A thorough history, physical examination, and basic laboratory studies are important to fully evaluate the patient and rule out medical and medication-related causes of insomnia and depression. Additionally, the selection of the appropriate antidepressant medication (selective serotonin reuptake inhibitors, tricyclic antidepressants [TCAs], monoamine oxidase inhibitors, or atypical antidepressants), adequate dosages, and a sufficient trial period are imperative in the treatment of depression in the elderly. In seniors, an adequate antidepressant trial is longer than that for younger adults, with a complete response often seen after six to 12 weeks. Nuances related to medication therapy in the geriatric population should be clearly expressed by pharmacists in recommendations and educational communications. The impact of aging and medical conditions associated with aging on the pharmacokinetic profile of a medication and the increased risk of associated side effects must be understood with regard to geriatric dosage guidelines, disease-drug contraindications (eg, TCAs and cardiac conduction defects), and drug interactions (eg, CYP450 inhibition and possible toxicities).

When sleep medication is deemed the best course of treatment after careful consideration of nonpharmacologic interventions (eg, sleep hygiene, stimulus-control therapy, and sleep-restriction therapy) in the elderly, short-acting nonbenzodiazepine hypnotics (zolpidem or zaleplon) are recommended. These medications reduce both sleep latency, due to their quick absorption and onset, and the risk of daytime sleepiness the following day, due to their short half-life. Caution should be exercised when a longer-acting hypnotic is prescribed in a geriatric patient since associated side effects may be particularly pronounced in seniors. Longer-acting hypnotic agents may be associated with changes in sleep architecture such as a reduction in delta or deep sleep, morning hangover with excessive daytime sleepiness, impaired motor coordination, and visuospatial problems that may contribute to an increased risk of injury. In an attempt to prevent rebound insomnia, a very gradual taper is recommended when termination of treatment is warranted.

Conclusion

When caring for older patients, it is important to make the distinction between pathological changes and normal aging. Remaining cognizant of this helps to avoid not only dismissing a treatable pathology as merely an accompaniment to old age but also treating a natural aging process as a disease while overlooking the possibility of iatrogenic effects.

Insomnia may be a symptom of medical and psychiatric conditions, changes in lifestyle, or medications, among other precipitating factors. When an elderly patient presents with complaints of insomnia, the clinician should assess for possible depression since many seniors do not seek help for or verbally express symptoms of this condition, which is common among them and is associated with morbidity and mortality. By raising awareness that insomnia, a symptom of depression for many people, may be reported more readily than depressive symptoms, pharmacists may become involved in identifying those at risk for depression and in facilitating the appropriate evaluation, intervention, and education of patients and their families and caregivers.

Treatment of a depressive disorder must begin with a comprehensive evaluation of the older person to rule out associated medical or physical conditions that may present as depressive illness or complicate the treatment of depression. A minimum evaluation of the older depressed patient should include a careful physical examination and laboratory studies including a complete blood cell count with differential; electrolyte determination; glucose, blood urea nitrogen, calcium, phosphorous, total protein, and serum albumin levels; liver function tests; and thyroid function tests. An electrocardiogram should be obtained. Current medications, (prescribed, over-the-counter medications, and those medications borrowed from neighbors and friends) should be reviewed.

Psychopharmacologic Treatment

The psychopharmacologic treatment of depressive disorders has advanced. Pharmacologic options now include cyclic antidepressants, monamine oxidase inhibitors, and the newer serotonin reuptake-inhibiting antidepressants. The selection of a specific antidepressant is determined by the older person’s symptoms and the side effect profile of the medication. The presence or absence of sleep problems, significant complaints of decreased energy, and the presence of cognitive difficulties are important considerations in the selection of specific medications.

Additional considerations in the treatment of depression are the presence of associated medical illnesses and medications prescribed for their treatment. The choice of an antidepressant medication in this case will be based on both the side effect profile of the antidepressant and the avoidance of potential drug-drug interactions. Because of the physiologic changes of aging (decreased renal blood flow, decrease in total body water, decrease in total lean body mass, decrease in microsomal enzyme activity, and an increase in total body fat), the doses of antidepressants used in the elderly are usually one third to one half the dose prescribed in younger patients.

The approach to the titration of an antidepressant is based on the caveat of starting with a lower dose and slowly increasing it, monitoring the older person for therapeutic response, and side effects. This approach has been summarized as “starting low and going slow(ly).” In some cases, older patients will require antidepressant doses similar to persons in their 30s and 40s. Obtaining blood levels of antidepressants in nonresponding elderly, depressed patients can be helpful in determining whether to increase the prescribed antidepressant or to move to the addition of lithium carbonate to augment the antidepressant effect of the initial medication. Unless the older person has had a history of successful treatment with a monoamine oxidase inhibitor in the past, monoamine oxidase inhibitors are not the first treatment of choice. As noted earlier, electroconvulsive therapy is the treatment of choice for the delusionally depressed older patient and the cachectic, profoundly withdrawn or actively suicidal elderly patient. Although a large body of literature exists on depressive illness, further studies on the efficacy of psychopharmacologic treatment of depression, particularly in the frail, US, ethnic, minority elderly are indicated.

