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24 1

In autogenic training, such responses (termed autogenic discharges) are not considered abnormal, and are thought to reflect the unloading of pent-up thoughts or muscular activity. A similar perspective is seen in many forms of meditation, where such anxiety is viewed as a too-rapid release, an unstressing, of emotional tension. Given the aversive nature of such responses, it is possible that relaxation-induced anxiety is a major contributor to the high dropout rate often seen in RT. However, in the hands of a skilled therapist, it may become a valuable part of ongoing training (as well as potentially useful in associated psychotherapy interventions) as the patient learns to relax and accept such experiences. Alternatively, the therapist can switch, at least initially, to a more structured form of relaxation (e.g., progressive muscle relaxation or biofeedback).
BIBLIOGRAPHY
1. Barlow DH: Cognitive-behavioral therapy for panic disorder. Current status. J Clin Psychiatry %(Supplement 2):32-37, 1997. 2. Benson H: The Relaxation Response. New York, Morrow, 1975. 3. Borkovec TD, Mathews AM, Chambers A, et al: The effects of relaxation training with cognitive or nondirective therapy and the role of relaxation-induced anxiety in the treatment of generalized anxiety. J Consult Clin Psycho1 55383-888, 1987. 4. Craske MG, Barlow DH: Panic disorder and agoraphobia. In Barlow DH (ed): Clinical Handbook of Psychological Disorders, 2nd ed. New York, Guilford Press, 1993. 5. Gatchel RJ, Blanchard EB (eds): Psychophysiological Disorders: Research and Clinical Applications. Washington, DC, American Psychological Association, 1993. 6. Kabat-Zinn J, Maisson AO, Kristeller J, et al: Effectiveness of a meditation-based stress reduction program in the treatment of anxiety disorders. Am J Psychiatry 149:936-943, 1992. 7. Lehrer PM, Carr R, Sargunaraj D, Woolfolk RL: Stress management technqiues: Are they all equivalent, or do they have specific effects? Biofeedback and Self-Regulation 19:353401, 1994. 8. Murphy LR: Stress management in work settings: A critical review of the health effects. Am J Health Promo 11:112-135, 1996. 9. Suinn RM: Anxiety Management Training: A Behavior Therapy. New York, Plenum Press, 1990.

47. MEDICAL TREATMENT OF DEPRESSION

Russell G. Vasile, M.D
1. What symptoms are affected by antidepressant medications?
Antidepressant medications exert their effects on the psychological and neurovegetative physical symptoms of depressive illness. Psychological symptoms include feelings of sadness, hopelessness, helplessness, worthlessness, guilt, and suicidal ideation. Physical symptoms include lack of energy, trouble concentrating, insomnia or hypersomnia, appetite disturbance (with weight loss or, less commonly, weight gain), diminished interest and/or pleasure in daily activities, psychomotor agitation or retardation, diminished libido, increased anxiety and/or agitation, and impaired cognitive function.

2. What are the factors in clinical presentation that suggest prescription of an antidepressant medication? The diagnosis of major depression-persistent presence of five or more of the above physical features together with psychological symptoms, for a period of 2 weeks-is a strong indication for prescribing antidepressant medications. Additionally, there is evidence that the persistent presence of psychological symptoms even in the absence of marked neurovegetative depressive features may be sufficient indication to prescribe antidepressant medications. Thus, patients with dysthymia also are candidates.

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3. What do antidepressants accomplish?

Antidepressant medications reverse the neurovegetative and psychological symptoms of depression, restoring a sense of well-being and normal function, as existed prior to the onset of the depressive episode. Antidepressant medications typically take at least '2 weeks to begin exerting their therapeutic effects and may take up to 6 weeks at adequate dosage before full therapeutic effect occurs. They are not euphoriants and do not induce elevation of mood in the absence of a depressive disorder. Before beginning antidepressant medication, the clinician should establish that there is no organic factor (such as anemia, frontal lobe tumor, or hypothyroidism), that is initiating and maintaining the depressive symptoms.

4. How do antidepressants work?

Current understanding suggests that they work by blocking the reuptake and degradation of important neurotransmitters including serotonin, norepinephrine, and epinephrine, enhancing their availability at the synaptic level. Thus, the transmission of neurochemical impulses in brain regions rich in noradrenergic and serotonergic neurons, which contribute to the regulation of neurovegetative and psychological function, is facilitated. Recent theories postulate that antidepressant medications mediate various intracellular signaling mechanisms that operate to increase or decrease specific neurotrophic factors. These factors are necessary for the functional viability of neuronal systems involved in the regulation of mood.

