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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 16 of 16. This is the beginning of the thread.
Posted by Bill L on November 27, 2002, at 13:32:31
This is an article I read today from docguide.com. It seems to be very well written. Happy Thanksgiving!
Options for Treatment-Resistant Depression
by Glen L. Stimmel, Pharm.D., BCPP, and Alice S. Myong, Pharm.D.
Psychiatric Times July 2002 Vol. XIX Issue 7
--------------------------------------------------------------------------------Educational Objectives:
After reading this article, you will be familiar with:
Definitions of treatment response and remission.
Strategies for augmenting and combining medication for patients with treatment-resistant depression (TRD).
Strategies for switching treatment.
Nonpharmacological options for treating TRD.
Who will benefit from reading this article?Psychiatrists, neurologists, primary care physicians, physician assistants, psychologists, psychiatric nurses, social workers and other mental health care professionals. Continuing education credit is available for most specialties. To determine if this article meets the requirements of your specialty, please contact your state licensing board.
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Dr. Stimmel is professor of clinical pharmacy and psychiatry for the Schools of Pharmacy and Medicine at University of Southern California (USC). Dr. Stimmel has indicated that he has received speaking honoraria from Organon Inc., Wyeth Pharmaceuticals and Pfizer Inc., and he has served as consultant for Janssen Pharmaceutica Products L.P., Eli Lilly and Company, AstraZeneca Pharmaceuticals LP and Pfizer Inc.Dr. Myong is a lecturer and resident in psychiatric pharmacy practice for the School of Pharmacy at USC. Dr. Myong has indicated that she has no financial relationships to disclose relating to the subject matter of this article.
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Treatment-resistant depression (TRD) is primarily a phenomenon of labeling. Patients are treatment-refractory only because they have been labeled as such by their clinician, even though most patients have the potential to respond to treatment (Guscott and Grof, 1991). The current standard in treating major depression is defined as full remission of symptoms and restoration of functioning (Nierenberg and Wright, 1999). Thus, it could be argued that most patients treated for an acute depressive episode are treatment-resistant since most do not achieve full remission of symptoms with the first somatic or psychosocial treatment they receive (Sackeim, 2001).
True TRD is usually defined, however, as a much smaller percentage of patients in whom contributory factors to treatment failure have been ruled out. When a patient presents with presumed TRD, the diagnosis requires re-evaluation to identify comorbid medical or psychiatric conditions that may be interfering with expected clinical response. The next step is to identify "pseudo-resistance," in which the patient, for whatever reason, did not have an adequate antidepressant trial.
Given an accurate diagnosis and an adequate antidepressant trial, patients can then be categorized as nonresponders to a single antidepressant drug or as patients with true TRD who fail at least two separate and adequate trials of antidepressants from two different pharmacological classes (O'Reardon and Amsterdam, 2001; Thase, 2002). The following discussion of augmentation and switching strategies is appropriate only for patients with true TRD.
Adequate Trial
Adequate antidepressant drug therapy for a major depressive episode has been well-defined in the clinical literature and in several national treatment guidelines. At least eight weeks at a full therapeutic dose is necessary to evaluate the efficacy of an antidepressant (O'Reardon and Amsterdam, 2001), and treatment must continue for an additional four to five months (American Psychiatric Association, 2000). Unfortunately, many patients with major depression do not receive an adequate course of therapy. It is estimated that 30% to 60% of patients referred for evaluation of treatment resistance have received inadequate treatment (Dawson et al., 1999; Keller et al., 1986; Keller et al., 1982; Souery et al., 2001; Souery et al., 1999). A large proportion of patients referred to university settings were found to never have received even one adequate antidepressant trial.
Remission Versus Response
Antidepressant response traditionally has been defined as a 50% reduction from baseline in depression rating scales. Clinical efficacy trials of most antidepressant drugs show a response rate of approximately 50% to 70%. For many patients, however, a 50% reduction in symptoms means they will continue to have significant residual symptoms. The new standard of practice in the treatment of major depression is to treat to full remission of symptoms (Nierenberg and Wright, 1999). Remission is usually defined as a 17-item Hamilton Rating Scale for Depression (HAM-D) score of either <7 or <10. Given these criteria, only 25% to 50% of patients in clinical trials achieve remission of symptoms (Nierenberg and DeCecco, 2001).
