Psychobiology and psychopharmacotherapy of unipolar major depression: A review

Psychobiology and Psychopharmacotherapy of Unipolar Major Depression: A Review Susan M. O'Toole and David A. Johnson Psychopharmacology has continually informed the biological perspective of major depression. Antidepressants affect a variety of neurotransmitters by a wide range of pharmacological actions. The complexity of these neurotransmitter receptor interactions likely underlies the discrepancies observed in biochemical and physiological responses among apparently clinically homogenous depressive subgroups. This report provides an integrated review of the neuroendocrine and neurochemical perspectives of unipolar depression and how these advances influence the psychopharmacotherapy of unipolar major depression. Copyright © 1997by W.B. Saunders Company

HE RESEARCH LITERATURE is rich with studies of the psychobiology and psychopharmacotherapy of major depression. Psychobiology can be defined as "the study of the biochemical foundations of thought, mood, emotion, affect, and behavior" (McEnany, 1992, p. 100), and major depression is defined as "five or more symptoms such as weight loss, sleep disturbance, fatigue, difficulty concentrating, and suicidal ideation during the same 2-week period representing a change from previous functioning; at least one of the symptoms is either depressed mood or loss of interest or pleasure most of the day, nearly every day" (American Psychiatric Association Diagnostic and Statistical Manual, 4th ed (DMS IV), 1994, p. 327). In the Epidemiologic Catchment area study (ECA), the annual incidence of major depression was about one per 100 person-years in men and two appearances of new cases per 100 person-years in

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From the Graduate School of Nursing, Duquesne University; the Neurosciences Research Center, MCP, Hahnemann University, Allegheny University of the Health Sciences; and the Department of PharmacologyToxicology, Graduate School of Pharmaceutical Studies, Duquesne University, Pittsburgh, PA. Address reprint requests to David A. Johnson, PhD, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282-1504. Copyright © 1997by W.B. Saunders Company 0883-9417/97/1106-000353.00/0

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women (Eaton, Kramer, Anthony, Dryman, Shapiro, & Locke, 1989). There is a paucity of nursing literature that synthesizes and integrates the psychobiology of depression and its treatment. This review article provides an integrated perspective of the psychobiology and psychopharmacotherapy of unipolar major depression and is directed toward the advanced practice nurse. It will also give an overview of four classes of antidepressants, including the mechanisms of action and side effect profiles. With the advent of new medications and advanced knowledge of the biochemical mechanisms underlying brain function, the advanced practice nurse must keep current with advances in the field of psychobiology and psychopharmacotherapy, to afford patients state of the art assessment and treatment. BRIEF HISTORICAL REVIEW

Psychopharmacology has continually informed the biological perspective of major depression. In the early 1950s, when reserpine was used as an antihypertensive agent, it was noted that a significant percentage of patients experienced symptoms of depression (Ayd 1956; Lemieux, Davignon, & Genest, 1956; Quetsch, Achor, Litin, & Faucett, 1959). This led to the observation that there may be a relationship between the functional state of one or more neurotransmitters and the clinical state of

Archives of Psychiatric Nursing, Vol. XI, No. 6 (December), 1997: pp 304-313

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depression because of the effects of this drug on the brain. In animal studies it was observed that reserpine depleted nerve endings of serotonin, dopamine, and norepinephrine (Carlsson, Rosongren, Bertler, & Nilsson, 1957; Shore & Brodie, 1957). These two observations resulted in the formulation of the amine hypothesis of affective disorders. The substance of the hypothesis is that depression is associated with a functional deficit of one or more brain neurotransmitter amines at specific central synapses (Bunny & Davis, 1965; Schildkraut, 1965; Prange, 1973). In the late 1950s, there was another unrelated observation regarding iproniazid. Patients receiving iproniazid for treatment of tuberculosis were noted to have improved mood and relief of depressive symptoms frequently associated with chronic illness (Kline, 1958). It was further noted that this drug can elevate brain amine levels by inhibiting the metabolizing enzyme monoamine oxidase (MAO) (Davidson, 1958). Thus, there were links between depression to each of two drugs: monoamine oxidase inhibitor (a mood-elevating drug that increased brain amines), and reserpine (a mood-depressing drug that decreased brain amines). Research on the neurochemistry of major depression over the past 40 years has continued to focus on these neurotransmitters in the brain.