5. Can antidepressants be used in conjunction with psychotherapy? Yes, and they are commonly used in this manner. Psychotherapy exerts its primary effect on the psychosocial and interpersonal adaptation of the patient, but has little impact on the neurovegetative symptoms of depression and is not effective for the treatment of severe depressive symptoms. Once a diagnosis of major depression is established, initiate antidepressant medications to afford relief of major depressive symptoms and supportive psychotherapy to enable maintenance of hope and a realistic perspective. The psychotherapy should emphasize a psychoeducational approach, which includes teaching the patient how to marshal social support from family and others. Moreover, when the major symptoms of depression resolve, many patients find insight-oriented psychotherapy helpful in reducing stress by altering maladaptive patterns of behavior. Several studies suggest that the combination of antidepressant medication and psychotherapy is the most comprehensive and effective approach for resolving an acute depressive episode.
6. What are the common antidepressant treatments? Selective serotonin reuptake inhibitors (SSRIs): fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa) Cyclic antidepressants: tricyclic antidepressants, such as imipramine (Tofranil) and amitriptyline (Elavil); heterocyclic or atypical antidepressants, such as amoxapine (Asendin), maprotiline (Ludiomil), bupropion (Wellbutrin), nefazodone (Serzone), trazodone (Desryl), mirtazapine (Remeron), venlafaxine (Effexor) Monoamine oxidase (MAO) inhibitors: phenelzine (Nardil), tranylcypromine (Painate), isocarboxazid (Marplan) A novel antidepressant with a unique chemical structure, venlafaxine (Effexor), has been introduced within the past year. In addition to effects on neurotransmitters (see Question 4), this antidepressant has dopamine-blocking properties.

7. Comment further on SSRIs. SSRIs, developed in the mid-l980s, have become the most popular antidepressants in the world due to their relatively benign side-effect profile and relative safety in overdose. Citalopram (Celexa) is a useful alternative for the patient who has experienced intolerable side effects (see Question 1 1 ) on other SSRIs. Citalopram also exhibits limited medication interactions as it appears to have less

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effect than other SSRIs on the cytochrome P40 enzymes and, therefore, may be a useful choice for patients requiring pharmacologic treatment for medical conditions.

8. Describe the cyclic antidepressants. The tricyclic antidepressants were first used in the early 1960s and subsequently were the standard in the field for many years. The heterocyclic antidepressants, reflecting a variation from the classic tricyclic molecular structure, have found a specific role in selected circumstances. They were introduced throughout the 1970s and 1980s. Each of these agents has specific clinical features that may be advantageous in specific circumstances: Amoxapine has significant dopamine blocking properties and may play a particular role in the treatment of psychotic depression. Trazodone has highly sedating properties and often is useful in the treatment of depressed patients with insomnia. It also is used in low dosage (25-50 mg in the evening) in conjunction with SSRI antidepressants, which usually are activating, to induce insomnia. Bupropion is a highly stimulating antidepressant, which may be of particular value in bipolar patients in the depressed phase of illness. Some clinical studies have suggested that it induces mania or hypomania less frequently than other antidepressants. Nefazodone is a less activating antidepressant with significant anxiolytic properties. It may be a useful choice in the anxious depressive who develops insomnia on standard SSRIs. Mirtazapine enhances central noradrenergic and 5-HT, transmission while blocking 5HT2 and 5HT3 receptors. It may be helpful in underweight patients, as weight gain and increased appetite can be associated with this medication. 9. What is the relationship between M A 0 inhibitors and tyramine? The MA0 antidepressants also were discovered over 20 years ago but fell out of popularity for a time because of adverse reactions, often severe and occasionally (rarely) fatal, involving ingestion of tyramine-containing foods. Prevention of this adverse side effect requires a special tyramine-free diet.

10. What do the antidepressants have in common? Similar rates of response to all antidepressant drugs have been documented. Antidepressant medications may not be fully effective before 6 weeks of administration at adequate dosage, although most treatment-responsive patients show a response 2-3 weeks into the treatment course. The choice of antidepressant is predicated on factors specific to the particular patient, such as tolerance to specific side effects, and previous history of response to a given antidepressant. 11. What are the common side effects of antidepressant treatment?
__
DRUG

PharmacoloRy of Antidepressant Medications

~~

MOST COMMON SIDE EFFECTS

Tricyclics Aniitriptyline Clomipramine Desipramine Doxepin Imipramine Nortriptyline Heterocyclics Amoxapine Bupropion Maprotiline Trazodone Nefazodone

Anticholinergic side effects predominate: dry mouth, constipation, drowsiness, orthostatic hypotension, urinary hesitancy. Weight gain excessive sweating, increased intraocular pressure may occur. Side effects vary within group. Amitriptyline and clomipramine are most anticholinergic; desipramine and nortriptyline are least anticholinergic. Amoxapine may induce mild parkinsonian symptoms. Bupropion may be associated with agitation, insomnia, and seizures. Trazodone is highly sedating, and has been associated with priapism in males. Maprotiline is sedating.
Table continued on following page

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Pharmacology of Antidepressant Medications (Cont.)
DRUG
MOST COMMON SIDE EFFECTS

SSRIs Fluoxetine Paroxetine Sertraline Citalopram Mixed reuptake blockers Venlafaxine (Effexor)

Insomnia, agitation, headache, and GI upset, typically nausea and cramping. Fluoxetine generally more activating (akethesia)than other SSRIs. Sertraline may have more pronounced GI side effects. Paroxetine has mild anticholinergic properties and may cause mild dry mouth. SSRI-likeside effects include agitation, nausea, headache, and GI distress. Hypertension may occur over time; ongoing BP monitoring required.

