In most surveys, the number of patients with absolute treatment resistance is very small. In some specialized tertiary referral clinics, only about 7% of patients remain depressed after 1 year of extensive investigations and treatment. However, extensive treatment involves many drug trials, singly and in combination, as well as ECT. Typically, people with absolute treatment resistance are older (mean age about 55), have been depressed for a longer period of time, and have insoluble life problems. Some help can be offered, even to this group of patients. Carefully prescribed, psychostimulants can help to decrease depression and increase energy. In this context, psychostimulants can be seen as psychic painkillers and their use can be compared with that of analgesics in other chronic pain syndromes.

Supportive and cognitive psychotherapy can also be of benefit. Supportive psychotherapy allows depressed patients to carry on in the face of a handicap; cognitive psychotherapy allows some patients to view the world differently, and this can lead to positive thinking and beneficial lifestyle changes, such as regular exercise, cessation of smoking, and reduction of alcohol consumption. Jogging has been reported to have an antidepressant effect.

Conclusion

Treatment-resistant depression is a relative term. All patients can at some point be considered relatively resistant to therapy, depending on how far the physician is willing to go in the patient’s treatment. The appropriate use of tricyclic or heterocyclic antidepressants or MAOIs can relieve the symptoms of at least two thirds of patients. Drug combinations, ECT, or augmentation strategies can, if vigorously applied, reduce the percentage of patients who are truly treatment resistant to about 7%. Considering the morbidity and mortality associated with depression, a vigorous approach to therapy is worthwhile.

Résumé

(French Language)

De nombreux facteurs peuvent influencer le résultat du traitement de la dépression, un problème de santé communautaire important et qui comporte un taux significatif de mortalité et de morbidité. Les deux tiers des patients répondront bien aux antidépresseurs. Les autres seront traités par d’autres moyens. Seuls 7% des patients seront absolument résistants au traitement, mais il est tout de même possible de leur venir en aide.

Introduction

Manic depression, also called bipolar disorder, afflicts some 4 million Americans. Characterized by severe mood swings between incredible elation and deep depression, the disorder has been difficult to treat. Many patients either do not respond to drug therapy or stop taking their medication because of unwanted side effects.

Now a new drug has entered the arena: Zyprexa (olanzapine), manufactured by Eli Lilly. Zyprexa had already been approved for the treatment of schizophrenia, and recently got the green light from the FDA for use in patients with manic depression.

Clinical Study Results

Studies evaluating the effectiveness of the drug in patients with acute mania showed that those who took Zyprexa (olanzapine) achieved a significantly greater improvement in their symptoms than patients who received a placebo. Other studies have shown that Zyprexa is as effective as lithium, another agent commonly used to treat manic depression.

What You Should Know

Like other drugs in its class, Zyprexa does have side effects, including dry mouth and weight gain. Drowsiness and dizziness have also been associated with Zyprexa, so patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that they will not experience these effects. Because there are other potential side effects, patients with manic depression who are interested in Zyprexa (olanzapine) should consult their physicians.

Zyprexa

Introduction

Bipolar disorder is a lifelong psychiatric disorder that features mood swings between mania and depression, and afflicts some 4 million Americans. Although lithium, valproate, carbamazepine, and antipsychotics have been prescribed to treat the disorder, many patients do not respond to these treatments or stop taking them due to unwanted side effects. Now there is another drug available for these patients: Eli Lilly received FDA approval to market Zyprexa (olanzapine) – a drug originally approved for schizophrenia – for the treatment of manic depression.

How It Works

Zyprexa is an antipsychotic drug. Although the exact mechanism of action is unknown, it is proposed that the drug’s activity is mediated through a combination of dopamine and serotonin type 2 (5-HT2) antagonism, as well as antagonism at other receptors with similar affinities.