Psychotherapeutic Treatment

Psychological development continues throughout the life cycle. Chronological age may or may not be comparable to the person’s development age. The physician and poet, William Carlos Williams, described the older patient’s mobilization to “reach for what can be added in later life.” Gould stated that elders in contact with their inner core presented with the inevitable hazards of late life faced these developmental stressors with greater strength and were able to bounce back. Their sense of meaning resided within them and was not an external sense of meaning based on power and status. The maintenance of self-esteem may be adaptively accomplished by the elder. The psychosocial perspective of self-esteem noted that several strategies were used by older persons to defend against the erosion of their self-esteem (Table 4).

The psychotherapeutic treatment of depressive illness in the elderly should be based on the biopsychosocial model conceptualized by Engle. The therapist needs to be sensitive to the intrapsychic processes of the older person and facilitate the patient’s recognition and understanding of these psychological processes. The biological sphere has an increased effect due to the physiologic changes of aging and the associated development of physical illnesses. Clarification of the social network and social supports of the older patient as well as the various social interactions of the patient will enable the therapist to assess the extent to which the older patient is at risk to feelings of isolation or alienation. The redefinition of meaningful activity and the establishment of new goals in the context of retirement from work is an important psychological task. A successful redefinition of roles will establish new directions and goals for the older, retired individual.

Niederehe noted that psychotherapeutic intervention in the elderly was more likely to be based on psychodynamic and socioenvironmental principles. As late-life depression has been associated often with risk factors such as stressful life events, family conflict, and the absence of social resources (family support and relations with confidants), these factors partially influence the specific therapeutic intervention selected. Niederehe also noted that the significant clinical literature that existed on the value of various psychosocial treatments in the elderly were predominantly theoretical articles, description of techniques, and reports of individual treatment cases. He found few articles that met acceptable methodological standards for psychotherapy outcome research and encouraged further work in this area.

Recently published practice guidelines for major depressive disorder in adults by the American Psychiatric Association suggest specific criteria for US psychiatrists and other mental health professionals to use in the selection of a behavioral, psychodynamic, or group psychotherapy approach to the psychotherapeutic treatment of depression. Because of the potential for relapse, the continuation of antidepressant medication beyond a 9-month period of treatment will need to be discussed with the patient in the context of his or her prior history of depressive illness and response to treatment. It is recommended that the full therapeutic dose of medication that produced a therapeutic response should be continued for a minimum of 16 to 20 weeks after remission of symptoms has been achieved.

Although controversial in the US, electroconvulsive therapy is the most effective treatment for major depressive disorder. In 50% of patients nonresponsive to anti-depressants, electroconvulsive therapy has produced a satisfactory response.

Conclusion

This article reviewed the epidemiologic data on the prevalence of major depressive disorders in community resident elderly and compared international prevalence rates of depressive symptoms (4.4% to 12.6%). The prevalence rate for major depressive disorder among US residents aged 55 years and older was reported to range from 0.81 % to 1.9% among community residents and from 12% to 42% among the medically ill elderly.

Specific factors associated with a report of depressive symptoms were identified from the literature: poor physical health due to medical illness; physical disability; single marital status due to being widowed, divorced, or separated; a restricted support networks resulting in social isolation; bereavement; poverty; and education ≤4 years.

The importance of recognizing alternative presentations of depressive disorder in the elderly was emphasized. Three presentations of late-life depression were described: masked depression, pseudodementia, and delusional depression. Four types of depressive illness in the older US residents were reported by the literature: major depressive disorder, dysthymia, depressive symptoms secondary to medical illness that did not met DSM-IV criteria for a depressive disorder, and a mixed depression anxiety syndrome.

Specific concerns for the treatment of depressive disorder with psychopharmacology and psychotherapy were discussed. Antidepressant medications were needed to facilitate the biochemical readjustment of neurotransmitter levels. Psychotherapy facilitated the reactivation of prior effective, psychological coping capacities, and reworked the destructive thought patterns associated with major depressive disorder for a patient with an uncomplicated major depression. The importance of considering the social network and social roles of the elder person was emphasized. The importance of continuing an antidepressant at the full therapeutic dose for a minimum of 16 to 20 weeks after remission of symptoms was emphasized. Finally, the effective role of electroconvulsive therapy in the treatment of late-life depressive disorders was described.

TCA/MAOIs were fortuitously discovered at a time when psychoanalytical and psychological theories of the etiology of depression reigned supreme in North America. The possibility that depressive disorders are ‘brain’ diseases with a pathophysiological basis was viewed with skepticism, and these medicines were largely ignored or improperly used until the late 1960s. By that time, biological theories of depression — based on the acute actions of these drugs — were becoming popular, and a waning of and disillusionment with psychoanalytic theories occurred.

Psychiatric advances have parallelled the dramatic advances in the neurosciences in the last two decades, with increasing evidence that major depressions are clearly medical syndromes with resulting central nervous system chemical/biological dysfunctions for which pharmacotherapy is the treatment of choice. Unfortunately, the public (and many physicians) have lagged a decade or two behind the research, and continue to view antidepressants as the equivalent of tranquilizers, anxiolytics, placebos or something to ‘dull’ the inherent psychological problems. To complicate the field further, in addition to the eight TCAs and three MAOIs marketed in Canada, the 1980s have witnessed the introduction of four new antidepressants with novel chemical structures, and perhaps a dozen new antidepressants will be marketed by 1990.