Noradrenergic and specific serotonergic antidepressant Mirtazapine M A 0 inhibitors Isocarboxazid Phenelzine Tranylcypromine

Weight gain, sedation. Orthostatichypotension, weight gain, adverse interactionswith tyraminecontaining foods. Adverse food interaction characterized by throbbing headache and BP elevation, with marked pressor response. Tranylcypromine activating; may induce insomnia. Phenelzine sedating; has a greater effect on (lowers) blood pressure.

12. Discuss antidepressant effects on sexual function. Cyclic antidepressants, SSRI antidepressants, and M A 0 inhibitors are not uncommonly associated with sexual dysfunction, including diminished libido, delayed ejaculation, and anorgasmia.
These side effects are much less likely to occur with bupropion, and are probably less likely to occur with mirtazapine and nefazodone. Helpful strategies for countering sexual side effects include lowering doses of antidepressant if possible, considering drug suspension for 1-2 days prior to sexual activity, or adding counteracting medicines, typically stimulants, such as yohimbine 5.4 mg qd, or the serotonin antagonist cyproheptadine, which is taken 30 minutes before sexual activity.

13. How might these medications affect weight? Weight gain may be encountered with cyclic antidepressants and M A 0 inhibitors, but is less likely with SSRIs. Weight loss has been reported with the use of SSRIs; thus, they should be used
with caution in the treatment of anorectic or underweight patients.

14. What are possible neurologic side effects? Neurologic side effects include an approximate 1 % risk of induction of seizures. This risk is associated with elevated antidepressant blood levels, and is more commonly associated with tricyclic antidepressants (TCAs) and bupropion as compared to SSRls and M A 0 inhibitors. Mild myoclonus and toxic confusional states, particularly in the elderly, also may be encountered, particularly with elevated blood levels of TCAs. 15. Describe potential cardiologic side effects. Cardiovascular side effects of antidepressant medications include orthostatic hypotension, commonly seen with TCAs, MA0 inhibitors, and bazodone. Among the TCAs, nortriptyline (Pamelor, Aventyl) and desipramine (Norpramin) induce less orthostatic hypotension. In patients with sinus node dysfunction, treatment with TCAs may on occasion induce bradyarrhythmias. Therapeutic concentrations of TCAs may lengthen the QT interval, which predisposes to the development of ventricular tachycardia. Cardiovascular side effects are less commonly observed with the SSRI antidepressants, as well as mirtazapine, nefazodone, and venlafaxine. Venlafaxine may contribute to essential hypertension, particularly at high doses (greater than 225 mg/qd), and monitoring of blood pressure is required.
16. Which antidepressants have side effects especially worth noting? Bupropion is quite activating and is associated with less sexual dysfunction than other antidepressants, but it has a tendency to induce insomnia and in high doses has caused a significant incidence of

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seizures in underweight patients. Trazodone has been associated with priapism in males, yet in low doses is often used adjunctively with SSRI antidepressants to facilitate sleep. Mirtazapine may be associated with weight gain in some patients, and at lower doses is often sedating.

17. What is important to remember about MA0 inhibitors? At least 2 weeks must elapse after discontinuation of other antidepressant medication prior to the initiation of treatment with MA0 inhibitors. For long half-life SSRIs such as fluoxetine (Prozac), 6 medication-free weeks must elapse prior to initiating MA0 inhibitor treatment.

