Gavin Andrews, Rocco Crino, Caroline Hunt, Lisa Lampe, Andrew Page, 423 pp, ISBN 0-521-46927-9, Cambridge University Press 1996

Writing for psychiatrists and clinical psychologists, Gavin Andrews and his co-authors claim that their book ‘provides most of the information needed for the successful treatment of patients with anxiety disorders‘. About three-quarters of the book is said to be unique in terms of format, consisting of ‘patient treatment manuals’ (PTMs) and accompanying ‘clinician’s guides’ (CGs) dealing with each of the five common primary anxiety disorders (panic disorder and agoraphobia; social phobia; specific phobias; obsessive-compulsive disorder; generalised anxiety disorder). Secondary anxiety disorders (for example, post-traumatic stress disorder) are not included.

The PTMs are self-help manuals and the purchaser of the book is at liberty to copy them for individual patients, who will use them as self-help manuals. They are ‘both the guidebook and the journey’; whereas the CGs, ‘for clinicians’ eyes only’, are about the art of therapy, containing advice about devising treatment programmes and critical issues in therapy. The rest of the book consists of an introductory section dealing with general issues in anxiety disorders and their treatment, and detailed contemporary (references up to and including 1993) reviews of the epidemiology, aetiology and evaluation of each disorder. The contents are grouped by disorder with four chapters on each — syndrome, treatment, PTM and CG. The PTMs are printed in single-column format, whereas the rest of the book, for clinician use, is printed in double columns. An initial chapter helpfully entitled ‘Read Me’ describes the layout and authors’ intentions.

The book’s claim to fame rests with the PTMs and CGs, which are designed to bridge the gap between knowing about something and knowing how to do it. ‘It’ is cognitive behaviour therapy, the treatment of choice in the anxiety disorders. Alas, there are no quick and easy solutions that can be applied in busy out-patient clinics or doctors’ surgeries. There is no avoiding up to 20 h of therapist-patient contact, preferably over a smaller number of weeks. The PTMs seem straightforward to use. The contents typically cover an introductory explanation, physical relaxation techniques, cognitive aspects, dealing with avoidance behaviours, problem solving, maintaining progress and recommended reading. There are a lot of words, which I suspect would deter many of my patients.

Is the book genuinely new, as claimed? The contents seem to me, a general adult psychiatrist, uncontroversial. The writing is clear and the information is easily accessible. The book is a useful source of information for teaching both clinical medical students and psychiatrists in training. Colleagues with an interest in the psychopharmacology of anxiety disorders have pronounced in its favour, although ‘one commented on the verbosity of the PTMs. What is new is the combination of theory and practice, so that a single volume can serve as introduction, reference, treatment manual and problem-solving guide for clinicians ‘at all levels of expertise’. However, in the UK, the various components will probably be accessed by different disciplines. NHS psychiatrists generally will not have the time to use the book as a treatment manual. Junior doctors would probably be able to use the PTMs and CGs as a (desirable) training experience, but the issue of supervision arises. The likeliest users in therapy would be clinical psychologists and nurse behaviour therapists: how this book compares with previous offerings I cannot say. It goes beyond the available self-help literature.

In my opinion this book deserves a place in any medical library for its clear and comprehensive theoretical overview, and its synthesis of theory and practice for all doctors whose work brings them into contact with anxious patients. Because of the constraints of working practices, few doctors will be able to use it to its full potential.

Discussing prevention of relapse or recurrence of major depression is beyond the scope of this paper but is clearly important. Long-term use of antidepressants is sometimes necessary particularly if patients have two or more episodes. Compliance becomes absolutely necessary, but side effects often cause patients to stop taking medications. Tricyclics and, to a lesser degree, traditional monoamine oxidase inhibitors (MAOIs) have many side effects because they act on the muscarinic, α₁-adrenergic, and histamine H₁ receptors. If an antidepressant is effective, the side effects can be managed.

The new antidepressants have become the agents of choice because they have fewer side effects. Sexual dysfunction is the most common reason for noncompliance and unfortunately is a relatively frequent problem with all antidepressants. Moclobemide and nefazodone seem to have the fewest sexual side effects.

For long-term therapy, doses that were effective for the acute episode should be continued. Clinical experience suggests a need for lifelong maintenance on antidepressants for patients older than 50 years at the time of first episode, for patients 40 years or older who have had two episodes, or for all patients with three or more episodes. If an antidepressant is discontinued, it should be withdrawn very gradually and signs of recurring depression monitored. Long-term use of lithium for prophylaxis of both bipolar disorder and major depression has also been shown to be very effective. There is a very high rate of attempted suicide among patients with major depression following lithium discontinuation.