Definition of Depression

‘Depression’ can be a confusing word for both patients and physicians. It can refer to a mood state (both normal and pathological), a symptom present in many medical and psychiatric syndromes, and the medical syndromal disorder for which antidepressant medicine is indicated. Affective disorder is the newer name (now used by psychiatrists) for depression, which attempts to avoid some of the diagnostic confusion with the word ‘depression’.

Affective disorders are now operationally defined because older diagnostic labels which were based on understanding how and why depressed patients are the way they are (e.g., reactive depression, neurotic depression, involutional depression) have lacked reliability. A mood disturbance in addition to at least four mental or physical symptoms that are present for at least two weeks are necessary to meet criteria for major depressive disorder.

There is a dysphoric mood or loss of interest or pleasure in all or most usual activities or pastimes. The dysphoric mood is characterized by symptoms such as feeling depressed, sad, blue, hopeless, low, ‘down in the dumps’, or irritable. At least four of the following mental or physical symptoms are present consistently for at least two weeks:

• poor appetite or weight loss (when not dieting) or increased appetite or significant weight gain.

• insomnia or hypersomnia.

• psychomotor agitation or retardation.

• loss of interest in usual activities, or decrease in sexual drive.

• loss of energy; fatigue.

• feelings of worthlessness, excessive reproach or inappropriate guilt (may be delusional).

• complaints or evidence of diminished ability to think or concentrate, such as slowed thinking or indecisiveness.

• recurring thoughts of death, wishes to be dead, suicidal thoughts or suicide attempt.

What distinguishes a major depression from an ‘upset’ or ‘normal’ un-happiness related to an unpleasant life change (e.g., bereavement, divorce, loss of job, etc.) is the consistency, persistence, and severity of symptoms. The use of collateral information from a significant other (spouse, parent, close friend) is almost always necessary in order to obtain perspective on whether the patient is different from his normal self — which always occurs in depressive illness.

Antidepressant pharmacotherapy is the treatment of choice for moderately severe affective disorders, with many alternative drugs being available.

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) are the oldest and most commonly prescribed antidepressants. Three decades of research have shown that these medicines are quite effective (two-thirds of all depressed patients who receive an adequate trial of a TCA will have complete remission of depressive symptoms).  An adequate trial is considered the minimum daily drug dose for at least four weeks (see Table 1).

The eight TCAs marketed in Canada differ in their side effect profiles, with amitriptyline and doxepin being more sedative; imipramine, desipramine, and protriptyline being more stimulating; and nortriptyline, trimipramine and clomipramine being intermediate on this continuum. A prudent initial drug choice is based on a theoretical patient/drug fit (e.g., a retarded depressed patient might do best on a more stimulating TCA while an agitated patient might find a more sedating drug preferable). There are clearly individual response differences among the TCAs and if a patient does poorly (either in clinical response or toleration of drug) with a medicine, a switch to a TCA at the other end of the spectrum is appropriate.

Physicians need to be more cognizant of the financial burden to patients of different medicines. As imipramine and amitriptyline are one-half to one-third the cost of the other TCAs (see Table 1) they should be used preferentially.

In terms of cardiotoxicity of the TCAs, the most important concept is that in ‘healthy’ hearts these medicines are quite safe in therapeutic doses.

TCAs have a quinidine-like action on cardiac conduction, and while not necessarily contraindicated they must be carefully monitored in patients with cardiac conduction defects. Recent work has suggested that doxepin is no more cardiotoxic than the other tricyclics. Postural hypotension in the first month of treatment may require careful monitoring in the elderly or frail patient and is probably the most troublesome cardiac side effect of TCAs.

The atropinic complaints of dry mouth, constipation, bloating, and blurry vision occur with depressive illness and TCAs. Determining whether the problem rests with the disease or the cure can be difficult. Encouraging the patient (or perhaps the physician!) to stick with a four-week course of treatment and the nuisance side effects of the medicine often results in dramatic improvement. Palliative treatments for dry mouth, constipation, urinary retention, and sexual dysfunction will increase drug compliance.

Studies have indicated that the most common reason for ineffective antidepressant drug response is an inadequate drug trial; the minimal therapeutic dose must be given for at least four weeks. I have found that patience, persistence, and enlisting the spouse as an ally enhance the patient’s adherence to the treatment plan.

Monoamine Oxidase Inhibitors

MAOIs are effective, relatively inexpensive antidepressants that are an excellent alternative treatment for patients unresponsive to TCAs or patients who cannot tolerate the atropinic side effects of TCAs. The range, clinical profile, and monthly cost are outlined in Table 1.

The risk of a hypertensive episode associated with ingestion of foods or drugs containing pressor amines is low, and past fears of using these medicines have likely been exaggerated. Indeed, recent reports have suggested that the drug and dietary precautions while taking MAOIs can be lessened considerably, which should greatly improve compliance.

