Question. I was diagnosed with major depression and have taken several antidepressants that do not work. I have been taking Prozac for about a month and am experiencing a severe decrease in sex drive. I was informed that cyproheptadine, yohimbine, or bethanachol can help, but I can find no information about these medications. Can you tell me about their cost, method of action, side effects, dosage and success rate?

Answer. There are, to my knowledge, few controlled studies of these agents for the treatment of psychotropic-induced sexual dysfunction; mainly, we are dependent on small uncontrolled case reports. Thus, it is hard to speak of “success rates” in any meaningful way. A good reference is the paper by FM Jacobsen, ( J Clin Psychiatry 1992; 53:119-122), discussing the use of yohimbine for Prozac-induced sexual dysfunction. Jacobsen, in a noncontrolled study, found that up to 90% of patients improved. Yohimbine boosts levels of norepinephrine, a chemical needed for normal sexual function (as well as normal mood). It is usually well-tolerated, but can occasionally cause nausea, anxiety, insomnia, or urinary frequency.

Cyproheptadine is a medication that interferes with the chemical serotonin- which is precisely the chemical that Prozac boosts. Thus, while cyproheptadine can counteract Prozac-induced sexual side effects, it can also “undermine” the antidepressant effect of the Prozac (or similar antidepressants). Bethanechol boosts yet another chemical called acetylcholine (as you can tell, sexual function involves a delicate balance of several chemicals), and is sometimes helpful in sexual dysfunction – though not spectacularly so, in my experience.

Other options include adding either a small amount of bupropion (Wellbutrin, another antidepressant) or buspirone (BuSpar) to the Prozac; both of these agents are usually well-tolerated, and may help counteract the Prozac’s sexual side effects. Another option, of course, is to switch to an agent (such as Wellbutrin or Serzone) that is less likely to cause sexual problems in the first place – but these are all options that should be discussed thoroughly with your doctor. As far as costs go, I suggest you check with a couple of pharmacies in your area, since prices can vary considerably.

Question. After I had a baby, I was diagnosed with postpartum depression and later postpartum psychosis. I tried many antidepressants and was also put on lithium after a manic phase. I also tried hormone replacement therapy, but nothing worked for me. ECT has been suggested several times, but I am very scared of this form of treatment. Is it possible to have postpartum depression that later develops into bipolar disorder, or was I bipolar all along? Will I have this for the rest if my life? Will my daughter be susceptible to bipolar disorder? Are there any other drugs that would be effective that don’t cause weight gain? What are your thoughts on ECT?

Answer. You have certainly had a very difficult course of illness, despite many reasonable treatment approaches. Postpartum psychosis is strongly correlated with the prior or subsequent appearance of bipolar disorder, and may be essentially a stress-induced manifestation of bipolar disorder. The stress being both the hormonal changes associated with birth (e.g., a massive drop in estrogen levels) and the pressures of motherhood. In that sense, it is likely that you were bipolar all along, though one can never prove that.

While estrogens may have an antidepressant effect, progesterone is sometimes associated with worsening of depression. Thus, I would reconsider use of Provera on a regular basis. Bipolar disorder is not curable, but it is treatable, notwithstanding the difficulties you have experienced, despite many medication trials. No one can say confidently that you will suffer from bipolar disorder for the rest of your life, but statistically, the odds are probably greater than 90% that a patient who has suffered one manic episode will eventually suffer another.

The depressed phases of bipolar illness also tend to recur. For these reasons, patients with bipolar disorder almost always require life-long treatment with mood stabilizers. The good news is that new and promising treatments are being developed, and it sounds as if several potentially helpful approaches have not yet been tried in your case.

As to your daughter, and the issue of hereditary factors in bipolar disorder: no one can confidently predict that your daughter will, or will not, develop a bipolar disorder. It is fair to say that, if you have it, your daughter has a substantially higher susceptibility to bipolar disorder than the average individual. Bipolar disorder is not like blond hair or blue eyes, it is not inherited in a predictable fashion that can be deduced from, say, the color of the parents’ eyes. Even between identical twins, the concordance rate (chances that both will suffer from the disorder) is about 60%. If it were solely a matter of genes, the concordance rate would be 100%. Apparently, other factors must come into play. As a rough generalization, if a child has one bipolar parent, the risk is about 25% that the child will develop the disorder and with two bipolar parents, the risk is about 60%.