Conclusion

Treatment-resistant depression is a relative term and depends on how far a physician is willing to go in treating a particular patient. Appropriate use of antidepressants can relieve symptoms in at least two thirds of cases. Drug combinations, electroconvulsive therapy (ECT), and augmentation strategies can, if vigorously applied, reduce the proportion of patients truly treatment resistant to about 7%. Considering the morbidity and mortality associated with depression, a vigorous approach to therapy is worthwhile. Long-term maintenance, once success is achieved, is essential.

Many less commonly used antidepressant therapies are supported by anecdotal evidence only. They include light therapy (non-seasonal affective disorder), high-dose TCA or MAOI therapy (only if serum levels can be monitored), intravenous clomipramine or maprotiline (allows for rapid perfusion, avoids first pass liver metabolism), bromocriptine, high-dose selegiline, and psychosurgery. Modern stereotaxic psychosurgical procedures offer symptom relief with minimal risk, and reports of large trials indicate that up to 60% of truly treatment-resistant patients either recover or are considerably improved.

Absolute treatment resistance

Very few patients show absolute treatment resistance. In specialized clinics, only about 7% of patients remain depressed after 1 year of extensive investigations and treatment. Extensive treatment involves many drug trials singly and in combination as well as one or more courses of electroconvulsive therapy (ECT). Patients with absolute treatment-resistant depression (TRD) are older (mean age about 55), have been depressed longer, and usually have insoluble life problems.

Even patients with absolute TRD can be helped. Antidepressants often give some relief, and carefully prescribed psychostimulants can improve mood and psychoenergize.

Supportive psychotherapy and CBT can also be of benefit. Supportive psychotherapy helps depressed patients to carry on and CBT allows patients to view the world more positively. Regular exercise and reduction of alcohol consumption also help.

Electroconvulsive therapy

An important and effective treatment for depression, electroconvulsive therapy (ECT) is effective in about 90% of cases of major depression. The success rate drops when it is used for drug-refractory cases. Using ECT depends on patient-related factors: it clearly is the treatment of choice for depression with psychomotor slowing, stupor, psychotic symptoms, or depression requiring rapid response because of suicidal risk or malnutrition. Use of ECT should be considered whenever therapeutic management is being reviewed and revised.

Triiodothyronine (T₃) augmentation

Thyroid hormone potentiation of tricyclic antidepressants (TCAs) can be useful. The thyrotropin-releasing hormone stimulation test should be done first, if available and convenient, to rule out grade three (subclinical) hypo thy roidism. If hypo thy roidism is present, it should be treated with thyroid replacement therapy. If the patient is euthyroid, low doses of T₃ (25 to 50 µg/d) can be given with the antidepressant for 10 to 14 days. Up to a third of depressed patients, particularly women, respond. Most experience with this approach has involved tricyclic antidepressants (TCAs), and the effect on the selective serotonin reuptake inhibitors (SSRIs) or other new agents is not well studied.

Tricyclic-fluoxetine combination

Some reports indicate that fluoxetine, when added to a TCA such as desipramine, can produce a robust and rapid response in many patients. This augmentation effect could be a result of increased TCA levels due to fluoxetine inhibition of the cytochrome P 450 system. Because fluoxetine can raise blood levels of tricyclic antidepressants (TCAs), routine serum levels of TCAs are recommended. Other TCA-SSRI combinations can also be tried. All selective serotonin reuptake inhibitors (SSRIs), however, effect the cytochrome P 450 System by raising TCA levels.

Tricyclic-MAOI combination

Some evidence suggests that this combination is more effective than either drug used alone for some patients. Ideally both drugs should be started simultaneously or the MAOI added to a TCA regimen. The safest combination seems to be phenelzine with either amitriptyline or doxepin. Clomipramine, imipramine, and the new agents, such as fluoxetine, should be avoided. Give low doses initially and pay rigid attention to dietary restrictions.

The SSRI combinations

Although no literature supports the practice, clinical experience suggests that lower doses of two selective serotonin reuptake inhibitors (SSRIs) together might work better than either alone.

Augmentation with L-tryptophan

L-tryptophan is the dietary precursor of brain serotonin. Reports confirm that L-tryptophan can enhance the antidepressant effect of monoamine oxidase inhibitors (MAOIs) as well as tricyclic antidepressants (TCAs) and lithium. This might apply to the new antidepressant agents as well. The high doses required (more than 3 to 4 g/d) make this approach cumbersome because the tablets are quite large.

Psychostimulants

Dextroamphetamine, methylphenidate, and to a lesser degree magnesium pemoline all have mood-elevating, psychoenergizing properties and have a place in the management of mood disorders. These drugs can be used alone or combined with antidepressants. Apathetic, elderly, and medically ill depressed patients often respond to psychostimulants when they cannot tolerate the side effects of antidepressants or a rapid response is necessary.

