Treatment-Resistant Depression Case 4: Level 4
John is a 45 yo male with treatment-resistant depression who presents for followup. He has tried multiple medications over the past 6 months including Celexa
and Wellbutrin (separate and together) along with CBT. His PHQ-9 one month
ago was 20, today it is 22. He states his marriage is on the rocks and he
frequently thinks of suicide. He owns a handgun and has thought he might be
better off dead. He says his wife is going to move out this weekend and he is at
the end of his rope.
1. What treatments for depression have proven benefit in reducing suicide?
2. What is the evidence for the use of atypical antipsychotics for the treatment of
depression? Psychostimulants?
3. What would you do for John if you saw him in clinic? How would you treat him if
he denied SI/HI? ( use the STAR*D trial or other EBM resources)
4. Who are candidates for ECT? Does it work?
1. Lithium is the only medication which has been shown to decrease the rate of
suicide in major depression. However, the use of lithium for augmentation may
be declining due to the need for serum levels, side effects on initiation (GI,
tremor, polyuria), and availability of other drug options. Although data on ECT for
decreasing suicide is conflicting, it is considered the most efficacious treatment
for severe major depression.
Patients with suicidal ideation at the start of treatment, antidepressants may
reduce thoughts of death or suicide. A meta-analysis of 16 RCTs (8477 adults
with major depression) found that suicidal thoughts and behavior decreased
significantly more with either fluoxetine or venlafaxine, than with placebo. The
effect appeared to be mediated by decreases in depressive symptoms.
There is no clear evidence that treatment of depressed patients with
antidepressant drugs increases risk of suicidality (ie, suicidal ideation, action to
prepare for an attempt, attempt or nonfatal self-harm, or death). However, there
may be an age-specific effect, such that antidepressants may raise the risk of
suicide attempts (nonfatal self-harm) or preparatory acts in patients aged 18 to
24 years during the first several weeks of treatment, have no effect upon patients
aged 25 to 30 years, and may lower the risk in patients 31 years and older. It is
not known whether there are other sociodemographic or clinical factors
associated with risk of suicidality in patients treated with antidepressants. In
addition, it is not known whether specific antidepressant drugs differ in their risk
of suicidality, or how polypharmacy affects the risk.
Social support and family connectedness is protective against suicide, while
family discord increases the risk of suicide. Pregnancy decreases the risk of
suicide, as does parenthood particularly for mothers. Religiosity and participating
in religious activities is associated with a lower risk of suicide. Immediate
psychiatric services, usually including hospitalization, are necessary in patients
felt to be at imminent risk for self-harm.
Patients in whom the risk of suicide is high but not imminent (eg, those with
depression or alcohol abuse who express a desire to commit suicide but who do
not have a specific plan) need aggressive treatment, but not necessarily
hospitalization. Older antidepressant medications such as tricyclic
antidepressants and monoamine oxidase inhibitors may be lethal if taken in high
doses; they should be avoided if possible in the depressed patient who has
expressed thoughts of suicide. The selective serotonin reuptake inhibitors
(SSRIs) appear to be much safer when taken in overdose and should be the
drugs of choice in potentially suicidal depressed patients.
As part of assessing or supporting a patient's ability to avoid acting on suicidal
thoughts, the concept of "contracting for safety" or agreeing to a "no harm
contract" has been used in clinical practice. The terms imply that patients can
promise clinicians that they will try not to harm themselves when they are
suicidal. The terms are not consistently defined or used, and clinicians generally
do not receive formal training in suicide prevention contracts. Additionally,
despite their wide use in clinical practice, there is little evidence that such
contracts actually reduce suicide. As such, contracts may provide a false sense
of security. Better tools include open dialogue between patients and clinicians to
establish a therapeutic alliance and the performance of ongoing comprehensive
assessments of suicide risk over time.
2. Second-generation antipsychotics are efficacious as augmentation for acute
unipolar major depression that does not respond to initial treatment with an
antidepressant. In combination with an antidepressant, they are also effective for
psychotic depression and the atypical antipsychotic quetiapine may be effective
as monotherapy for nonpsychotic depression. The efficacy of atypical
antipsychotics for major depression is hypothesized to be the result of effects
upon serotonergic, noradrenergic, and dopaminergic systems.
A meta-analysis of 16 RCTs examined the efficacy of adjunctive aripiprazole,
olanzapine, quetiapine, or risperidone in 3480 patients with nonpsychotic,
unipolar major depression who failed at least one course of monotherapy with
various antidepressants (usually an SSRI or SNRI). Remission occurred in
significantly more patients who received an adjunctive antipsychotic compared
with adjunctive placebo (31 vs. 17 percent). Discontinuation because of adverse
side effects was significantly higher in patients who received an adjunctive
antipsychotic compared with adjunctive placebo (9 vs. 2 percent). Neither
remission nor response rates differed significantly among the four antipsychotics.