Now, as to treatments, first let me say that most psychotropic medications are capable of causing weight gain of varying degrees. This is certainly true of valproate (Epilim, Depakote), Tegretol, chlorpromazine (Largactil, Thorazine) and many others. There are several medications that might be useful in rapidly-cycling bipolar disorder, and it would be worth discussing these with your doctors. First, though, I would make sure that your thyroid functions have been carefully checked. Rapid-cycling is associated with low thyroid function, and this is best detected by looking at a chemical called TSH. If this is even slightly elevated, it may signify early hypothyroidism, which can exacerbate mood swings.

Regardless of whether your thyroid function is normal or not, thyroid hormone (thyroxine, T4) may be useful as a mood stabilizer in combination with lithium and/or valproate. Other anticonvulsant mood stabilizers, such as gabapentin or lamotrigine, may also be useful, though the data are very preliminary on these agents. All antidepressants run the risk of worsening rapid cycling bipolar illness, and are generally best avoided if possible. However, if one must use an antidepressant, there is modest evidence that bupropion (Wellbutrin) is less likely to promote cycling than other agents.

Special antidepressants called MAOIs are also sometimes useful, but still present a risk in terms of cycling. The use of risperidone (Risperdal) or clozapine (Clozaril) is sometimes helpful in bipolar disorder refractory to standard treatments. In the case of Risperdal, this should be in combination with a mood stabilizer. Of the agents I’ve discussed so far, thyroid hormone and bupropion would not be likely to promote weight gain. I would seriously consider ECT (electroconvulsive therapy) as well. It is both a safe and effective treatment for both the depressed and manic phases of bipolar disorder, and may be continued on an outpatient, maintenance basis (e.g., once monthly). While ECT can cause minor degrees of memory impairment, it does not cause brain damage.

Some patients will report loss of memories for events immediately before and after the treatments, but people do not lose important personal memories or become unable to learn new information, once a few weeks have passed after treatment. I do wish you well with whatever course you choose.

The Treatment of Anxiety Disorders: Clinician’s Guide and Patient Treatment Manuals

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.

Drug Use In Assisted Suicide And Euthanasia

Editors: Margaret P. Battin, Arthur G. Lipman
Pharmaceutical Products Press, 10 Alice St, Binghamton, NY 13904-1580 USA
1996/360 pp

Balanced discussion of a controversial topic

Overall Rating

Very good

Strengths

Balanced discussion of ethical, personal, legal, and pharmaceutical aspects of assisted suicide and euthanasia

Audience

All those (potentially) involved in decision making regarding assisted suicide and euthanasia

It is generally assumed that death by assisted suicide or euthanasia is to be caused by lethal doses of drugs, not guns or other violent means. This book addresses issues about the use of drugs in actively bringing about death. However, it offers much more than the title and the purpose suggest.

Many chapters, some written by opponents of assisted suicide and euthanasia and others by advocates of these practices, offer excellent discussions of multiple aspects of assisted suicide and euthanasia, creating deep awareness of the complex issues involved. The perspective of pharmacists, which has often been overlooked, provides insightful information about pharmacists’ attitudes about the use of drugs intended to end the lives of terminally ill patients. Concrete and specific information about the actual practice of drug use in assisted suicide and euthanasia is included.

An important message that is conveyed throughout the book is that, whether we favour or oppose these practices, we cannot deny that they happen. One of the papers demonstrates that self-enacted and assisted death is more common than previously suspected and provides a moving account of what happens when drugs fail.

Palliative care and pain control, which are often suggested as alternatives to assisted suicide and euthanasia, receive ample attention. However, as some papers suggest, it is not always the experience of pain but unbearable suffering that leads terminally ill patients to ask for termination of their lives.

A particularly important issue for physicians is the attention paid to patient-physician communication and the need for long-range planning with patients and families regarding pain control and symptom management.

The final section of the book contains many position statements of various organizations in the United States, followed by a series of brief clinical vignettes and commentaries. These provide a basis for readers to analyze their personal positions on active life-ending acts.

Everyone interested in end-of-life decision making is likely to find something valuable in this book.

Prophylaxis

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.

Less common approaches.

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.

Common strategies for treatment resistance.

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.

Major depression is best managed through a treatment algorithm. The more resistant to treatment a patient’s illness is, the further treatment proceeds through the steps. As each trial of therapy is deemed ineffective, diagnosis should be reviewed and physical and psychosocial factors reassessed before making a decision about the next step. Psychotherapy is an essential accompaniment to any form of somatic treatment. Supportive psychotherapy offers reassurance and time for patients to talk about their pain and also provides support and education. Destructive lifestyles, guilt, low self-esteem, and anger are some of the issues that might need to be addressed. Some patients need to be referred for formal psychotherapy.

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.

Are there underlying physical factors?

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.