Treatment Options
Treatment options for the nonresponding patient with an accurate diagnosis of major depression uncomplicated by other psychiatric and medical conditions include optimizing the existing antidepressant therapy, augmenting therapy or switching therapy.
For the many patients who receive an inadequate dose or duration of therapy, all attempts should be directed to optimizing their ongoing therapy. Adverse effects, partial response, noncompliance and unrealistic patient expectations may all contribute to the lack of treatment success and must be addressed.
For the remaining patients with true TRD, treatment options include a number of possible augmentation strategies or switching therapy. Table 1 describes representative studies of the more viable treatment options.
Augmentation
The two older, established augmentation strategies are lithium and thyroid. Lithium is the only augmentation strategy that has adequate controlled clinical trials as an augmenting agent. More recently, strategies have been investigated that add a different mechanism of action to yield additional clinical efficacy and that lack the negative adverse effects possible from lithium. Newer augmentation strategies discussed are generally only supported by case reports and open trial data. They are based primarily upon theoretical advantages of multiple mechanism approaches to achieve remission of depressive symptoms.
Lithium. Lithium carbonate is the most extensively studied augmentation strategy, although not the most widely used (Joffe et al., 1993; Rybakowski et al., 1999). Fava (2001) reported that 11 double-blind, controlled trials of lithium augmentation in depression have been published; of those, 10 reported the observed response rate, which averaged 52% for a total of 135 lithium-treated patients. Lithium's proposed mechanism of action is reduction of postsynaptic serotonergic activity, which reduces the negative feedback to presynaptic serotonergic neurons and thus increases serotonin levels in the synapse. Lithium also may have effects on other neurotransmitter systems and neuromodulators. Lithium blood levels >0.4 mEq/L are most effective. This usually translates into doses ranging from 600 mg/day to 1500 mg/day.
A significant proportion of lithium-treated patients may report bothersome side effects (Fava, 2001). Adverse effects that may be experienced with lithium augmentation are hand tremor, gastrointestinal upset, polyuria and polydipsia, weight gain, hypothyroidism, dermatological problems, and diabetes insipidus-like syndrome.
Thyroid. The addition of liothyronine (Cytomel), a synthetic form of the natural thyroid hormone triiodothyronine (T3), to an existing regimen also has been studied as an augmentation strategy (Joffe et al., 1993). The mechanism of action of thyroid augmentation is unclear, but may be related to the correction of a subclinical hypothyroid state imperceptible through usual thyroid function testing (e.g., thyroid-stimulating hormone [TSH] suppression test or free thyroxine [FT4] levels).
Adverse effects are uncommon, but may include nervousness and insomnia (Fava, 2001), irritability, sweating, and possible cardiac arrhythmias. Use of T3 may interfere with thyroid metabolism if taken chronically, so its use should generally be limited to two or three weeks. Doses of T3 between 25 mcg/day to 50 mcg/day are more effective than T4 (Joffe and Singer, 1990).
Buspirone. Buspirone (BuSpar) augmentation has not been as frequently or as thoroughly studied as lithium or thyroid. Although it is an anxiolytic, buspirone may have augmentative antidepressant effects. Buspirone is believed to aid in the alleviation of depressive symptomatology by enhancing net 5-HT1A-mediated synaptic activity via desensitization of presynaptic 5-HT1A receptors and down-regulation of postsynaptic 5-HT2 receptors.
Doses range from 20 mg/day to 50 mg/day with a response usually being observed within a three-week period. One study found that buspirone augmentation to a selective serotonin reuptake inhibitor antidepressant regimen (fluoxetine [Prozac], paroxetine [Paxil] or citalopram [Celexa]) resulted in 59% of patients showing complete or partial remission of their depressive symptomatology (Dimitriou and Dimitriou, 1998). Similarly, among patients with buspirone augmentation of clomipramine (Anafranil) treatment, 63% showed complete or partial remission.