NEUROENDOCRINE

Several neurotransmitter systems implicated in hypothalamic-pituitary-adrenocortical (HPA) axis regulation have been hypothesized to be dysfunctional in major depression, including norepinephrine, serotonin, dopamine, and acetylcholine (Janowsky & Overstreet, 1995). Central nervous system (CNS) cholinergic systems are highly interactive with other neurotransmitter and neuromodulator systems (Karczmar, 1993), and they are anatomically organized as global systems, thus enhancing their capacity to mediate behavior and cognition (Woolf, 1991). Stokes, Mass, Davis, Koslow, Casper, & Stoll, (1987) suggested that cortisol induces alterations in the neurotransmitter systems that may contribute to the pathogenesis of depression. In turn, monoamines and their receptors can affect neuroendocrine activity. Therefore, the direction of the causal arrow is unclear. Of value in understanding the neurochemistry of major depression is whether the HPA axis hyperactiv-

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ity can be related to neurotransmission dysfunction(s) in this illness. Selye was a pioneer in scientific investigations exploring the effects of life stress on psychophysiological functioning. Selye (1978) described a generalized response to stressors involving the autonomic nervous and the endocrine systems, which he termed the "general adaptation syndrome." This syndrome has three stages: (1) an alarm reaction, the initial response to stress; (2) resistance, the changes that occur in body organs; and (3) exhaustion, when the adaptive responses fail. If the stressors are chronic and there is no opportunity to regain homeostasis, illness may result. Mason (1968; 1971) expounded on earlier studies and clarified that some pituitary and adrenal hormones are elevated after exposure to a stressor, whereas others become suppressed. His work suggested that the integrated response of different hormones offered the best explanation of the neuroendocrine responses to life stressors (Rahe, 1995). Hypercortisolemia has long been recognized as an essential part of a normal adaptational process to stress and has been shown to alter mood, cognition, and behavior (Stern & Prange, 1995; Stokes, 1995). The hypothalamus and pituitary are contiguous structures, richly connected with the limbic and thalamic regions of the brain involved in regulation of sleep, appetite, reward, and libido (Holsboer, 1995). The neuroendocrine structure is a complex and integrated system. "It involves the release of anterior pituitary hormones by various hypothalamic factors, a feedback control of that release by circulating target organ hormones, and an overriding control on the entire system by internal biological rhythms or external events affecting the hypothalamus" (Green, Mooney, Posener, & Schildkraut, 1995, p. 1095). Control of many of the hypothalamic neuroendocrine-releasing and -inhibiting hormones is regulated, in part, by monoaminergic and/or acetylcholine (ACh) neurons. HPA axis hyperactivity is the most prominent neuroendocrine abnormality in major depression, as reflected by increased circulating corticotrophin and cortisol concentrations, and cortisol resistance to the dexamethasone suppression test (DST) (nonsuppression). This well-studied neuroendocrine abnormality occurs in 30% to 50% of depressed patients (Carroll et al., 1981; Holsboer, 1992; Rubin, 1989). The abnormal DST responses persist

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for weeks even during active pharmacological treatment of depression and only normalized gradually as the patient's condition improved (Holsboer, 1992). The nonsuppression of cortisol is considered a state-dependent abnormality because it is present only during the active illness state and returns to normal gradually with remission of the active depressive symptoms. Several other abnormalities of neuroendocrine function have been noted in a lower percentage of depressed patients; (1) failure or dysfunction of feedback inhibition measured by the DST, so that the HPA axis remains hyperactive after resolution of a transient stressor (Arana, Baldessarini, & Omsteen, 1985) and (2) abnormalities of circadian regulation of the HPA axis, including blunting of the daily cortisol rhythm and an early rise in nocturnal secretion of cortisol (Sachar, Hellman, Roffwarg, Halpern, Fukushima, & Gallagher, 1973; Sherman, Pfohl, & Winokur, 1984; Jarrett, Miewald, Fedorka, Coble, Kupfer, & Greenhouse, 1987). The following structures in the CNS have been implicated in depression. The basal forebrain has been implicated in behavioral arousal, motivated behavior, attention, learning, and memory. The projections of the basal forebrain complex to the amygdala (involved in emotions) and hippocampus (involved in short-term memory) are important areas for stimulation and negative feedback of the HPA axis, respectively, and to the cortex, where metabolic changes have been noted in depression (Wainer, Steininger, Roback, Burke-Watson, Mufson, & Kordower, 1993). These structures provide a unifying framework for the hypothesis of dysregulated CNS cholinergic transmission influencing the HPA axis in major depression (Dilsaver, 1986).