18. What factors influence the choice of antidepressant medications? Since all antidepressants are equally effective in clinical trials, factors specific to a given patient influence choice of antidepressant. Depressive illness is heterogeneous in symptom expression, and individual patients exhibit different side effect patterns and treatment responses. If a patient has had an excellent response to a specific antidepressant in the past, it likely is the best choice for future administration. Similarly, if there is a history of a first-degree relative having had an excellent response to an antidepressant, the likelihood of the patient having a good response is enhanced. In addition, antidepressant side effects are an important consideration. If a patient has insomnia, an antidepressant with sedative properties is advantageous. Conversely, if a patient is experiencing lethargy and hypersomnia, a more activating antidepressant is helpful. Antidepressantsthat induce orthostatic hypotension should be avoided in the management of patients at risk for falls, such as the elderly. Another factor is safety in overdose. The SSRIs and nefazodone, venlafaxine, bupropion, and mirtazapine have a clear advantage in this regard as they are substantially safer in overdose than other antidepressants, especially TCAs. Ingestion of 2000 mg of a TCA (a 10-day supply of 200 mg/qd) can be fatal. 19. How might antidepressantmedications be combined? Combination with adjunctive medications, such as lithium carbonate 600-1200 mg qd, or triiodothyronine 25-50 mcg qd, can enhance efficacy. In some treatment-resistant patients, combinations of antidepressant medications such as low-dose Prozac 10-20 mg qd and low-dose desipramine 25-50 mg qd may be considered, provided that antidepressant blood levels are carefully monitored, as toxic levels of desipramine can result due to medication interactions. Clinicians often combine SSRl antidepressants with bupropion, mirtazapine, or mirtazapine plus bupropion. Busipirone (Buspar) also can be used synergistically with antidepressant medication. 20. Are there specific types of depression that respond more consistently to specific antidepressant treatments? Yes. While all antidepressants are equally effective in general, specific subtypes of depressive disorder appear to respond preferentially to different antidepressant treatments. These subtypes include: Manic-depressive illness Atypical depression Psychotic depression Melancholia
Mujor Depressive Disorder Subgroups
SUBGROUP ESSENTIAL FEATURES DIAGNOSTIC ISSUES TREATMENT ISSUES PROGNOSTIC FEATURES

Psychotic

Delusions Hallucinations

More likely to be bipolar than nonpsychotic types; may be misdiagnosed as schizophrenia

Usually a recurrent Antipsychotic plus illness antidepressant more Subsequent episodes effective treatment usually psychotic than antidepressantPsychosis affect consoalone nant in depressed ECT highly effective patients Patients with mood incongruent featureshave poorer prognosis
Tuble continued on following page

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Major Depressive Disorder Subgroups (Cont.)

SUBGROUP

ESSENTIAL FEATURES

DIAGNOSTIC ISSUES

TREATMENT ISSUES

PROGNOSTIC FEATURES

Melancholic

Anhedonia Unreactive mood Severe vegetative depressive symptoms

Can be misdiagAntidepressant medinosed as dementia; cation essential more common in ECT highly effective elderly patients if medications fail to produce remission TCAs less effective than MA0 inhibitors; SSRIs show promise as therapeutic agents

Maintenance treatment should be considered if recurrent episodes occur Unclear

Atypical

Patients tend to be Reactive mood Overeating and younger May be misdiagoversleeping nosed as personalRejection sensiity disorder tivity Waves of fatigue Prominent anxiety and irritability Onset in low-light months More frequent in nonequatorial latitudes

Seasonal

May respond to anti depressants Phototherapy is effective option Hospital treatment required Medical treatment necessary

Recurs seasonally

Postpartum

Acute onset (<30 Often heralds days) in postbipolar disorder partum period Severe, labile mood symptoms

50% chance of recurrence in next postpartum period Associated with vulnerability to switch to mania and bipolar illness

ECT = electroconvulsive therapy.

21. Which antidepressants are best for atypical depression? MAO-I antidepressants are more efficacious than classic TCAs for the treatment of atypical depression. Atypical depressions are characterized by overeating, oversleeping, prominent anxiety and phobic concerns, and worsening of depression in the evenings. Emotional lability, irritability, rejection sensitivity, and a dramatic, histrionic, yet dysthymic interpersonal style (sometimes termed hysteroid dysphoria) also may characterize these patients. Another atypical depressive symptom is the sensation of episodic waves of leaden fatigue. Specifically, the M A 0 inhibitor phenelzine is distinctly superior to the TCA imipramine in the treatment of this subtype. SSRIs also are highly effective and unlike M A 0 inhibitors do not require attention to dietary concerns.

22. Panidanxiety disorders respond more consistently to which medications? The SSRI antidepressants paroxetine and sertraline are effective in the treatment of panic disorder,
and now carry this indication. Imipramine also has distinct anti-panic properties, and may be a preferential choice for patients with comorbid panic and depressive illness who cannot tolerate SSRI antidepressants. Venlafaxine has been approved for treatment of generalized anxiety disorder. Nefazodone and mirtazapine also can reduce anxiety symptoms in depressed patients; they may have a dual efficacy. MA0 inhibitors have demonstrated efficacy for the treatment of patients with panic andor phobic symptoms, and warrant consideration in patients for whom SSRls are ineffective or intolerable.

23. Which antidepressants are most effective for psychotic depression?

Depressive disorders associated with psychotic features respond to antidepressants when combined with antipsychotic medications. Psychotic depression also exhibits a high rate of response to electroconvulsive therapy. Some clinicians feel that amoxapine may have superior efficacy to other

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antidepressants in the treatment of psychotic depression. Increasingly, the novel neuroleptic, risperidone (Risperdal), 1-3 mg qd, is added. For patients with bipolar tendencies, consider olanzapine (Zyprexa) 5 mg qd, as it appears to have mood-stabilizing as well as anti-psychotic characteristics.