Psychostimulants are also useful for patients who do not respond to any antidepressant and are truly treatment resistant. Non-response to one psychostimulant does not predict non-response to another. There is no evidence of addiction or dose escalation although clearly this class of drugs needs to be prescribed cautiously and monitored carefully. Using psychostimulants is somewhat similar to prescribing analgesics for chronic pain conditions and can be justified considering the morbidity associated with major depression.

Cognitive behavioural therapy (CBT)

This therapy can be very useful for treating chronic depression, such as dysthymia, and can be helpful as an augmentation strategy in conjunction with pharmacotherapy for treatment-resistant patients. Several studies have demonstrated the effectiveness of CBT, a technique that family physicians can easily learn.

If lithium augmentation is ineffective, it should be discontinued and the antidepressant changed (Table 5). A lack of response to one of the newer agents in a class, such as the selective serotonin reuptake inhibitors (SSRIs), does not predict lack of response to others in that class. If the first drug used was a reversible inhibitors of monoamine oxidase A (RIMA) with only one drug in the class, the switch should be to an SSRI. If the original drug was an SSRI, a second SSRI, a RIMA, or other newer agents should be tried. If a TCA or MAOI was used first, the switch should also be to one of the new classes of antidepressants.

The tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) should be kept as third-line antidepressants. Evidence shows that response to an SSRI does not determine response to a TCA. One study has shown that 60.5% of patients who failed to respond to SSRI monotherapy responded when switched to a noradrenergic TCA. Most tricyclic antidepressants (TCAs) have both serotonergic and noradrenergic properties. Desipramine and nortriptyline are somewhat more noradrenergic than the others. Venlafaxine, a new selective serotonin and noradrenaline reuptake inhibitor (SSNRI) might also be considered.

If atypical symptoms, such as panic attacks or anxiety, are present, an MAOI or reversible inhibitors of monoamine oxidase A (RIMA) should be considered after a suitable washout period for the previously used antidepressant (10 to 14 days for most antidepressants; up to 5 weeks for fluoxetine because of an active metabolite).

If the second antidepressant is not effective, lithium augmentation should be tried once more before the antidepressant is changed again.

Strategies before changing antidepressants

Higher dose

For the new antidepressant compounds, most manufacturers recommend standard doses. If side effects are minimal, doses usually can be increased and tolerated well. Increasing the dose should be tried before adding other antidepressants or switching drugs.

Lithium augmentation

For patients who have failed to respond to an adequate course of an antidepressant, lithium augmentation is the most reasonable next step (Table 4 summarizes augmentation strategies). About 30% to 50% of patients respond to this technique, and it seems to work with all of the antidepressants (although less is known about how it works with the newer agents). Lithium, an antidepressant and mood stabilizer when used alone, appears to augment other drugs by enhancing postsynaptic receptor sensitivity.

To use this technique, the antidepressant should be continued at the current dose and lithium started at a dose of 300 mg three times a day. A positive response can occur in 5 to 12 days. If the response is positive, patients should continue to receive lithium for at least 6 months and in some cases for the duration of antidepressant therapy. Lithium levels should be monitored and kept within the therapeutic range of 0.6 to 1.0 mmol/L, and thyroid status should be closely followed.

Many physical diseases present with depressive symptoms or complicate depressive illness (Table 2). Some of these illnesses remain undetected for years and account for an apparent treatment-resistant depression (TRD). Normal thyroid function is particularly important; even mild or subclinical hypothyroidism can impair response to antidepressants. Hypothyroidism can be induced by lithium therapy, and many drugs, both medical and nonmedical, can cause depression or complicate treatment (Table 3).

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Are there underlying psychosocial factors?

Psychological and social factors, such as unresolved neurotic conflicts, a history of sexual abuse, current marital or work conflicts, unemployment, and poverty, can exacerbate mood disorders. Psychotherapy must be part of the treatment plan.

Is the current course of treatment adequate?

The most frequent reason for patients not responding to treatment is inadequate use of antidepressants. Surveys have shown that two thirds of correctly diagnosed patients do not receive adequate treatment, even under specialist care. Inadequate dose is the most common reason for treatment failure. One third of patients do not respond to the first course of antidepressants; this proportion decreases with use of consecutive antidepressant trials.

The dose and duration of an antidepressant drug trial must be adequate. For most antidepressants, this means the maximum recommended daily dose for at least 3 to 5 weeks. Unpleasant side effects sometimes lead to noncompliance, and serum levels are sometimes subtherapeutic despite what seems to be an adequate dose. Other factors, such as alcohol or drug use or abuse, might affect serum levels.