tween neurons (Fig 1). The release of neurotransmitters into the synaptic cleft allows for the electrophysiological signal to be passed from the axon terminal of an activated cell to the next cell, Neurotransmitters are stored in membrane-bound vesicles in the axon terminals, and when the cell is stimulated, these vesicles migrate to the cell membrane and release the neurotransmitters into the synaptic cleft. Neurotransmitters, once released, may become attached to membrane-bound receptors on the postsynaptic cell, be reabsorbed back into the presynaptic cell's axonal terminal ("reuptake") or attach to autoreceptors on the presynaptic cell which regulate neurotransmitters release (Bloom, 1995; Cooper, Bloom, & Roth, 1991). Second messengers which are stimulated after activation of receptors, such as the cyclic nucleotides adenosine monosphosphate (cAMP), activate processes that result in changes in cell membrane conformation or permeability. These processes alter the permeability of ion channels for sodium, potassium, calcium, and/or chloride which modify neurotransmission. The modifications that result are presynaptic; in the amount of transmitter released, postsynaptic; in the firing rate of the cell, and in the number and sensitivity of receptors available (presynaptic and postsynaptic) (Cooper et al, 1991). Receptors are responsive to changes in the cellular milieu, and thus, help to maintain homeostasis. Neuronal activation that is prolonged or excessive may result in increased numbers of

presynapdc neuron ~

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NEUROCHEMICAL

"Neurons are the class of cells whose physical interconnections constitute the circuitry of the brain, spinal cord, and the peripheral nervous system and give rise to the multicellular ensembles of neurons which carry out the functions of the nervous system. Neurons communicate chemically by releasing and responding to a wide range of chemical substances, referred to in the aggregate as neurotransmitters" (Bloom, 1995, p. 5) The neuronal synapse is the basic functional unit for the electrochemical process of neurotransmission and the essential junction of signal transduction be-

• •

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• °gee oo plesynaptic autoreceptor

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storage vesicles

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Fig 1.

Neuronal synapse.

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presynaptic inhibitory sites (upregulation) or in decreased numbers of postsynaptic sites (downregulation). An increased number and/or affinity of receptors may result from treatment with drugs that block postsynaptic sites. (Cooper, 1991). Receptors are specialized proteins that have the unique ability to bind specific molecules. Neurotransmitters, neuromodulators, and hormones all have specific receptors and some neurotransmitters have more than one receptor type to which they bind (Richelson, 1995). Receptors and their actions have been increasingly implicated in the pathophysiology of depression as well as the mechanism of action of various antidepressants. Receptors may be increased in number and/or affinity by treatment with antidepressants. Many antidepressants downregulate postsynaptic [3-adrenergic receptors, however a time course of 2 to 3 weeks usually is required for the attenuation of symptoms of depression. This delay corresponds to the time needed to induce the downregulation of receptors (Sulser, Ventulani, & Mobley, 1978; Halbreich, Weinberg, Stewart, Klein, Weitzmann, & Quitkin, 1981; Siever & Davis, 1985). The monoamine neurotransmitters norephineprine (NE) and serotonin (5-HT) influence many behaviors such as mood, memory, sleep, and appetite (Dinan, 1996; Leonard, 1996). These major neurotransmitters are also associated with depression. One theory of depression is that it is a result of alterations in release of NE and 5-HT (Owens & Nemeroff, 1994). NE and 5-HT are released in response to depolarizing stimuli, resulting in receptor activation that elicits pre- and postsynaptic responses. These transmitters are then cleared by transporter proteins from the extracellular space. These transporter proteins are important because they are the molecular targets for several classes of antidepressants (Barker & Blakely, 1995). Serotonergic neurons are found primarily in the median and dorsal raphe nuclei of the midbrain and upper pons of the brain stem and have distinct projection patterns to the cerebral cortex, hypothalamus, thalamus, basal ganglia, septum, and hippocampus (Baraban & Coyle, 1995; Cooper et al., 1991). It has been suggested that serotonergic neurotransmission has both inhibitory and facilitatory functions (Carroll, 1991). S erotonergic neurons project axons to the suprachiasmatic nucleus of the hypothalamus and are presumed to play a role in the regulation of circadian rhythms and