The most frequent side effect with MAOIs is not hyper- but postural hypotension which typically does not occur until two weeks into treatment.

As with TCAs, a therapeutic trial of four weeks at a minimum therapeutic dose is necessary for symptom remission.

Others Antidepressants

Maprotiline (Ludiomil)

Maprotiline, while referred to as a tetracyclic, is really a tricyclic compound with a bridge. It is a transition medicine from the TCAs to the newer antidepressants.

Studies indicate maprotiline is as effective as tricyclics in major depression, with few atropinic side effects. The dose range is similar to most tricyclics. Other than its stimulating mild atropinic drug profile, it offers few advantages over the TCAs, and it is considerably more expensive than imipra-mine or amitriptyline (see Table 1).

Trazodone (Desyrel)

Trazodone is a triazolopyridine which has peripheral a-adrenergic and 5-HT antagonistic activity with minimal anticholinergic activity. It is an effective antidepressant for mild to moderate (i.e., outpatient) depressive states, but extensive evaluations in more severe affective disorders have not been completed. It is a sedating but not atropinic medicine, and is quite expensive. The therapeutic dose is usually twice that of TCAs (300-600 mg/day). It should be considered a third-line medicine if TCAs or MAOIs are ineffective, not tolerated, or contraindicated. Data are insufficient at this time to say whether trazodone is more or less cardiotoxic than traditional antidepressants.

Nomifensine (Merital)

Nomifensine is a tetrahydroisoquinoline compound with dopaminergic/noradrenergic activity and minimal anticholinergic activity. There are relatively few North American studies on the efficacy of nomifensine, although the completed work suggests that in doses of 100 to 250 mg/day, nomifensine is as effective as TCAs in treating major depression.18 Side effects may include insomnia, headache, and an unpleasant motor agitation. I feel that the jury is still out on the advantages of nomifensine over TCAs and MAOIs, and that nomifensine should be selected as a third-line drug for depression.

Amoxapine (Asendin)

The dibenzoxapine amoxapine is the demethylated derivative of the neuroleptic loxapine. It has strong adrenergic and weak neuroleptic properties. Studies indicate it is as effective as tricyclics in doses of 300-600 mg/day, but the early claims of a faster onset of action have not been replicated.

I believe the equivalent safety of amoxapine is less when compared to other antidepressants as first-line treatments. Neuroleptics should be avoided in depressive illness because of the risk of tardive dyskinesia, and extra pyramidal side effects do occur with amoxapine. An alarming number of deaths from amoxapine overdoses (when compared to tricyclic overdoses) have been reported, suggesting amoxapine may have a lower therapeutic index than tricyclics.

Conclusions

In summarizing the new antidepressants, it appears they may be as effective as the TCAs and MAOIs, but clearly are not more so. The new medicines often have different side effects from the older ones, which may or may not offer clinical advantages. These drugs are considerably more expensive.

Accordingly, my choice of which antidepressants to use is still the tricyclics. Imipramine (if the patient’s depressive symptoms are more retarded or hypochondriacal) or amitriptyline (if the patient’s motor activity is more agitated) are first choices in major depressive disorders. If the TCA is ineffective or intolerable, then an alternative TCA or an MAOI is indicated. Emphasis on the necessity of an adequate therapeutic trial to the patient and his family, frequent reassurance of future symptom relief, education for patient and family about the nature of the illness, and treating nuisance side effects when they occur lead to symptom remission in well over 90% of all patients.

Résumé

(French Language)

Au Canada, le marché des antidépresseurs comprend actuellement 15 antidépresseurs efficaces (huit tricycliques, trois inhibiteurs de la mono-amine oxydase et quatre médicaments dont la structure chimique est nouvelle). Les tricycliques demeurent encore le premier choix dans le cas des dépressions majeures à cause de leur efficacité prouvée sur une période de plus de trente ans, le profil bien connu de leurs effets secondaires et le coût inférieur de l’imipramine et de l’amitriptyline comparativement aux autres tricycliques et aux nouveaux antidépresseurs. Les inhibiteurs de la mono-amine oxydase sont une excellente alternative et sont beaucoup plus sécuritaires que ne l’avaient suggéré certains rapports antérieurs. La maprotiline ne présente que peu d’avantages comparativement aux tricycliques et est significativement plus coûteuse. Le trazodone peut faire partie des médicaments de deuxième ou troisième choix, l’avantage étant son peu d’effets anticholinergiques. On n’a pas encore procédé à une évaluation clinique adéquate de la nomifensine. Quant à l’amoxapine, ses propriétés neuroleptiques et cardiotoxiques suggèrent de prescrire en premier lieu d’autres médicaments.

This textbook combines a disease-oriented and a drug-specific approach to therapeutics. It is intended to guide prescribers in initiating or altering drug therapy, and it incorporates issues concerning risk, benefit, quality of life and cost-effectiveness. Although the book appears to be intended for primary care clinicians, some of the topics covered concern conditions treated by specialists.

More than 50 clinical pharmacologists and pharmacists contributed to the book. The five editors ensured that each chapter conforms to a standard format and that the contents are evidence based.