24. Which medications are best for manic-depressiveillness? Many clinicians feel that the antidepressant bupropion is a superior choice for the treatment of manic-depressive patients in the depressed phase of their illness, because it is less likely to induce mania than other antidepressants. Limited data suggests that paroxetine (Paxil) also is less likely to induce mania. Avoid TCAs because they are most likely to induce mania.

25. Which personality disorder traits respond best to which antidepressants?

Clinical trials currently underway suggest that SSRI antidepressants may have specific benefits in depressed patients with a proclivity towards inappropriate anger and impulsivity. Indeed, SSRIs reduce impulsivity and inappropriate anger in nondepressed patients with borderline or antisocial personality disorder.

26. True or false: In higher doses, SSRI antidepressantsare highly effective for the treatment of OCD symptoms. True. Fluvoxamine (Luvox) is specifically marketed in the U.S. with an OCD indication. The antidepressant clomipramine (Ananfranil) has specific beneficial effects on OC symptoms and may be a preferential choice for patients with depression and associated OCD or OC symptoms.
27. Is phototherapy helpful in depression? In some patients who experience depression during low-light months, 30 minutes of bright, white artificial light in the morning and/or evening hours can reduce symptoms. Phototherapy-responsive patients also may respond to antidepressant medication, and the two can be used in combination. Phototherapy generally is not associated with side effects, but some patients report irritability, insomnia, or increased anxiety during the course of treatment, particularly if phototherapy is combined with antidepressant medication.

28. When should electroconvulsivetherapy (ECT) be considered? When the patient has failed to respond to several antidepressant medication trials. When the patient is experiencing threatening acute symptoms such as intense suicidal pressure, food refusal, or catatonic stupor, which require a rapid antidepressant response. ECT can be effective within days (antidepressants commonly require 2-3 weeks). When the patient has agitation and/or psychotic symptoms, characterized by delusions or hallucination. When antidepressant medications are associated with unacceptable side effects. When the patient has a history of a positive response to previous ECT treatments. When the patient has a medical condition that precludes the use of antidepressants.

29. Is ECT an adjunct to antidepressants?

During the course of ECT, antidepressant medication treatment is suspended, although low-dose antianxiety medication may be used. High-dose antianxiety medications may interfere with the efficacy of ECT.

30. Is ECT effective? ECT has shown a high rate of success in patients exhibiting marked neurovegetative symptoms, including marked agitation or psychomotor retardation, and in patients with psychotic depression. ECT has an excellent safety profile and rapid onset of action. There are no absolute contraindications. However, ECT causes a transient elevation in blood pressure, heart rate, cardiac workload, and blood-brain barrier permeability. Therefore, it should be considered with caution in patients with recent myocardial infarction, cardiac arrhythmias, and intracranial space-occupying lesions; consultation is advised.

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31. Describe the side effects of ECT. The most common side effects are a transient postictal confusional state and anterograde and retrograde periods of memory disturbance, which may take 2-3 weeks to resolve after completion of the course of ECT. Therapy usually consists of three treatments per week for up to 4 weeks. Recent advances in ECT instrumentation have reduced cognitive side effects and permitted some patients to be treated as out-patients, with careful day program andor family monitoring.
32. Can electrode placement affect results? Yes. There are two standard electrode placement positions, unilateral nondominant hemisphere placement and bilateral electrode placement, which utilizes a bitemporal positioning. Generally, bilateral electrode placement is reserved for patients who fail to respond optimally to unilateral treatment. A disadvantage of bilateral treatments is that they cause somewhat more confusion and transient memory impairment than unilateral treatments.

33. Are there any new approaches to treating depression somatically? An experimental alternative to ECT, transcranial magnetic stimulation (TMS), currently is being evaluated in clinical research trials. This treatment involves highly topographically selective mild electrical stimulation of the left anterolateral prefrontal cortex. It does not require general anesthesia and has few side effects. TMS shows promise as an antidepressant treatment. It remains to be seen whether it will be a viable alternative to ECT.
34. How successful is pharmacologic treatment of depression? Initial pharmacologic interventions are ineffective in 20-30% of patients with a major depressive disorder. The most common factors are inadequacy of dosage and treatment duration and failure to detect and treat a coexisting medical or psychiatric disorder. The duration of treatment required before a medication trial can be ruled a failure is 6 weeks. Blood levels of antidepressant medication can be assessed for adequacy of dosage, although appropriate levels are not precisely established for every antidepressant medication.