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hypothalamic-pituitary-hormonal function (Depue & Spoont, 1986). Disturbances of appetite, sleep, libido, aggressivity, and violent suicidal behavior are associated with reduced serotonergic neurotransmission (Golden & Gilmore, 1990; Malone & Mann, 1993). The locus coeruleus, sympathetic nervous system, and adrenal glands are areas where NE is synthesized. NE binds to two major classes of adrenergic receptors, c~ and [3. Presynaptic c~2receptors regulate the release of NE from presynaptic neurons, [31 receptors which are usually postsynaptic, (Sulser et al., 1978) are reported to be downregulated in rat brains after chronic administration of antidepressants. Some antidepressants affect the NE system by blocking neurotransmitter reuptake, and therefore allow NE to remain in the synapse longer and in turn increase receptor binding. However, decreased NE has not been shown in the majority of depressed patients in studies of their plasma, urine, cerebrospinal fluid samples, nor in postmortem assays of brain tissue of suicide victims (Coppen & Doogan, 1988; Delgado, Price, Heninger, & Churney, 1992; Potter, Grossman, & Rudorfer, 1993). It is still being investigated whether other types of molecules, such as purines, lipids, and steroids play a role in intercellular transmission (Bloom, 1995). The complexity of these neurotransmitter receptor interactions may at least partly explain the discrepancies observed in biochemical and physiological research among apparently clinically homogenous depressive subgroups. PHARMACOTHERAPY OF UNIPOLAR DEPRESSION

The monoamine oxidase inhibitors (MAOIs) and the tricyclic antidepressants (TCAs) were chance discoveries introduced in the 1950s as treatments for depression. Since then other classifications of antidepressants have been introduced. These drugs affect a variety of neurotransmitters by a wide range of pharmacological actions. This section will give an overview of four classes of antidepressants which includes the mechanisms of action and side effect profiles. Monoamine Oxidase Inhibitors

The MAOIs are considered first generation antidepressants. They function by blocking MAO so that it can not metabolize NE and 5-HT and

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therefore allow the increased binding of these neurotransmitters with their respective receptors. A delay in up to 4 weeks in therapeutic response to MAOIs may be explained by the alterations in receptor characteristics rather than by increased neurotransmitter concentration (Himmelhoch, 1995; Post, 1995). The MAOIs are used to treat moderate to severe depression in patients who have not responded to other antidepressant therapy. These drugs should be initiated either under close supervision or hospitalization. The main side effects of the MAOIs are listed in Table 1. Serious hypertensive crises are not usually dose related and are associated with a distinctive reaction which can be fatal. MAOIs should be tapered to avoid drug withdrawal symptoms, including sleeplessness, nausea, vomiting, irritability, and rapid eye movement rebound (Himmelhoch, 1995). MAOIs may produce variable hypotensive responses, most likely caused by central inhibition of vasomotor centers. Inhibition of MAO in the gastrointestinal tract and liver can result in systemic absorption of large amounts of tyramine, normally metabolized by MAO in intestinal and hepatic cells, which can cause severe hypertension because of an induction of a massive release of NE. MAOIs also interfere with the hepatic metabolism of many drugs. Table 1. The Main Side Effects of the MAOIs, Symptoms of Hypertensive Crisis, and Dietary Restrictions Side Effects Cardiovascular: tachycardia, syncope, hypertension, dizziness Central Nervous System: insomnia, weakness, drowsiness, tremors, paresthesia, chills, stimulation Autonomic Nervous System: dry mouth, blurred vision, urinary retention Immune: allergic skin rash Metabolic: weight gain, edema Gastrointestinal: nausea, diarrhea, abdominal pain, constipation, anorexia Musculoskeletal: muscle spasms Hypertensive Crises: occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, nausea or vomiting, sweating, photophobia, tachycardia or bradycardia, constricting chest pain, dilated pupils, intracranial bleeding, death Dietary Restrictions (Tyramine-free diet): no cheese, (except cottage cheese and cream cheese); sour cream, pickled herring, liver, meat prepared with meat tenderizers, soy sauce, pods of broad beans, canned figs, raisins, avocados, chocolate, alcohol, caviar