The textbook consists of two parts. The first part is disease oriented; in each chapter the material is presented in response to nine standard questions, such as “What are my goals of treatment?” and “What drug should I use as initial treatment?” The diseases covered include not only those from internal medicine (e.g., cardiovascular, endocrine and gastrointestinal diseases) but also psychiatric, obstetric and gynecologic conditions. A separate chapter is devoted to AIDS-related illnesses. Dermatologic conditions such as psoriasis, acne and fungal infections are not covered, although bacterial cellulitis is discussed in the chapter on infectious diseases. The final chapter in part 1 is on drug-induced adverse reactions, mainly rashes, anaphylaxis and gastrointestinal reactions.

The second part of the book consists of monographs for most of the drugs referred to in the first part. However, some important drugs mentioned in the first part are missing (e.g., etidronate). The monographs are also organized as responses to standard questions (e.g., “When should I use this drug?” and “What route and dosage should I use?”).

The major strength of this book is its dual approach. Combining a disease-oriented therapeutics book with a compendium on drug products is brilliant. Readers are not burdened with the task of filtering information that is not required, yet supplementary information is at their fingertips. The table of contents is detailed and helpful but an index would have been beneficial.

A critical challenge for the authors is to keep such a broad therapeutics book up to date with the rapidly evolving literature. Although the book was published in 1996, some areas (such as new regimens to eradicate Helicobacter pylori infection and new evidence about prophylaxis of peptic ulcers caused by nonsteroidal anti-inflammatory drugs) already need updating.

In the past year, two other Canadian books on therapeutics — Therapeutic Choices and Drugs of Choice — have been published. These books are not as comprehensive or detailed as Drug Therapy. Therefore, Drug Therapy is a helpful resource when there is enough time to absorb its contents, whereas the two previously published books serve as quick references.

This book can be recommended as a useful resource for primary care practitioners or trainees.

Ariadne Montare, 33, a Manhattan lawyer, has battled the combination for over a year-ever since she was diagnosed with fibromyalgia, a syndrome characterized by sleep disturbances, muscle pain, and overwhelming fatigue.

“When I first started experiencing pain and depression together, it was like the chicken and the egg riddle,” she says. “I couldn’t tell which came first, or if they were separate or linked.”

Montare battled the two alone for months, convinced at times that the moodiness that accompanied her pain was all in her head. “I’d never thought of myself as an unhappy person,” she says, “yet here I was, unable to get out of bed.” That is, until her doctor hit upon the right treatment combination, which includes pain medication and antidepressants.

Montare’s struggles are far from unusual. Studies show that approximately 20% to 70% of chronic pain patients also suffer from major depression. Researchers further report that patients with clinical depression are more likely than their depression-free counterparts to develop headaches and chest pain.

New research suggests that the neurotransmitter serotonin plays a significant role in creating such synergy. Serotonin is responsible for regulating a variety of mental and physiologic functions, including sleep, mood, and anxiety. Many experts believe a lack of serotonin may play the same role in pain as it does in depression — enhancing its perception — and, as a result, disrupting sleep and heightening anxiety. “Serotonin, which plays a role in the perception of pain, is also a factor in our perception of depression,” explains Patrick Randolph, Ph.D.. Dr. Randolph is the Director of Psychological Services in the Pain Management Center at Texas Tech University Health Sciences Center in Lubbock.

What may hurt the most, however, is that many patients are regarded as malingerers, whose problems wax and wane with their need for attention or a day off from work. Randolph points to stress as a prime culprit. “Stress causes the sympathetic nervous system to go into overdrive, which, in turn, produces prolonged muscle spasms and releases pain-producing substances.” Montare agrees. “I feel better when I’m not at work and worse when I’m [under] stress.”

The most effective way to cope with an unending cycle of pain and depression is with an interdisciplinary approach. “By using the power of medicine, mind, and body, you can help break the cycle and improve your quality of life,” says Randolph. Here’s what you need to do:

* Take your medication regularly as prescribed by your physician.

* Try yoga.
“The mind-body benefits of yoga can be helpful,” says Randolph. “One of the best things about yoga is that everyone starts out making slow, small movements. It reacquaints people with their bodies and helps them realize that they can reach physical goals and actually feel good at the same time.”
He has proof: Dr. Randolph’s latest study examined chronic pain patients who took part in an 8-week program that included meditation and yoga. Eighty percent said that their ability to cope with the stress of life improved, and 79% reported they felt better.

* Talk to a therapist.
Many people who experience chronic pain suffer major life losses, whether it’s a job or a lifestyle. “These losses can be quite devastating,” says Randolph. “Grieving for them with a therapist helps you work through this pain and helps you rethink your expectations of yourself and others.” Ariadne Montare agrees. She used to “get frustrated and berate myself” if she had to cancel high-energy social plans. “Now, instead of getting upset, I invite friends to do something I can enjoy close to home instead.”
Understanding the way you relate to pain is also important. A study done at Brown University in Providence, Rhode Island, found that chronic pain patients who believed pain would impair their daily functioning were more likely than others to suffer impairments. “A therapist can help you learn to separate your feelings about pain from the pain itself. Also, she or he can help improve the way you cope, thereby reducing your chances of succumbing to depression,” says Randolph.