If the antidepressant is a tricyclic (TCA), determining serum levels could be important for management; tests are readily available at most centres. Nortriptyline has a therapeutic range of 50 to 140 ng/mL (178 to 499 nmol/L). Other tricyclic antidepressants (TCAs) have a less precise range (about 150 to 200 ng/mL or 535 to 1070 nmol/L). Establishing serum levels can help to ensure compliance; ensure adequate absorption; and assist in dose adjustment for special groups such as the elderly or medically ill, when severe or unusual side effects are present or during apparent treatment failure. Serum levels unfortunately have not been established for other classes of antidepressants.

The most common causes of noncompliance are disabling or unpleasant side effects, particularly those that cause sexual dysfunction. Most side effects are transient; if persistent, they usually can be easily managed.

Many patients are reluctant to take antidepressants. They sometimes feel they are relying on a pharmacologic “crutch,” or that they are unworthy of receiving help. They fear addiction, worry about side effects, or could have delusional beliefs about being poisoned.

Inadequate response to therapy can be iatrogenic. Lack of understanding of the biologic basis of depression, failure to educate patients and families, failure to conduct adequate treatment trials, or reluctance to prescribe the newer antidepressants, monoamine oxidase inhibitors (MAOIs), or electroconvulsive therapy (ECT) are factors.

Treatment for anxiety disorders often involves a combination of pharmacologic and psychological approaches. Nonpharmacologic interventions and therapies are essential at some point of treatment, and pharmacists need to be familiar with these approaches. Once an accurate diagnosis of the anxiety disorder is made by physical and/or laboratory assessment, any drugs or substances that the patient may be taking that exacerbates the anxiety disorder need to be identified and stopped. Treatment should start with bibliotherapy–essentially giving large doses of information about the nature, etiology, presentation, and treatment of the anxiety disorder. (See TABLE 5.)

This patient education should be followed by effective pharmacologic treatment to stop the panic attacks and to help with anticipatory anxiety around having another panic attack or anxiety symptoms. Once the actual physical anxiety events are eliminated, a wide variety of cognitive, behavioral and supportive psychotherapies are available to help reshape the behavioral effects of the disorder. This will allow patients to make changes in their lives and resume the social, occupational, and day-to-day activities that have been impaired by the anxiety disorder.

Attitudes and behaviors on both the patients’ and practitioners’ behalf contribute to the patient’s reticence in seeking treatment. Patients may think, “Am I the only person who has this problem?” or, “I should be able to get over this on my own.” or, “What do I have to be anxious about?” Practitioners and their staff may trivialize the illness or concur with the patient’s doubts over, “What do you have to be anxious about?” Practitioners may offer ineffective recommendations, such as, “Just relax”, or, “There’s nothing to worry about.” or, “Go for a walk… take the day off.” These recommendations, coupled with past ineffective pharmacological treatments, may prevent many patients from seeking treatment for a condition in which both the patient and practitioner have concern that the condition actually exists. Patients who experience cardiovascular symptoms may seek treatment in the emergency department for a wide range of catastrophic fears, from that of having a “heart attack” to a “stroke,” only to be told, “There is nothing wrong with you. You are perfectly healthy!” The objective signs of anxiety are often transient, and there is a wide overlap with other possible disorders. Coupled with a lack of sophisticated technology to detect a panic attack, both patients and practitioners may have persistent doubt as to the validity of a panic attack.

Patients may feel embarrassed when describing symptoms or be at a loss to adequately describe them and feel inadequate for not having a better description. They may fear that others will judge them harshly. Alternatively, they may judge themselves harshly, with thoughts such as: “Nothing can be done,” “There’s nothing wrong,” “I think I’m going crazy,” “People will think I’m crazy,” or, “I will be committed to a mental institution.”

When anxiety disorders, especially panic disorder, remain untreated or are inadequately treated, one can expect patients to contribute to high medical utilization with subsequent increase in costs, time, and procedures, and a decrease in available services to others.

A large number of patients with an anxiety disorder never seek treatment. These reasons will be discussed in depth in the next section. Those who do seek help often turn to practitioners in acute care clinics or emergency departments. As many as 28% to 57% of patients with panic attacks will seek treatment in the emergency room of a hospital. This is the most logical place for the patient to go, since a panic attack is usually experienced as “life-threatening” to the patient. Patients seldom seek initial treatment from psychiatrists, even though psychiatrists are often the best informed and educated to deliver effective treatment.

Because so many patients seek treatment from their primary care providers, there has been an increased effort to train these practitioners to recognize and treat the most common anxiety disorders. Primary care settings in which patients may seek treatment include family medicine, obstetrics-gynecology, and dermatology. Often, patients may seek treatment from specialists based on the primary organ system that is affected; patients tend to focus on one symptom above the others and seek out specialists to treat that problem.