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Phenelzine (Nardil, Parke-Davis, Morris Plains, NJ), Isocarboxazid (Marplan, Roche, Nutley, NJ), and Pargyline (Eutonyl, Abbott, N. Chicago, IL) are MAOIs that bind irreversibly to monoamine oxidase, while Tranylcypromine (Paruate, Smithkline-Beecham, Pittsburgh, PA) binds reversibly. These drugs can be used in the treatment of psychotic depression, melancholia, and reactive depressions of moderate to severe intensity. The MAOIs are often selected to treat refractory depressions after failure to respond to a clinical trial of a TCA, atypical antidepressant, or a selective serotonin reuptake inhibitors (SSRI). These drugs should be administered with care in patients with cerebrovascular or cardiovascular disorders, a history of recurrent or frequent headaches, liver damage, or blood dyscrasias. Tranylcypromine should not be administered in combination with other MAOIs, TCAs, sympathomimetics, fluoxetine (no causal relationship has been established, but a death has occurred after the initiation of a MAOI shortly after discontinuation of fluoxetine--allow for 5 weeks between discontinuation of fluoxetine before starting tranylcypromine (Himmelhoch, 1995). Patients also need to be placed on a tyramine-free diet (Table 1). Dietary restrictions should continue for at least 2 weeks after termination of treatment with a MAOI.

Tricyclic Antidepressants Tricyclics exert their effect by blocking the reuptake of NE and 5-HT, thereby, increasing their synaptic concentrations (Preskorn & Irwin, 1982). This class of medications have multiple mechanisms of action which occur in a relatively narrow range of concentration. TCAs are effective in the treatment of all subtypes of depression, however, TCAs may precipitate hypomanic episodes in patients with bipolar depression. Because of side effects, the dosage of TCAs should be initiated at a low level and increased gradually, observing the clinical response and any evidence of intolerance related to side effects. Abrupt cessation of TCAs after prolonged treatment may produce a withdrawal syndrome that includes nausea, headache, and malaise. Even after gradual dosage reduction there has been reported, within 2 weeks, transient symptoms of irritability, restlessness, and dream and sleep disturbances (Kessel & Simpson, 1995). The major side effects

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of the TCAs encompass several organ systems and are listed in Table 2. TCAs are not reconunended for use during the acute recovery phase after myocardial infarction nor in the case of acute congestive heart failure because they have serious cardiotoxic effects. These cardiotoxic effects can occur at 10 times the therapeutic dose, therefore overdoses of relatively small amounts of medication can be fatal (Burke & Preskorn, 1995). Amitriptyline (Elavil, Zeneca, Wilmington, DE) is a prototype for the tricyclics used in the treatment of depressive illness. Because it is also sedating, it is especially beneficial for depressions that have an associated anxiety component. Amitriptyline inhibits the reuptake of NE and 5-HT in adrenergic and serotonergic neurons. This action, pharmacologically, may potentiate or prolong neuronal activity because reuptake of these biogenic amines is important physiologically in terminating transmitting activity. This interference with the reuptake of NE and/or 5-HT is believed to underlie the antidepressant activity of amitriptyline and the other TCAs (Kessel & Simpson, 1995; Post, 1995).

Atypical Antidepressants Atypical antidepressants are chemically unrelated to other antidepressants. However, they possess some actions similar to other antidepressant classifications. Anticholinergic actions are generally lower with the atypical antidepressants than

Table 2. The Major Side Effects of the TCAs

Side Effects Cardiovascular: myocardial infarction, stroke, nonspecific electrocardiogram changes, heart block, arrhythmia, orthostatic hypotension Central Nervous System: coma, seizures, hallucinations, disorientation, ataxia, tremors, peripheral neuropathy, paresthesias of extremities, extrapyramidal symptoms, and tardive dyskinesia Autonomic Nervous System (anticholinergic side effects): paralytic ileus, hyperpyrexia, urinary retention, constipation, blurred vision, increased intraocular pressure, mydriasis, and dry mouth Immune: allergic skin rash, uticaria, photosensitization, edema of face and tongue Hematopoetic: agranulocytosis, leukopenia: Gastrointestinal: nausea, vomiting, anorexia, peculiar taste Endocrine: testicular swelling and gynecomastia in men, breast enlargement and galactorrhea in women, libido disturbances, disturbances of blood sugar levels.