* Try cognitive re-framing.
Chronic pain may prevent you from doing some of the things you love, but it doesn’t have to prevent you from enjoying yourself. Cognitive re-framing is a technique that helps you evaluate the activities you enjoy, then select the aspects of the activity you can still incorporate into your life. If you love tennis but your arthritis prohibits you from playing, think about what made you love it in the first place. Was it being outdoors? Competing against other people? Finding new ways to incorporate these elements into your life will make you feel less helpless and help you learn new activities as well.

* Practice stress management
“Meditation induces deep relaxation, and it allows people to help separate emotions from the physical experience of pain,” says Randolph. From a psychological and physiologic standpoint, relaxation is the best state from which to deal with pain. “Pain causes the body to go into fight or flight mode, forcing up blood pressure and stress hormones. The result: lowered resistance to more pain and depression,” says Randolph. The relaxation that results from meditation helps to shut these damaging responses down. Randolph adds that “biofeedback and stress management therapy can also provide similar results.”

Mechanism of Action Mirtazapine (Remeron) appears to exert its antidepressant effect in a unique way. It blocks central presynaptic alpha2-adrenergic receptors, which results in an increased release of norepinephrine and serotonin. In addition, it strongly blocks serotonergic 5-hydroxytryptamine (5-HT2 and 5-HT3) and histaminic H1 receptors and weakly blocks peripheral alpha1-adrenergic and muscarinic receptors.

Pharmacokinetics Mirtazapine (Remeron) Following oral absorption, mirtazapine is rapidly and completely absorbed, with peak plasma levels achieved within about two hours; neither the rate nor extent of absorption is significantly affected by food. It is extensively metabolized in the liver, by the cytochrome P450 isoenzymes 2D6, 1A2, and 3A4, primarily to inactive metabolites, and excreted mainly in urine. Its half-life of elimination is between 20 and 40 hours, which implies that steady state levels at a given dose would be achieved within approximately five days, and it exhibits about 85% plasma protein-binding.

Clinical Trials Mirtazapine (Remeron) The results of four six-week, double-blind studies of Mirtazapine (Remeron) in the treatment of major depression have been reported in the literature. In a trial of 90 outpatients with major depression, 50% of patients taking mirtazapine (10–35 mg/day) improved, compared with 28% of patients taking placebo. By the end of the study, 18 of the mirtazapine and 26 of the placebo patients had dropped out.

In two studies, mirtazapine was compared with amitriptyline. In the earlier of the two, 90 of 150 patients completed the six-week study. The average daily dose of mirtazapine was 18 mg and that of amitriptyline was 111 mg. Of the completers, 63% of the patients improved with mirtazapine, 69% with amitriptyline and 48% with placebo.4 In the other study, improvement was seen in 70%, 58% and 33% of patients treated with mirtazapine (average daily dose of 22 mg), amitriptyline (average daily dose of 133 mg), and placebo, respectively.5 Overall, the high dropout rates and questionable therapeutic amitriptyline doses make the results of these studies difficult to interpret.

In a study of 200 hospitalized patients comparing Mirtazapine (Remeron) (24–72 mg/day) with trazodone (150–450 mg/day), mirtazapine was shown to be significantly more effective than trazodone.

No trials have been published comparing Mirtazapine (Remeron) with any of the selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, paroxetine), nor has there been systematic investigation of its efficacy over the long-term (i.e., six or more months) treatment period required for a major depressive episode.

Adverse Effects and Toxicity The most common adverse effect reported with Mirtazapine (Remeron) is transient somnolence, which occurs in at least 50% of patients, followed by increased appetite and weight gain, dizziness, dry mouth and constipation, all of which would be expected based on the drug’s pharmacologic profile (see Table 1). In premarketing trials, two of 2,796 patients who received mirtazapine developed agranulocytosis and one developed severe neutropenia. Nonfasting cholesterol levels increased to 20% or more above the upper limits of normal in 15% and increases in aminotransferase activity occurred in 2% of patients treated with Mirtazapine (Remeron). No clinically significant electrocardiographic changes have been reported.

An 81-year-old woman was admitted to intensive care in a semi-comatose state following ingestion (according to family members) of sixty 15-mg mirtazapine tablets and fourteen 15-mg Mirtazapine (Remeron) tablets the day prior to admission. Within an hour, the patient awoke with only one side effect, somnolence, which dissipated over three days. No significant effects were noted in cardiopulmonary function, and no seizures were observed. If this case reflects what can be generally expected with overdose, mirtazapine appears to be relatively safe.