Zyprexa (olanzapine): Clinical Study Results

A randomized, double-blind, placebo-controlled study was conducted over a 3-week period in patients with acute mania. Clinical response was compared between 70 patients who received 10 mg Zyprexa once daily and 69 patients who received placebo. After the first day of treatment, the Zyprexa dose was adjusted upward or downward, as clinically indicated, by one capsule, within the permitted range of one to four capsules. Clinical response was defined as a decrease of 50% or more in the Young Mania Rating Scale total score, from baseline to endpoint. At the end of the study period, significantly more patients taking Zyprexa (48.6%) showed clinical improvement than those taking placebo (24.2%). Although somnolence, dry mouth, dizziness and weight gain occurred more often with Zyprexa than with placebo, no patients discontinued treatment due to these side effects.

What the Patient Should Know

As with other antipsychotic drugs, Zyprexa (olanzapine) is associated with several side effects. Since orthostatic hypotension has been reported with Zyprexa, patients who experience this effect should be advised to avoid standing up too quickly. Because somnolence and dizziness have been associated with Zyprexa, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that they will not experience these effects. Patients should not breast-feed during Zyprexa treatment and should inform their physicians if they become pregnant while on the treatment. They should also avoid alcohol and tell their physicians if they are taking other medications, since Zyprexa may interact with other drugs (for example, it may potentiate the effect of antihypertensive drugs and antagonize those of levodopa and dopamine agonists). Since Zyprexa may elevate transaminase levels, it should be used with caution in patients with hepatic impairment. Patients with a history of seizures should tell their physicians, since Zyprexa may increase the risk of seizures. Other side effects associated with Zyprexa (olanzapine) include restlessness, constipation, dry mouth, and weight gain.

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.

Problem of the Young

It is not so universally recognized that sleep disorders also affect the young. Although there are few large-scale epidemiologic studies of daytime sleepiness in adolescents and young adults, existing data suggest that problem sleepiness affects a significant percentage of youths. About 25% of American children aged 1–5 experience some kind of sleep disturbance. From 20%–25% of 9th through 12th grade students reportedly experience behaviors associated with problem sleepiness, such as difficulty getting up for school, falling asleep in school, or struggling to stay awake while doing homework. According to one report, 54%–75% of adolescents and young adults expressed “a wish for more sleep” because they were experiencing morning tiredness. In a survey of high school students, it was found that many students got less than 6.5 hours of sleep on school nights; only 15% reported sleeping 8.5 hours or more.

Together, these data indicate a widespread pattern in childhood of inadequate sleep and consequent problem sleepiness. The chart lists some of the more common problems associated with poor sleep patterns.

Physician Visits

Sleep problems in children 16 years old or younger are severe enough to trigger many visits to physicians by anxious parents. The most widely prescribed drugs for sleep disorders are psychotherapeutics, sedatives, and antihistamines. Drugs regularly prescribed include diphenhydra-mine, chloral hydrate and Imipramine (sold as Antideprin, Deprimin, Deprinol, Depsonil, Dynaprin, Eupramin, Imipramil, Irmin, Janimine, Melipramin, Surplix, Tofranil).

Answer. I am not aware of any controlled, persuasive evidence that Thorazine (chlorpromazine) or any standard antipsychotic – in low doses or high – is particularly effective as an antidepressant. The exception to this claim may be in so-called delusional depression, in which psychotic features are present; antipsychotics such as Thorazine may be somewhat effective for the agitation and delusional thinking in this condition, but probably not for the core depressive features, such as lack of pleasure, lack of energy, and slowing of mental functions. On the other hand, depression is often encountered as a side effect of standard antipsychotics (neuroleptics).

Having said all this, I would hasten to add that new, atypical antipsychotics, such as risperidone and clozapine, do, indeed, seem to have antidepressant properties. However, the standard treatment of depression remains the antidepressants.

Vestra: Introduction

As a selective norepinephrine reuptake inhibitor (SNRI), Vestra is the first of a new class of antidepressant drugs. This new mechanism of action appears to produce fewer side effects, such as nausea, headache, and sexual dysfunction, compared with traditional antidepressants. Vestra also possesses a faster onset of action compared to selective serotonin reuptake inhibitors (SSRI), tricyclics, and monoamine oxidase inhibitors, commonly used to treat depression.