35. What steps should be taken if a medication fails? If a patient does not respond to an antidepressant medication despite adequate dosage and sufficient duration, other interventions are required. Reassess possible medical factors contributing to treatment resistance. Rule out comorbid psychiatric conditions including anxiety disorders, alcohol or substance abuse, neuropsychiatric disorders, and personality disorders. Identify chronic psychosocial stressors as potential complicating factors. (See flow chart on facing page.) Assuming none of the above issues is operative, possible modification of antidepressant treatment could include: Changing to an alternate class of antidepressant medication. Using adjunctive medications to boost antidepressant response. Using combinations of antidepressant medications. Considering the use of ECT as a treatment alternative.

36. What might changing to an alternate class of antidepressant involve? Three options are: using an SSRI if a TCA has failed, switching to a mixed agent such as venlafaxine (Effexor), and considering an M A 0 inhibitor. Many clinicians combine a low dose of a TCA such as desipramine, 30 mg qd, with an SSRI medication such as sertraline (Zoloft), 100 mg qd. Take care to use low doses of TCAs for these purposes, as medication interactions with SSRI antidepressants drive up TCA blood levels. Alternative antidepressants including nefazodone and mirtazapine warrant consideration as options. Note that serious adverse reactions can occur if SSRI and MA0 inhibitor medications are combined; therefore, a waiting period of up to 6 weeks is required before beginning an M A 0 inhibitor following a trial of a long-half-life SSRI agent such as fluoxetine.

Medical Treatment of Depression

SSRll TCN Others

249

JI JI Measure plasma level when appropriate

EnsureAdequate Dose and Time Clearly Better Continued Treatment Partial Response

No Response

4
Continue antidepressant Add: Lithium Carbonate Use Blood Level to Adjust Dose Clearly Better
(aftere p p w

.1
Change antidrepressant class,s ).,MA01
'8 waking time)

I 4

imDroved
I

If no benefits D/C Llthium

(25 P@Y)

No R c iponse

Continue treatment for at least 6 months Consider indefinite maintenance if history of recurrent depression

Depending on symptoms, consider 1. antipsychotic agent 2. change class 3. add: carbamazepine 4. ECT

Flow chart for approaching treatment-resistantdepression

37. Which adjunctive medications can boost antidepressant response? Commonly added are: lithium carbonate, in a standard dosage of 300 mg tid; Cytomel (T3), 25-50 mcg; or low doses of stimulants such as methylphenidate (Ritalin), 5-10 mg qd. Some clinicians add busipirone (Buspar), a serotonergic antianxiety medication, to an antidepressant regimen to enhance antidepressant response. Hormonal treatments, such as estrogen in women, are less well established as adjunctive agents.
38. Describe some antidepressant combinations that may be helpful. Treatment-resistant patients may respond to a low-dose SSRI plus a low-dose TCA, typically fluoxetine, 10-20 mg qd, with desipramine, 10-20 mg qd. Also consider bupropion (Wellbutrin), nefazodone (Serzone), mirtazapine (Remeron), and venlafaxine (Effexor), all of which have slightly different biochemical properties from the SSRIs. Combinations of these agents, e.g., combining bupropion with nefazodone or mirtazapine, may be tried. In treatment-refractory cases, combinations such as bupropion and mirtazapine, or bupropion and nefazodone, can be helpful. Note that it is less optimal to combine two simulating or two sedating antidepressants, and it is inadvisable to combine any antidepressant with an M A 0 inhibitor. A 2-week washout period is recommended before beginning an alternative antidepressant trial following a failed M A 0 inhibitor trial.

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Medical Treatment of Depression

39. When is electroconvulsive therapy an alternative approach? ECT is an option in treatment-resistant patients failing to respond to any of the interventions above. Approximately 50% of medication-resistant patients exhibit a positive response to ECT. The novel antidepressant venlafaxine, which acts on both noradrenergic and serotonergic neuronal systems, has shown promise in a subgroup of patients who have responded to other antidepressants. Venlafaxine generally is well tolerated, but has a spectrum of side effects (e.g., nausea, insomnia, and anxiety) similar to to the SSRIs.