Drug Interaction Mirtazapine (Remeron) is a substrate of cytochrome P450 isoenzymes 2D6, 1A2, and 3A4; however, it does not appear to inhibit these isoenzymes. Although no systematic studies of isoenzyme-related interactions have been completed, it is reasonable to expect that mirtazapine would have little, if any, effect on drugs metabolized by isoenzymes 2D6, 1A2, or 3A4; on the other hand, concomitant use of inhibitors or inducers of these enzymes could respectively increase or decrease blood levels of mirtazapine. Mirtazapine (Remeron) in combination with benzodiazepines or ethanol may result in additive effects with respect to sedation and psychomotor impairment. Since concurrent use of mirtazapine and monoamine oxidase inhibitors (MAOIs) could theoretically lead to a hypertensive crisis (due to noradrenergic excess) or a serotonin syndrome (due to serotonergic excess), the manufacturer recommends that the two not be used in combination and that there be at least a 14-day washout period between discontinuation of an MAOI and initiation of mirtazapine or the reverse.

Dosage Mirtazapine (Remeron) The recommended starting dose of mirtazapine (available in 15- and 30-mg scored tablets) is 15 mg/day, at bedtime. This can be increased at intervals of one to two weeks up to a maximum dose of 45 mg/day. Reduced dosages may be necessary in the elderly and in patients with moderate to severe renal or hepatic disease.

Conclusion Mirtazapine’s chemical structure and mechanism of action are unique among the antidepressants. However, from the mid-1980s to the mid-1990s, a major goal in the development of new antidepressants was to find agents very specific and narrow in their pharmacologic actions (e.g., only affecting serotonin); ironically, mirtazapine has “mixed” activity with respect to actions on central norepinephrine and serotonin, and on other receptor systems. More must be known about the benefits versus the disadvantages of this “mixed” activity and the incidence of agranulocytosis and neutropenia, as well as the drug’s toxicity profile and short-term and long-term efficacy as compared with other newer antidepressants, to determine where the drug fits into our antidepressant armamentarium.

Most recently, the selective serotonin reuptake inhibitors (SSRIs) have provided an alternative to the older pharmacologic treatments. Although paroxetine and, very recently, sertraline have FDA-approved indications for the treatment of panic disorder, a significant body of literature exists, as well, for fluvoxamine and, to a lesser extent, fluoxetine. Sheehan and Harnett-Sheehan have comprehensively reviewed the role of SSRIs and Jefferson has reviewed the antidepressants in general in the treatment of panic disorder. As a group, these agents are significantly different from the tricyclic antidepressants, monoamine oxidase inhibitors, and benzodiazepines. They demonstrate little or no abuse potential, orthostatic hypotension, anticholinergic side effects, sedation, or ability to produce hypertension secondary to drug-drug and drug-food interactions. On the whole, they display a profile of CNS-stimulating side effects (e.g., anxiety, insomnia, headaches, nausea, weight loss). Among the serotonin reuptake inhibitors, fluoxetine is the most stimulating and fluvoxamine the least. In addition, paroxetine appears to have some mild anticholinergic properties, and they differ from one another with respect to the drug-drug interactions in which they are involved via P450 isoenzymes. Half-lives of elimination of the parent compounds and their active metabolites constitute another important difference among the four (see Table 2). All four of the SSRIs have been studied in panic disorder with the greatest number of published reports involving fluvoxamine, the largest number of patients treated with paroxetine, and the least number of published reports involving fluoxetine and sertraline.

• Fluoxetine: Based on a total of 195 patients in three open-label studies and one double-blind comparison with desipramine, fluoxetine (10-80 mg/day) has shown some efficacy in the treatment of panic disorder. However, patients appear to be very sensitive to its activating effects, resulting in high dropout rates. Starting doses as low as 2.5 mg/day may be necessary for successful treatment of patients; employing this approach, Schneier et al. reported that 76% of 25 patients with panic disorder markedly improved.

• Fluvoxamine: In multiple double-blind studies, involving over 1,000 patients, fluvoxamine has been shown to be more effective than placebo, maprotiline, and ritanserin (not available in the U.S.) and equal in efficacy to clomipramine and imipramine in the treatment of panic disorder. In one such study, lasting 8 weeks, Black et al. compared fluvoxamine (up to 300 mg/day), cognitive behavior therapy, and placebo in 75 patients. At week 4, 57% of patients taking fluvoxamine, 40% receiving cognitive therapy, and 22% of those taking placebo showed at least moderate improvement. At week 8, 81% of the fluvoxamine group, 53% of the cognitive therapy group, and 29% of the placebo group were free of panic attacks; the difference between the fluvoxamine and placebo groups was statistically significant.

• Sertraline: Sertraline (50, 100, and 200 mg/day fixed doses), in a 12-week, multicenter, placebo-controlled study of 320 patients with panic disorder, significantly reduced the number of panic attacks at the 100 and 200 mg/day doses. Of concern, 22% of patients receiving sertraline discontinued treatment secondary to adverse effects, while there were no dropouts in the placebo group.

• Paroxetine: The efficacy of paroxetine in the treatment of panic disorder has been studied in over 1,200 patients and reported in three published studies and three presentations. All of these trials were double-blind and placebo-controlled, and overall, paroxetine (40-60 mg/day) was found to be superior to placebo and equal to either clomipramine (150 mg/day) or alprazolam (6 mg/day). Onset of action can be slow, however, with a 50% reduction in panic attacks not occurring until week 6 and a reduction to one or zero attacks lasting three consecutive weeks not occurring until week 12. In a 10-week, fixed-dose (10, 20, and 40 mg/day) study of 278 patients, significant differences from placebo were seen only in the patients treated with 40 mg/day.