Vestra: How It Works

A lack of norepinephrine in the central nervous system (CNS) of depressed individuals is hypothesized to be responsible for several specific symptoms of depression, such as lack of energy, interest, and motivation. Vestra inhibits the reuptake of norepinephrine by the presynaptic nerve terminals. As a result, the neurotransmitter remains in the synapse for a longer period of time.

Vestra: Clinical Study Results

Several clinical studies were conducted to determine the safety, efficacy, and tolerability of Vestra. One study involved 283 patients with recurrent DSM-III-R major depression. These patients were randomized to receive either Vestra or placebo for 46 weeks in a double-blind phase. Vestra was associated with a significantly lower relapse rate than placebo (22% vs. 56%; p < 0.001), as well as a greater cumulative probability of maintained response (p = 0.0001) during long-term treatment. The proportion of relapse- free patients who remained in the study was significantly higher in the Vestra group than in the placebo group at the end of the first six months (61% vs. 40%) and the second six months (88% vs. 59%) of treatment.

A double-blind, randomized, parallel-group, multicenter trial, including 168 patients with acute major depressive episodes, was conducted to compare Vestra to fluoxetine, an SSRI. The patients were administered either Vestra 8-10 mg/day or oral fluoxetine 20-40 mg/day for 8 weeks. Both treatments were found to be similarly effective as assessed by the mean reduction in total Hamilton Depression Rating Score, percentage of responders and patients in remission, Clinical Global Impression severity of illness and global improvement scores, and the Montgomery-Asberg Depression Rating Scale. A sub-analysis of patients with severe depression showed Vestra to have superior efficacy compared to fluoxetine. Both treatments resulted in improvement in Social Adaption Self-evaluation Scale total scores; however, the improvement was more evident in patients who received Vestra and achieved remission.

Vestra: What the Patient Should Know

Although clinical trials have shown a reduced risk for nausea, diarrhea, and somnolence with Vestra compared with fluoxetine, the patient should be aware that an increase in risk for dry mouth, constipation, hypotension, paresthesia, urinary hesitancy, and flushing was observed with Vestra in the trials.

Answer. I can understand how the stigma of your depression might be a source of distress to you, even though we now have a number of excellent role models of successful mental health professionals who suffer from mood disorders. An excellent example is Dr. Kay Redfield Jamison, author of An Unquiet Mind; Jamison herself suffers from bipolar disorder, and has confronted this publicly and in her writing.

Regarding rates of relapse or recurrence of major depression: the bad news is, major depression tends to be a recurrent illness. As a group, about 55% of individuals with a single episode of major depression will go on to have a second episode. Individuals who have had two episodes have a 70% chance of having a third. The good news is that with appropriate medication and psychotherapy, the outlook is quite favorable. Frank et al (Arch Gen Psychiatry, Dec. 1990) found that when patients with recurrent depression were treated with imipramine 200 mg per day in combination with interpersonal therapy, nearly 80% went for three years without a recurrence of major depression. This has generally been my clinical experience with patients who initially do well on various antidepressants (including Wellbutrin) and are maintained in appropriate psychotherapy.

I am not aware of any studies that have actually determined rates of major depression among mental health professionals. However, there are several studies of professional “burnout” that you may be interested in. Clark et al (Hospital & Community Psychiatry, August 1987) looked at burnout among psychiatrists in community mental health centers and found that 46 of 96 expressed dissatisfaction with their work. Another study of burnout found that among the psychiatric staff of a large HMO, “high emotional exhaustion and depersonalization” were found, based on the Maslach Burnout Inventory (Snibbe et al, Psychol Rep, 1989; 65:775-80). You may also be interested in the article by Cushway & Tyler on “stress in clinical psychologists” (Int J Soc Psychiatry, Summer 1996).

Regarding signs to watch for, this could become a problem if it begins to preoccupy you. Hypervigilance usually creates its own problems, in my experience. Symptoms I am sure you are familiar with-sleep disturbance, loss of appetite, reduced energy, etc. – would be of concern, of course. If it is of any consolation, I have personally known or treated a number of mental health professionals with major depression, and you are far from alone in this respect. Your professional practice organization might have more information and/or referrals for support. Good luck!