309 Table 3. The Major Side Effects of the Atypical Antidepressants

Side Effects Cardiovascular: orthostatic hypotension, tachycardia, atrial fibrillation, shortness of breath, dizziness Central Nervous System: tremor, tingling of extremities, paresthesia, akathesia, difficulty concentrating, confusion, impaired memory, disorientation, excitement, anxiety, insomnia, drowsiness, slurred speech, lethargy, fatigue, headache Autonomic Nervous System (anticholinergic side effects): blurred vision, nasal congestion, urinary retention, sweating, lightheadedness, hypersalivation Immune: red, tired, and itchy eyes Gastrointestinal: nausea, vomiting, bad taste in mouth Musculoskeletal: achy joints

with the TCAs. The most common side effects of the atypical antidepressants are listed in Table 3. Trazodone (Deseryl, Mead Johnson Pharmaceuticals, Evansville, IN) blocks ~1- and oL2-receptors and inhibits 5-HT reuptake. Trazodone seems to act as a 5-HT agonist at higher doses and as a 5-HT antagonist at lower doses, This drug has no influence on the reuptake of NE within the CNS, nor does it inhibit monoamine oxidase. Antidepressant activity is believed to be produced by the blocking or the reuptake of serotonin at the presynaptic membrane. Long-term treatment can also affect postsynaptic neuronal receptor binding sites (Barry & Schatzberg, 1995). Trazodone is helpful with sleep, which is thought to be an effect of c~-adrenergic and histamine blocking actions and is often prescribed to augment SSRIs as a sedative. There is no rebound or withdrawal phenomena with trazodone. Trazodone is used in the treatment of major depression, generalized anxiety disorder, and insomnia. This drug should be used with caution in patients with cardiac disease (should not be used in acute recovery phase of myocardial infarction), liver disease, and renal impairment. Trazodone has been associated with the occurrence of priapism which required in surgical interventions in 33% of the cases reported (Barry & Schatzberg, 1995).

Selective Serotonin Reuptake Inhibitors The selective 5-HT reuptake inhibitors have greater practical ease of use and have a more selective action on a single receptor site than other classes of antidepressants. These newer antidepressants are the product of research focused specifically on 5-HT and its receptor sites. The SSRIs are

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more effective than placebos and as effective as TCAs. The SSRIs, like the TCAs are a class of broad-acting antidepressants. The SSRIs block the reabsorption of serotonin by the presynaptic neuron, which causes more neurotransmitter to be available to bind to the receptors of the postsynaptic neuron but have little to no effect on the reuptake of norepinephrine or dopamine. They also have little to no effect on cholinergic, histaminergic, or adrenergic receptors, therefore, the side effects associated with the blockade of these receptors are not of clinical significance (Nemeroff, 1994). Because neurotransmitters exhibit a specificity of action, the SSRIs have different side effects and actions than the traditional antidepressants. Anticholinergic actions are significantly lower in the SSRIs than with the TCAs. However, there is a syndrome associated with the sudden withdrawal from SSRIs, that is characterized by tremor, paresthesia, derealization, and depersonalization (Deakin, 1996). Moreover, the effectiveness of SSRIs in long-term use has not been systematically evaluated in controlled trials. Therefore, patients administered SSRIs for extended periods should be periodically reevaluated for the long-term use of these drugs. The side effect profiles of the newer medications increase as they are used in higher doses and for longer durations. The main side effects of the SSRIs include: gastrointestinal effects (vomiting, nausea, diarrhea, dyspepsia); sexual effects (anorgasmia, delayed ejaculation); immune (rash and allergic reactions), anxiety, headache, insomnia, altered appetite and weight, dry mouth, asthenia, activation of hypomania/mania, and seizures (Grebb, 1995). However, the total side effect profile is smaller than that associated with the TCAs. The most common side effects of SSRIs are nausea and insomnia. The release of 5-HT in the gut or centrally results in nausea and vomiting. The nausea tends to diminish with prolonged treatment. Sleep disturbances are a common symptoms of depression, and the SSRIs can cause sleep disturbances. After treatment with a SSRI, successful clinical response usually occurs within 3 to 4 weeks. The concurrent use of a MAOI and fluoxetine or starting treatment with fluoxetine or sertraline shortly after discontinuing a MAOI can result in serotonergic syndrome characterized by: excitement, rigidity, diaphoresis, hyperthermia, and auto-

