-
Medical Treatment of Depression 24 1
In autogenic training, such responses (termed autogenic
discharges) are not considered abnor- mal, 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
thera- pist, 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 nondirec-
tive 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 physi-
cal symptoms of depressive illness. Psychological symptoms
include feelings of sadness, hopeless- ness, 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 cogni-
tive 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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242 Medical Treatment of Depression
3. What do antidepressants accomplish? Antidepressant
medications reverse the neurovegetative and psychological symptoms
of depres-
sion, restoring a sense of well-being and normal function, as
existed prior to the onset of the depres- sive 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 or- ganic factor (such as anemia,
frontal lobe tumor, or hypothyroidism), that is initiating and
maintain- ing the depressive symptoms.
4. How do antidepressants work? Current understanding suggests
that they work by blocking the reuptake and degradation of im-
portant 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 nec- essary 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 real- istic 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), mirtaza- pine (Remeron), venlafaxine (Effexor)
Monoamine oxidase (MAO) inhibitors: phenelzine (Nardil),
tranylcypromine (Painate), iso- carboxazid (Marplan)
A novel antidepressant with a unique chemical structure,
venlafaxine (Effexor), has been intro- duced within the past year.
In addition to effects on neurotransmitters (see Question 4), this
antide- pressant 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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Medical Treatment of Depression 243
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 stan-
dard 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 pa- tients 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, al- though 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 toler- ance to
specific side effects, and previous history of response to a given
antidepressant.
11. What are the common side effects of antidepressant
treatment?
PharmacoloRy of Antidepressant Medications __ ~~ DRUG 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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244 Medical Treatment of Depression
Pharmacology of Antidepressant Medications (Cont.) DRUG
SSRIs Fluoxetine Paroxetine Sertraline Citalopram
Mixed reuptake blockers Venlafaxine (Effexor)
Noradrenergic and specific serotonergic antidepressant
Mirtazapine M A 0 inhibitors
Isocarboxazid Phenelzine Trany lcypromine
MOST COMMON SIDE EFFECTS
Insomnia, agitation, headache, and GI upset, typically nausea
and cramp- ing. 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-like side effects include agitation, nausea, headache, and
GI distress. Hypertension may occur over time; ongoing BP
monitoring required.
Weight gain, sedation.
Orthostatic hypotension, weight gain, adverse interactions with
tyramine- containing foods. Adverse food interaction characterized
by throbbing headache and BP elevation, with marked pressor
response. Tranylcy- promine 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 MA0 inhibitors are not
uncommonly associ-
ated 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 low- ering 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 MA0 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 as-
sociated with elevated antidepressant blood levels, and is more
commonly associated with tricyclic antidepressants (TCAs) and
bupropion as compared to SSRls and MA0 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 antidepres-
sants, but it has a tendency to induce insomnia and in high
doses has caused a significant incidence of
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Medical Treatment of Depression 245
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 dif-
ferent 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. Antidepressants that induce orthostatic
hy- potension 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 mir- tazapine have a clear advantage in
this regard as they are substantially safer in overdose than other
antide- pressants, especially TCAs. Ingestion of 2000 mg of a TCA
(a 10-day supply of 200 mg/qd) can be fatal.
19. How might antidepressant medications be combined?
Combination with adjunctive medications, such as lithium carbonate
600-1200 mg qd, or tri-
iodothyronine 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 antide- pressant treatments?
Yes. While all antidepressants are equally effective in general,
specific subtypes of depressive dis- order appear to respond
preferentially to different antidepressant treatments. These
subtypes include:
Atypical depression Psychotic depression Melancholia
Manic-depressive illness
Mujor Depressive Disorder Subgroups ESSENTIAL DIAGNOSTIC
SUBGROUP FEATURES ISSUES TREATMENT
ISSUES
Psychotic Delusions More likely to be Hallucinations bipolar
than non-
psychotic types; may be misdiag- nosed as schizo- phrenia
Antipsychotic plus antidepressant more effective treatment than
antidepressant- alone
ECT highly effective
Tuble
PROGNOSTIC FEATURES
Usually a recurrent illness
Subsequent episodes usually psychotic
Psychosis affect conso- nant in depressed patients
Patients with mood incongruent features- have poorer
prognosis
continued on following page
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246 Medical Treatment of Depression
Major Depressive Disorder Subgroups (Cont.) ESSENTIAL DIAGNOSTIC
TREATMENT PROGNOSTIC
SUBGROUP FEATURES ISSUES ISSUES FEATURES
Melancholic
Atypical
Seasonal
Postpartum
Anhedonia Unreactive mood Severe vegeta-
tive depressive symptoms
Reactive mood Overeating and
oversleeping Rejection sensi-
tivity Waves of fatigue Prominent anxiety
and irritability
Can be misdiag- nosed as dementia; more common in elderly
patients
Patients tend to be
May be misdiag- younger
nosed as personal- ity disorder
Onset in low-light More frequent in months nonequatorial
latitudes
Acute onset (
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Medical Treatment of Depression 247
antidepressants in the treatment of psychotic depression.