Landen et al. (1998) conducted the only randomized, double-blind, placebo-controlled trial of buspirone augmentation of an SSRI. The study failed to show any statistically significant difference between the buspirone- and placebo-augmented groups. However, the study investigators noted that the study results may be inconclusive due to the unusually high placebo response and that 69.4% of patients responded in a follow-up of open SSRI plus buspirone treatment.
Buspirone is fairly well tolerated; side effects such as lightheadedness and nausea usually occur early in treatment and are usually transient. The development of serotonin syndrome when buspirone is added to a current regimen containing monoamine oxidase inhibitors or other serotonergic agents is a possible yet very rare occurrence.
Pindolol. Most of the literature on pindolol (Visken) is anecdotal and is primarily focused on its use as an agent to speed the onset of action of SSRIs, rather than as an augmentation strategy (Bordet et al., 1998; Maes et al., 1999; Perez et al., 1997). Pindolol is a ß-blocker and 5-HT1A-receptor antagonist (Fava, 2001). It is believed to increase extracellular release of serotonin by SSRIs at synaptic terminals through disinhibition of the neuronal firing rate by blockade of somatodendritic 5-HT1A receptors. Doses for pindolol usually range from 2.5 mg/day to 7.5 mg/day, given for up to six weeks.
Adverse effects may include nausea, diarrhea and mild bradycardia. One study found that when patients with TRD were given pindolol to potentiate their antidepressants, they exhibited increased irritability (Blier and Bergeron, 1998).
Bupropion. Bodkin et al. (1997) evaluated the efficacy of combining bupropion (Wellbutrin) and SSRIs by retrospective analysis in a group of 27 subjects who were only partially responsive to adequate doses and duration of either an SSRI or bupropion as monotherapy.
With combination therapy, 70% (n=19) showed significant clinical response compared to either agent alone. Mean daily doses were bupropion 243 mg (range=100 mg to 450 mg) and 31 mg of an SSRI (range=7 mg to 60 mg of fluoxetine or its equivalent).
Notable adverse effects of combined treatment were sexual dysfunction, insomnia, reduced energy level and tremor. The incidence of these adverse effects was generally similar to that seen with monotherapy of either treatment. Panic attacks have also been reported with the combination of bupropion and SSRIs (Bodkin et al., 1997; Young, 1996).
Venlafaxine. Theoretically, augmentation with venlafaxine (Effexor) in a patient who had previously been taking an SSRI or a tricyclic antidepressant would be beneficial due to its additional mechanism of action. Venlafaxine acts as a reuptake inhibitor of both serotonin and norepinephrine, thus adding adrenergic activity to an SSRI's serotonergic effect.
Gómez Gómez and Teixidó Perramón (2000) added venlafaxine to either clomipramine (Anafranil) or imipramine (Tofranil) in depressed patients who had shown only partial response to maximal doses of one of those TCAs. They found a sustained positive response to venlafaxine augmentation in nine patients (82% of the sample), with seven patients (64% of the sample) reaching full remission and sustaining it over a two-year period. No significant changes in blood pressure, heart rate, electrocardiogram or blood tricyclic levels were found.
Currently there are only anecdotal reports of venlafaxine 75 mg/day to 300 mg/day as a successful augmentation strategy for SSRI nonresponders (Fava, 2001). The possibility of hypertension (more likely at doses >225 mg/day) necessitates blood pressure monitoring.
Mirtazapine. Carpenter et al. (1999) reported positive results with mirtazapine (Remeron) 15 mg/day to 30 mg/day augmentation of various SSRIs, venlafaxine or desipramine (Norpramin). At the end of four weeks of open-label augmentation, 55% (n=11) of previously refractory patients became responders to treatment. In a double-blind, controlled study, researchers found a significantly higher response rate to the combination of paroxetine and mirtazapine than monotherapy with either drug (Debonnel et al., 2000, as cited in Fava, 2001).