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nomic hyperactivity. This syndrome can lead to coma and/or death (Grimsley & Jann, 1992). Fluoxetine (Prozac, Dista, Indianapolis, IN) is used to treat depression, obsessive compulsive disorder, and bulimia. Fluoxetine is metabolized mostly in the liver to norfluoxetine which is also a 5-HT reuptake inhibitor. This process contributes to the long duration of action of fluoxetine. Treatment with fluoxetine often results in the side effects of anxiety, agitation, and anorexia. As stated earlier this drug can be activating and interfere with sleep, therefore if this occurs the dose may be split (morning and at lunchtime) (Schatzberg, 1995). IMPLICATIONS FOR ADVANCED PRACTICE NURSES

The selection of medication should include the fundamental criteria of efficacy, side effect profile, and cost to the client. Because antidepressants have different mechanisms of action it seems logical that there would be differences in either their overall efficacy or their spectrum of activity. There is no scientific evidence, however that the efficacy of a specific medication or a specific antidepressant class is greater than another (Burke & Preskorn, 1995). MAOIs cannot not be used in combination with tricyclic antidepressants, because the combination can precipitate a hypertensive crises, severe convulsions, or death, nor with selective 5-HT reuptake inhibitors because a serotonergic syndrome can occur. When a MAOI is being substituted for a TCA, a minimum of 14 days should be allowed to elapse after cessation of one drug and the initiation of the next (Himmelhoch, 1995). The SSRIs are contraindicated in patients using MAOIs and a 14 day waiting period after the discontinuation of therapy with a MAOI should be observed before initiating fluoxetine. Overall, treatment options include medication, psychotherapy, a combination of both, or electroconvulsive therapy. If medication is indicated, than the assessment should include a psychopharmacological assessment. The components of this assessment include: the target symptoms, history of past treatment and responses, family history of treatment and responses, actions of medication and their side effect profile, medication management issues, precantions/contraindications, and interactive effects with other medications. Other clinical responsibilities include; client education, monitoring of medication (pharmacokinetics/pharmacodynamics), re-

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assessment of target symptoms, expected timing of medication effects, and duration of treatment with tapering methods and schedules, and finally relapse prevention. Careful monitoring of medications can increase compliance because side effects that are considered intolerable to the patient can be decreased and/or eliminated. CONCLUSION

It is imperative for the advanced practice nurse to become and remain knowledgeable of current research findings in the field of psychobiology and psychopharmacology to provide effective, costefficient, patient-centered care. By gaining an understanding of the physiological changes that occur with depression and psychopharmacological outcomes, a more effective approach to treating this disorder can be developed. REFERENCES American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed). Washington, DC: Author. Arana, G.W., Baldessarini, R.J., & Ornsteen, M. (1985). The dexamethasone suppression test for diagnosis and prognosis in psychiatry: Commentary and review. Archives of General Psychiatry, 42, 1193-1204. Ayd, E (1956). Thorazine and serpasil treatment of private neuropsychiatric patients. American Journal of Psychiatry, 113, 16. Baraban, J.M. & Coyle, J.T. (1995). Monoamine neurotransmitters. In H.I. Kaplan & B.J. Sadock (Eds.), Comprehensive textbook of Psychiatry/VI, (pp. 25-32). Philadelphia: Williams & Wilkins. Barker, E.I. & Blakely, R.D. (1995). Norepinephrine and Serotonin Transporters: Molecular Targets Of Antidepressant drugs. In EE. Bloom & DJ. Kupfer (Eds.), Psy-

chophamacology; The fourth generation of progress, (pp. 321-333). New York: Raven Press. Barry, J.J. & Schatzberg, A.E (1995). Trazodone and Nefazodone. In H.I. Kaplan & B.J. Sadock (Eds.), Comprehensive textbook of Psychiatry/VI, (pp. 2089-2096). Philadelphia: Williams & Wilkins. Bloom, EE. (1995). Introduction to preclinical neuro-psychopharmacology. In EE. Bloom & D.J. Kupfer (Eds.), Psy-

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