Answer. The short, no-frills answer to your question is that any of the major antidepressants or anxiolytics are probably safe, now that the most vulnerable period of organ-formation (the first trimester) has passed. I see no reason why Zoloft and/or Klonopin could not be restarted, if the clinical situation is severe enough to warrant the modest risks. An OB/GYN consult is always a reasonable precaution, but I would not necessarily be governed by it, if you believe your patient must be on a medication. If you care to read on, here is the more complicated story:

With respect to antidepressants (ADs) in pregnancy, most data come from studies of tricyclics and fluoxetine(Prozac); we have only a modicum of information about newer agents such as sertraline (Zoloft), paroxetine (Paxil), venlafaxine (Effexor) and nefazodone (Serzone). The tricyclics (e.g., desipramine (Norpramin), imipramine (Tofranil), nortriptyline (Pamelor)) appear to have little potential for teratogenicity. Similarly, a recent study by Pastuszak and colleagues (1993) found no evidence of teratogenicity in 128 women taking fluoxetine during the first trimester, when compared to matched controls. While there was a trend toward higher miscarriage rates in the fluoxetine group compared to controls taking known non-teratogens, the risk was small (relative risk, 1.9) and comparable to that of tricyclics. (Interestingly, depression itself may also raise the risk of miscarriage). A recent study by Chambers et al. (New England Journal of Medicine 1996, vol. 335, pp. 1010-1015) found no significant differences between fluoxetine-treated pregnant women and controls in spontaneous pregnancy loss or major structural anomalies; however, the incidence of three or more minor anomalies was significantly higher in the fluoxetine cohort.

This study has been widely criticized, however, on a number of methodologic grounds. The more anticholinergic tricyclics (e.g., amitriptyline, doxepin) can occasionally induce fetal tachyarrythmias, urinary retention or intestinal obstruction. Clomipramine (Anafranil), a tricyclic used mainly in the treatment of obsessive-compulsive disorder, also has substantial anticholinergic effects, and would be expected to produce similar effects in the neonate. Wisner et al (1993) found that the doses of tricyclic antidepressant required to achieve remission actually increased during the second half of pregnancy, reaching 1.6 times the mean dose required when the patients were not pregnant. This was attributed, in part, to enhanced hepatic metabolism of antidepressants during pregnancy and to increased volume of distribution. Neonatal irritability, tachypnea, tremor and hypotonia may result from either tricyclic toxicity or withdrawal. It is therefore prudent to monitor maternal blood levels of tricyclics throughout pregnancy and gradually to reduce the dosage during the week before delivery.

Little is known about the excretion of antidepressants into breast milk or the effects of this on the nursing infant. Some studies indicate that several antidepressants or their metabolites can accumulate in breast milk, possibly peaking at about 4-6 hours after an oral dose. (See the review by Wisner et al. in the September 1996 issue of the American Journal of Psychiatry). It is not clear to what extent antidepressants accumulate in the blood of the nursing infant or whether significant adverse effects result from such accumulation. Wisner et al. (1996) conclude that sertraline is a good choice, with respect to breast-feeding. However, many clinicians feel that breast-feeding is best avoided when the mother is taking antidepressants postpartum.

Miller (1994) concluded that the tricyclics of choice during pregnancy are desipramine and nortriptyline, due to the comparative wealth of data about them, the ability to monitor serum levels and a favorable side effect profile. Alternatively, fluoxetine (Prozac) may be a reasonable choice for the pregnant patient with major depression, in light of the data from Pastuszak et al. Finally, the clinician should keep in mind that ECT appears to be a safe and effective alternative for the pregnant patient with severe depression.

With respect to benzodiazepines (BZDs): In the 70s and 80s, diazepam (Valium) was found to be associated with cleft lip and palate in the fetus and other benzodiazepines were suspected of this association. More recently, one Swedish group has linked maternal use of benzodiazepines during pregnancy with both impaired intrauterine growth and various dysmorphic birth defects. A recent review concluded that the available data indicate a positive association between first-trimester in utero exposure to benzodiazepines and a specific anomaly oral cleft.