Differences in efficacy between adjunctive aripiprazole, olanzapine, quetiapine,
or risperidone have not been demonstrated, but no head-to-head randomized
trials have been conducted. In addition, it is possible that secondary clinical
effects may differentially affect the utility of adjunctive antipsychotics for treating
major depression. As an example, quetiapine is a sedating atypical antipsychotic
and is useful for insomnia. Olanzapine causes the most weight gain, which may
help patients with anorexia and excessive weight loss. It is reasonable to use an
adjunctive antipsychotic with any antidepressant. In randomized trials, the
antipsychotic was usually added to a selective serotonin reuptake inhibitor or a
serotonin-norepinephrine reuptake inhibitor. Improvement of depressive
symptoms with adjunctive second generation antipsychotics largely occurred
within the first two weeks of treatment.
Psychostimulants: two randomized trials involving 411 patients with treatmentresistant depression (and fatigue in most cases) compared augmentation of
antidepressant treatment with modafinil or placebo. There was no significant
difference in reducing depressive symptoms, indicating that modafinil
augmentation is not efficacious. Methylphenidate as adjunctive treatment was
also not effective in reducing depressive symptoms.
3. See attached figures for assistance and/or www.star-d.org
For initial treatment of depression, the effectiveness of antidepressant medication
is comparable between classes; therefore, selection of a particular
antidepressant should largely be based on the side effect profile of the drug, any
history of response in the patient or a family member, and cost of the medication.
Evidence regarding psychotherapy and pharmacotherapy has recently been
enhanced by results from the STAR*D (Sequenced Treatment Alternatives to
Relieve Depression) study, a seven-year randomized controlled trial (RCT) that
evaluated medication switching and augmentation in 3,671 outpatients with
unipolar depression. Citalopram (Celexa) was the initial treatment (20mg daily,
titrated to 60mg daily if needed). Three additional levels of treatment were
included, based on response. Each treatment level was sustained for at least 12
weeks (if the drug was tolerated) before response was determined.
The STAR*D trial found that patients who received CBT after failing to respond to
citalopram (with or without continued citalopram) had similar rates of response
(i.e., at least 50% improvements in symptoms compared with baseline) and
remission (i.e., resolution of symptoms) as those who received other medication
regimens. Patients who received CBT alone (rather than in conjunction with
citalopram) achieved remission less rapidly, but they also had fewer adverse
effects than those who were switched to other medications.
A systematic review identified 16 RCTs of treatment resistant depression, all of
which were considered too small to detect an important clinical response. (Br J
Psychiatry 2002)
The STAR*D trial significantly expanded the evidence base for pharmacotherapy
of treatment-resistant unipolar major depression. Remission rates after the first
level of treatment were 37%; after the second level, 31%; after the third level, 14
percent; and after the fourth level, 13 percent. The cumulative remission rate was
67%. In general, patients who required more treatment steps had higher relapse
rates. Ultimately, fewer than one half of patients achieved sustained remission,
even after all four treatment levels.
There were significant differences between only three treatment strategies tested
in the STAR*D trial. Augmentation of citalopram with bupropion resulted in
slightly improved response rates and fewer adverse effects compared with
buspirone (Buspar), but no difference in remission rates. Augmentation of the
level 2 treatment with T3 resulted in fewer adverse effects than augmentation
with lithium, but there was no difference in effectiveness. Venlafaxine plus
mirtazapine resulted in slightly improved response rates and fewer adverse
effects compared with tranylcypromine (Parnate). Beyond these findings, the
STAR*D trial did not find that any of the studied treatments are better than
another. Other evidence suggests that augmentation of second-generation
antidepressants or TCAs with pindolol, lithium, or methylphenidate (Ritalin) is not
effective for treatment resistant depression.
4. ECT is used primarily for treatment-resistant depression, although it may be used
in high-risk cases of severe or psychotic depression, or when pharmacotherapy
is contraindicated or not tolerated. It is more effective than placebo, simulated
ECT or antidepressants, although long-term effectiveness is unclear. The primary
side effect is short-term cognitive impairment (learning impairment and memory
deficit), which generally resolves within days to weeks. Cognitive impairment may
be inversely related to treatment effectiveness (greater with bilateral and highdose therapy). Overall, ECT is more efficacious than any other treatment for
severe major depression.