Increasingly, the novel neuroleptic, risperi- done (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-depressive illness?
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 antidepressants are
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-re- sponsive patients also may
respond to antidepressant medication, and the two can be used in
combi- nation. Phototherapy generally is not associated with side
effects, but some patients report irritability, insomnia, or
increased anxiety during the course of treatment, particularly if
photother- apy is combined with antidepressant medication.
28. When should electroconvulsive therapy (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 pres-
sure, food refusal, or catatonic stupor, which require a rapid
antidepressant response. ECT can be ef- fective within days
(antidepressants commonly require 2-3 weeks).
When the patient has agitation and/or psychotic symptoms,
characterized by delusions or hal- lucination.
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 effi- cacy of ECT.
30. Is ECT effective? ECT has shown a high rate of success in
patients exhibiting marked neurovegetative symptoms, in-
cluding 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 infarc- tion, cardiac
arrhythmias, and intracranial space-occupying lesions; consultation
is advised.
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248 Medical Treatment of Depression
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, bi- lateral electrode placement
is reserved for patients who fail to respond optimally to
unilateral treat- ment. 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 depres-
sive 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 suffi-
cient 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 psy- chosocial stressors as
potential complicating factors. (See flow chart on facing
page.)
Assuming none of the above issues is operative, possible
modification of antidepressant treat- ment 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 ven-
lafaxine (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 com- bined; therefore, a waiting period
of up to 6 weeks is required before beginning an MA0 inhibitor
following a trial of a long-half-life SSRI agent such as
fluoxetine.
-
Medical Treatment of Depression
f Clearly I imDroved Better 4 If no benefits No Rc D/C
Llthium
249
SSRll TCN Others
Ensure Adequate Dose and Time
Measure plasma level when appropriate
JI JI I
4 i 4 .1
Clearly Better Partial Response No Response
Continued Treatment Continue antidepressant Change
antidrepressant Add: Lithium Carbonate class,s ).,MA01
(after eppw '8 waking time) Use Blood Level to Adjust Dose
(25 P@Y)
I
iponse
Continue treatment for at least 6 months Consider indefinite
maintenance if history of recurrent depression
Depending on symptoms, consider 1. antipsychotic agent
3. add: carbamazepine 4. ECT
2. change class
Flow chart for approaching treatment-resistant depression
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 clini- cians 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), ne- fazodone (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, combina- tions 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 MA0 inhibitor. A 2-week washout period is
recommended before beginning an alternative antidepressant trial
following a failed MA0 in- hibitor trial.
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250 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 sys- tems, 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 mainte- nance antidepressant
medication. Note that adequate dosage is an important factor in
effective pro- phylaxis 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 fac- tors (see Questions 1 and 2 ) , treatment
should be continued for 6 months to 1 year prior to attempt- ing a
gradual tapering of antidepressant medication.
Decisions regarding precisely when to taper medication are best
made collaboratively by the pa- tient 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 fluoxe- tine
(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 antide-
pressant medications. Monitoring of cardiac status in the
elderly by obtaining serial electrocardio- grams 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 fol- lowing 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 al- ternative antidepressant with
less cardiac toxicity, such as an SSRI, may be necessary.
44. What other psychiatric conditions commonly 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
cog-
Temporal lobe epilepsy and neurologic conditions impacting the
frontal lobes (particularly the nitive side effects of
antidepressant medication.)
left anterolateral prefrontal cortex)
-
Medical Treatment of Depression 25 I
45. What common medication interactions can influence
antidepressant treatment? 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
en- zymes 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 anticholiner- gic antidepressants, do
well with low doses of antidepressants. If TCAs are to be used,
low-dose de- sipramine 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 an-
timuscarinic 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.
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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 broadcast- ing, catatonia, bizarre
behavior, and associated symptoms such as hypervigilance,
agitation, and irr- tability. 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
increas- ingly are used as first-line agents (see Question 21).
2. List the different typical antipsychotic medications by
chemical class, specifying relative potency in chlorpromazine
equivalents and usual range of daily oral dose.
Potency and Range of Oral Dose of Neuroleptics APPROXIMATE
AMOUNT (MG) OF
DRUG NEEDED TO EQUAL 100 ANTIPSYCHOTIC AGENT RANGE OF DAILY ORAL
GENERIC NAME (TRADE NAME) MG OF CHLORPROMAZINE DOSE (MG)
Aliphatic
Piperazine Chlorpromazine (Thorazine)
Fluphenazine (Permitil,
Perphenazine (Trilafon) Prochlorperazine (Compazine)
Trifluoperazine (Stelazine)
Prolixin)
I00 25-2000
2 1 4 0
10 4-64 IS 15-150 5 2-40
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