Diazepam may double the risk of oral cleft, while alprazolam may increase the risk by more than 11-fold. However, most available data suggest that BZDs do not markedly increase the absolute risk of cleft palate or other congenital abnormalities in exposed fetuses. Thus, the baseline risk of cleft palate is about 6 in 10,000. With alprazolam exposure during the first trimester, the risk may rise to 7 in 1000, still less than 1%. The teratogenicity of lorazepam (Ativan) is less clear. Clonazepam (Klonopin) has not been evaluated for teratogenesis in controlled studies of human subjects; however, based on animal data, clonazepam seems to have low teratogenic potential (Altshuler et al, 1996) . The presence of alcohol and other substance abuse in pregnant women using benzodiazepines complicates interpretation of the data. Infants exposed to BZDs either in the last trimester or at the time of parturition may show muscular hypotonicity, failure to feed, impaired temperature regulation, apnea and low Apgar scores). The data on behavioral teratogenicity and developmental delay are inconclusive.

There is also some evidence that benzodiazepines may increase duration of labor and lead to prolonged withdrawal symptoms in the neonate, when mothers have been maintained on these agents throughout pregnancy. Withdrawal effects may be more likely when high doses of short-acting benzodiazepines have been used. Benzodiazepines should not be stopped suddenly during pregnancy, rather, tapered slowly as delivery approaches. The non-benzodiazepine anxiolytic buspirone (BuSpar) has been shown to increase the number of stillbirths in rats, when given in high doses; however, there are insufficient data in humans to determine the risks of buspirone during pregnancy.

While there is evidence that several benzodiazepines (e.g., diazepam, lorazepam, oxazepam) are excreted into breast milk, the actual levels of BZDs detected in breast milk seem to be fairly low and the consequent risk to the infant, quite small. Lorazepam seems to have minimal accumulation in the fetus and the percentage of the maternal dose of lorazepam to which a nursing infant is exposed is roughly 2.2%. Thus, use of low dose lorazepam in the nursing mother – particularly on a prn, or short-term basis – is probably safe for the infant. The excretion of buspirone into human breast milk has not been adequately studied.

Given the above risks, are benzodiazepines contraindicated during pregnancy? There is no absolute contraindication. Rather, the modest risks of BZD exposure must be weighed against the severity of the patient’s condition; the risks of no medication; and the risks of alternative medications. For example, inadequately treated panic attacks may themselves pose a risk to the fetus. Tricyclic antidepressants, fluoxetine and perhaps other SSRIs, may be reasonable alternatives to benzodiazepines for the treatment of panic disorder during pregnancy . Cognitive-behavioral therapy (CBT) may also be helpful in a variety of anxiety disorders and may reduce the need for psychotropics during pregnancy.

Answer. I am providing you with a list of commonly used antidepressants, as well as their usual doses:

Maintenance Dosage and Tablet Size for Non-MAOI Antidepressants

With respect to non-addictive medications for anxiety, it is first important to realize that the term addiction is defined in many ways. The medications most commonly used in the treatment of anxiety – the benzodiazepines, such as Valium, Librium, Ativan, etc. – are not highly addictive for the vast majority of people who are prescribed them for the right reasons. These agents may be abused or become habit-forming, however, in individuals with a history of alcohol and substance abuse, and, very rarely, in individuals who do not have such problems. The antianxiety agent buspirone (BuSpar) is a good alternative, and is not habit-forming or prone to abuse; however, while buspirone is useful for generalized anxiety, it is not helpful for panic attacks or obsessive-compulsive states.

Sometimes, low doses of the older tricyclic agents, such as doxepin 15-25 mg/day, may be useful for generalized anxiety in patients who are not good candidates for benzodiazepines. If you want more details about available medications for mood and anxiety disorders, you may want to call the NIMH Depression Awareness program.