Conclusions

Currently available data indicate that the serotonin reuptake inhibitors are emerging as distinct options in the treatment of panic disorder. As with the older treatments, onset of action can be slow, effective doses are similar to those needed in treating major depression, and, at times, drug discontinuation secondary to adverse effects can be a significant problem. Overall, however, the SSRIs have a number of advantages over the older options, particularly with respect to adverse effects and abuse and dependence potential, and are already viewed by many prescribers as first-line agents, especially in patients with panic disorder and concomitant major depression. Further information on long-term efficacy as well as comparisons of each of the serotonin reuptake inhibitors with the others would be helpful in fully assessing their place in the treatment of panic disorder.

Epidemiology and Clinical Features

Panic disorder is one of the primary anxiety disorders described in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) of the American Psychiatric Association. It is a chronic disorder with a lifetime prevalence estimated to be between 1.5% and 3.5% and an onset generally in early adulthood. It is characterized by the occurrence of recurrent, unexpected panic attacks followed by at least one month of persistent concern about experiencing further attacks, worry about the consequences of the attacks, or a significant change in behavior secondary to the attacks. The attacks may last seconds to minutes and are characterized by dyspnea, palpitations, tremulousness, dizziness, hot and cold flashes, diaphoresis, chest pain, feelings of unreality, numbness or tingling, faintness, fear of going crazy, and fear of dying (see Table 1). These attacks are extremely frightening and disabling; many of these patients are seen in the medical emergency room because they think they are having a heart attack. If a sufficient number of panic attacks occur, patients may develop anticipatory anxiety (i.e., anxiety associated with the fear of the next occurrence) as well as avoidant behavior. When this avoidant behavior severely restricts the daily activity of the individual (i.e., avoiding public places and/or leaving home for fear of having a panic attack during which help will not be available), the diagnosis of panic disorder with agoraphobia is made. Up to 70% of patients with panic disorder fulfill the diagnostic criteria for major depression at some point in their lives.

Traditional Treatments

Until recently, primarily three drugs have been used in the pharmacotherapy of panic disorder: the tricyclic antidepressant imipramine; the monoamine oxidase inhibitor phenelzine; and the benzodiazepine alprazolam. Among the three, only alprazolam has an FDA approved indication for the treatment of panic disorder; however, all three have demonstrated efficacy. Often, imipramine would be selected for patients with concomitant depression and avoided in patients who could not tolerate the sedative, anticholinergic, hypotensive, or cardiac conduction adverse effects. Phenelzine may have an advantage in patients with significant phobic avoidance; however, it is commonly reserved as a last resort due to fear over drug-drug and drug-food interactions resulting in possible hypertensive crises. Alprazolam would be given to patients with significant anticipatory anxiety, as well as those who could not tolerate imipramine, and avoided in patients who would be adversely affected by the drug’s tendency to produce sedation and psychomotor impairment. In addition, most prescribers would avoid use of this agent in any patients with a history of alcohol or substance abuse due to its abuse potential. More recently, clonazepam was approved by the FDA for the treatment of panic disorder. Compared with alprazolam, it has the advantage of a longer half-life of elimination, reducing the frequency of dosing as well as the inter-dose rebound anxiety sometimes seen with alprazolam.

Table 4 describes dosing schedules for benzodiazepine and antipsychotics used to treat agitation and aggression. Oral administration of any of the medications is preferred when the patient is cooperative, except in cases of acute risk of self-harm or danger to others. The agitated individual should first be given the opportunity to take their medication by mouth. Giving the patient a choice also offers a needed sense of empowerment and may improve future cooperation. However, if the patient is uncooperative, combative, or “cheeks” medication, then IM administration is used. IM dosing gives assurance that the dose was received, eliminating any problems with noncompliance. However, many patients may resist the injection, often aggressively, in cases of involuntarily medicating a patient.

Pharmacokinetically, the fastest onset of effect occurs with the intravenous (IV) route, however in most psychiatric settings, IV access is not available. A patient may need the IM form initially, but should be converted to oral tablets or solution once cooperation is assured.

Patients being treated for acute agitation should be observed every 15 to 30 minutes for the first 2 hours following medication administration to identify adverse effects (orthostasis, dystonia, confusion, lethargy, sedation) and to determine response. If the patient remains agitated, the dose can usually be repeated in the next 1-2 hours with minimal risk. Even if they calm, over the next 24 hours or longer patients should be watched for a return of the agitated behaviors. In most patients, orders for medications to treat agitation and aggression are written as “prn.” If the patient needs repeated doses of the “prn,” it may be best to schedule the medication for the next few days, then switch back to a “prn” status once the behavior is better controlled. (Such orders should state the amount of drug not to be exceeded within 24 hours.)

Others: Hydroxyzine and diphenhydramine are sometimes used alone to treat agitation and aggression. The literature does not support this practice as they offer no benefit over benzodiazepines and antipsychotics. They do not impact the underlying disease state, creating improvement only because of sedative effects, and carry a risk of anticholinergic effects or orthostasis.