40. Describe the phases of treatment with antidepressant medication. Antidepressant treatment can be divided into three phases: acute treatment, which occurs in the initial stages of a depressive episode; continuation treatment, which covers the 6 months following the acute phase; and maintenance treatment, or chronic preventive treatment.
41. When is maintenance treatment appropriate? Increasing evidence suggests that patients who have had three or more major depressive episodes, or histories of chronic low-grade depressive symptomatology are candidates for maintenance antidepressant medication. Note that adequate dosage is an important factor in effective prophylaxis of depression; thus, full dosage of medications should be administered for maintenance treatment. If a patient has had one initial depressive episode and does not exhibit any of the risk factors (see Questions 1 and 2 ) , treatment should be continued for 6 months to 1 year prior to attempting a gradual tapering of antidepressant medication. Decisions regarding precisely when to taper medication are best made collaboratively by the patient and doctor, with full consideration of the patients life circumstances, including the likelihood of a recurrent episode of depression. 42. Why is tapering important? Withdrawal symptoms may occur with the abrupt discontinuation of antidepressant medications. Withdrawal symptoms include feelings of malaise, agitation, lightheadedness, confusion, and increased dysphoria. The likelihood of withdrawal phenomena occurring is most pronounced with short-half-life antidepressants such as paroxetine (Paxil) as compared to long-half-life medications such as fluoxetine (Prozac). As a precaution, all antidepressants should be tapered over several days, if possible.
43. What are the risks of long-term treatment with antidepressants? There are no well established long-term risks associated with chronic administration of antidepressant medications. Monitoring of cardiac status in the elderly by obtaining serial electrocardiograms and episodic assessment of liver function tests is recommended. Chronic administration of lithium carbonate requires periodic assessment (q 6-12 months unless symptomatic) of CBC with differential, thyroid tests, and measures of renal function including urine concentrating capacity following water restriction. Since an increasing number of patients require maintenance antidepressant treatment, problems necessitating treatment modification may become more common simply due to the time factor. For example, the development of coronary vascular disease may lead to a risk of arrhythmia, and an alternative antidepressant with less cardiac toxicity, such as an SSRI, may be necessary.
44. What other psychiatric conditionscommonly influence the medical treatment of depression? It is crucial to have a high index of awareness of other psychiatric conditions that can influence and adversely affect the treatment of depressive disorder. These include: Substance abuse, particularly alcoholism Anxiety disorders, including panic disorder Personality disorders, most commonly borderline personality disorder Dementia superimposed on depression (The elderly are especially sensitive to the adverse cognitive side effects of antidepressant medication.) Temporal lobe epilepsy and neurologic conditions impacting the frontal lobes (particularly the left anterolateral prefrontal cortex)

Medical Treatment of Depression

45. What common medication interactions can influence antidepressanttreatment?

25 I

Antidepressants can potentiate the sedative and central nervous system effects of a variety of medications, including antihistamines, barbiturates, and anticonvulsants. Do not use barbiturates with M A 0 inhibitors-this is a potentially fatal combination. TCA blood levels can be increased sharply with concomitant usage of SSRIs. M A 0 inhibitors and SSRI antidepressants should never be combined, as a potentially fatal serotonergic syndrome may occur. Many antidepressants can inhibit enzyme systems involved in the breakdown of common medications such as warfarin and digoxin. Citalopram (Celexa) appears to have less effect than other SSRIs on the P450 family of enzymes and thus may be favored in the medically complicated patient. Carefully investigate medication interactions !

46. What are the treatment implications of concurrent general medical disorders? Sympathomimetic agents, such as bronchodilators for asthma, must be avoided in patients on
M A 0 inhibitors. Additionally, patients on M A 0 inhibitors should never be given meperidine, as fatal drug interaction may occur. Patients with cardiac disease, including subclinical sinus node conduction disease or a history of ventricular arrhythmia, are best treated with bupropion, fluoxetine, sertraline, or ECT as opposed to TCAs. Patients with dementia, given their vulnerability to adverse cognitive side effects of anticholinergic antidepressants, do well with low doses of antidepressants. If TCAs are to be used, low-dose desipramine or nortriptyline, which have minimal anticholinergic properties compared to other TCAs, are advised. Bupropion, fluoxetine, or trazodone with lower anticholinergic effects may be preferable. Narrow angle glaucoma is a relative contraindication to anticholinergic antidepressants. Obstructive uropathy usually secondary to prostatism mitigates against the use of highly antimuscarinic antidepressants. SSRI antidepressants, desipramine, or bupropion are advised in this circumstance. Severe depression in pregnancy can be safely treated with ECT. The relative risk (particularly in the first trimester of pregnancy) of inducing birth defects, versus the benefits of antidepressant medication, should be reviewed on a case-by-case basis. Accumulating evidence supports the view that fluoxetine also is quite safe in pregnancy. BIBLIOGRAPHY
I. Abramowicz M: Drugs for psychiatric disorders. Med Lett Drugs Ther 36(933):89-95, 1994. 2. Altshuler L, Post RM, Leverich GS, et al: Antidepressant-induced mania and cycle acceleration: A controversy revisited. Am J Psychiatry 152:1130-1138, 1995.

