 7
After the failure of an adequate clinical trial of
medication in a patient where reassessment sheds no light on any
further unresolved factors, a different agent should be used. Although
an SRI has less chance of being effective in patients who have
already failed a number of trials of other SRIs, some of these
patients will in fact ultimately respond to a new SRI.164
Given the possible superiority of clomipramine in certain cases of OCD
and depression, it may be argued that all OCD patients who have
failed to respond to one or more of the SSRIs deserve a trial of
clomipramine.165 While results of studies correlating
plasma drug levels and therapeutic response in OCD have been mixed, in
the case of clomipramine, obtaining drug levels at high doses may be
useful. Anecdotal experience suggests that certain non-SRI agents, such
as the classical MAOIs and venlafaxine, may on occasion be effective
in treatment-resistant OCD.166 Recent trials of intravenous clomipramine also show efficacy in treatment-resistant OCD.167
For patients who have failed multiple medication and
behavioural treatments (including intensive partial or full
hospitalization programs),168 and where severity of the disorder is marked, neurosurgery should also be considered.169
Several studies have suggested that specific lesions to the
corticostriatal pathways may lead to significant reduction in OCD
symptoms in treatment-refractory patients. Patients can be referred to
specialized centers in the United States, Sweden, and elsewhere for
such treatments. ECT may anecdotally be helpful for some OCD patients,170
and research on transcranial magnetic stimulation or deep-brain
stimulation in OCD may ultimately provide new methods of treatment.171
Resource ...Dan J. Stein, MD, PhD
Credits/Source-http://www.primarypsychiatry.com/aspx/ArticleDetail.aspx?articleid=764
Primary Psychiatry. 2004;11(6):55-78
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