3. Ayd Jr F: Nefazadone: The latest FDA-approved antidepressant. International Drug Therapy Newsletter 30:4, April 1995. 4. Blacker D: Maintenance treatment of major depression: A review of the literature.Ham Rev Psychiatry 4: 1-9, 1996. 5 . Coccaro EF, Kavoussi RJ: Fluoxetine and impulsive aggressive behavior in personality-disordered subjects. Arch Gen Psychiatry 54:1081-1088, 1997. 6. Cohen LS, Altshuler LL: Pharmacologic management of psychiatric illness during pregnancy and the postpartum period. Psychiatr Clin North Am (Annual of Drug Therapy) 4 2 - 6 0 , 1997. 7. Covey LS, Glassman AH, Stetner F: Major depression following smoking cessation. Am J Psychiatry 154: 263-265, 1997. 8. Duman RS, Heninger GR, Nestler EJ: A molecular and cellular theory of depression.Arch Gen Psychiatry 54597-606, 1997. 9. Ereshefsky L, Riesenman C, Francis Lam YW: Serotonin selective reuptake inhibitor drug interactions and the cytochrome P450 system. J Clin Psychiatry 57(supp 8):17-25, 1996. 10. Fawcett J, Marcus RN, Anton S, et al: Response of anxiety and agitation symptoms during nefazodone treatment of major depression. J Clin Psychiatry 56(supp 6):3742, 1995. 1 I . Flint AJ, Rifat SL: Two-year outcome of psychotic depression in late life. Am J Psychiatry 155:178-183, 1998. 12. Frazer A: Antidepressants.J Clin Psychiatry 58(suppl6):9-25, 1997. 13. Freeman MP, Stoll AL: Mood stabilizer combinations: A review of safety and efficacy.Am J Psychiatry 155: 12-21, 1998. 14. Gatti F, Bellini L, Gasperini M, et al: Fluvoxamine alone in the treatment of delusional depression. Am J Psychiatry 153:414416, 1996.

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Antipsychotic Medications

15. Gelenberg AJ: The P450 family. Biological Therapies in Psychiatry Newsletter. Vol. 18(8), August 1995. 16. Gershon S: Current therapeutic profile of lithium. Arch Gen Psychiatry 54, 1997. 17. Kupfer DJ, et al: Three year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry 47:1093-1099, 1990. 18. Leonard BE: New approaches to the treatment of depression. J Clin Psychiatry 57(suppl4), 1996. 19. Nelson JC: Safety and tolerability of the new antidepressants. J Clin Psychiatry 58(suppl6):26-31, 1997. 20. Nemeroff CB, Devane CL, Pollock BG, et al: Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 153:311-320, 1996. 2 1. Nierenberg AA, Feighner JP, Rudolph R, et al: Venlafaxine for treatment-resistant unipolar depression. J Clin Psychopharmacol 14:4 1 9 4 2 3 , 1994. 22. Quitkin FM, McGrath PJ, Stewart AW, et al: Atypical depression, panic attacks, and response to imipramine and phenelzine: A replication. Arch Gen Psychiatry 47:935-941, 1990. 23. SchatzbergA F Fluoxetine in the treatment of comorbid anxiety and depression. J Clin Psychiatry 135-12, 1995. 24. Schatzberg AF, Cole JO, Debattista C: Manual of Clinical Psychopharmacology. 3rd ed. Washington, DC, American Psychiatric Press, 1997. 25. The Medical Letter: Citalopram for depression. 40(1041), December 4, 1998. 26. Wheatley DP, van Morraert M, Timmerman L, Kremer CME: Mirtazapine: Efficacy and tolerability in comparison with fluoxetine in patients with moderate to severe major depressive disorder. J Clin Psychiatry 59:306-3 12, 1998. 27. Wisner KL, Perel JM, Findling RL: Antidepressant treatment during breast feeding. Am J Psychiatry 153: 1132-1 137, 1996.

48. ANTIPSYCHOTIC MEDICATIONS

Herbert T.Nagamoto, M . D
1. What are antipsychotic medications? Antipsychotic medications are used to treat psychotic symptoms in patients with schizophrenia and other conditions. Symptoms may include hallucinations, delusions, paranoia, thought broadcasting, catatonia, bizarre behavior, and associated symptoms such as hypervigilance, agitation, and irrtability. Typical antipsychotic medications also have neurologic side effects, leading to the alternate designation of neuroleptics (of the neuron). Antipsychotic medications are divided into typical agents, which are similar to haloperidol, and atypical agents, as exemplified by clozapine, which have different therapeutic and side-effect profiles and a different mechanism of action. This is a rapidly evolving area of psychopharmacology, and the newer atypical antipsychotic agents increasingly are used as first-line agents (see Question 21).
2. List the different typical antipsychotic medications by chemical class, specifying relative potency in chlorpromazineequivalents and usual range of daily oral dose.

Potency and Range of Oral Dose of Neuroleptics

ANTIPSYCHOTIC AGENT GENERIC NAME (TRADE NAME) APPROXIMATE AMOUNT (MG) OF DRUG NEEDED TO EQUAL 100 MG OF CHLORPROMAZINE RANGE OF DAILY ORAL DOSE (MG)

Aliphatic
Chlorpromazine (Thorazine)

I00
2
10 IS

25-2000
140 4-64 15-150 2-40
Table continued on following page

Piperazine
Fluphenazine (Permitil, Prolixin) Perphenazine (Trilafon) Prochlorperazine (Compazine) Trifluoperazine (Stelazine)