Like venlafaxine, mirtazapine has a dual mechanism of increasing serotonergic and noradrenergic activity. Mirtazapine also blocks postsynaptic 5-HT2 and 5-HT3 receptors, further contributing to selective 5-HT1A receptor activity (Stimmel et al., 1997).
Possible adverse effects of mirtazapine include weight gain and sedation (could have deleterious effects on patient compliance), agitation, and gastrointestinal distress.
Atypical antipsychotics. Ostroff and Nelson (1999) reported a case series of eight patients with major depression unresponsive to fluoxetine or paroxetine. Risperidone (Risperdal) 0.5 mg/day to 1.0 mg/day was added to the SSRI therapy. Based upon HAM-D scores, all eight patients had remission of depressive symptoms within the first week of risperidone therapy. One concern regarding adding risperidone to paroxetine therapy is the cytochrome P450 2D6 isoenzyme-inhibition effect of paroxetine on risperidone that results in increased likelihood of adverse effects, including extrapyramidal side effects. No controlled trials have yet been reported with risperidone. In a case report, the addition of risperidone to the MAOI tranylcypromine (Parnate) also resulted in improvement (Stoll and Haura, 2000).
Shelton et al. (2001) conducted a randomized, double-blinded, placebo-controlled trial in 28 patients with fluoxetine and olanzapine (Zyprexa). Concomitant use of olanzapine 5 mg/day to 20 mg/day in addition to fluoxetine doses of up to 60 mg/day resulted in 60% response rates in patients previously unresponsive to treatment with fluoxetine alone. Clinical response to the combination therapy was observed within the first week of the eight-week study. Possible side effects include somnolence, increased appetite, weight gain, asthenia, headache, dry mouth and nervousness.
It is hypothesized that the coadministration of olanzapine with fluoxetine results in a pharmacodynamic synergy, in which norepinephrine and serotonin levels increase to much higher levels in the prefrontal cortex than when either is administered alone.
Other pharmacological approaches. Many other augmentation and combination strategies involving antidepressants and other agents are being studied. Such strategies include anticonvulsants such as carbamazepine (Tegretol) and divalproex sodium (Depakote); dopaminergic drugs such as pergolide (Permax) and amantadine (Symmetrel); psychostimulants such as methylphenidate (Ritalin, Concerta, Methylin, Metadate), dextroamphetamine (Dexedrine, Adderall) or pemoline (Cylert); a2-antagonists such as yohimbine (Yocon, Yohimex) and nefazodone (Serzone) (Charney et al., 1986; Fava, 2001; Nelson, 2000; Nierenberg et al., 1998; Rybakowski et al., 1999).
The studies and anecdotal reports regarding these agents show inconclusive or contradictory results. Additionally, augmentation with some of these options proved to predispose to adverse effects and the potential for serotonin syndrome when serotonergic agents were used to augment SSRIs (Fava, 2001).
Options for Switching
Switch to an MAOI. Monoamine oxidase inhibitors remain a very effective strategy for refractory depression. McGrath et al. (1993) found a statistically significant difference in the response rates between groups in a double-blind, crossover trial of imipramine and phenelzine (Nardil), where phenelzine proved to be more effective for patients who had been unresponsive to imipramine.
Despite very good efficacy, MAOIs are rarely used (Fava, 2000) because of strict dietary restrictions, serious drug-drug interactions (e.g., fluoxetine or imipramine switch to tranylcypromine) and the risk of hypertensive crisis.
Switch to bupropion. Until the more recent data regarding venlafaxine and mirtazapine became available, a common switching strategy was to move from an SSRI to bupropion in refractory depression, despite a paucity of published data. Fava (2000) noted that clinicians switched patients to bupropion in search for a drug with an improved adverse-effect profile rather than to enhance efficacy. Switching from an SSRI to bupropion is often chosen when the patient has experienced sexual dysfunction and a less than optimal response (Marangell, 2001).
Switch to venlafaxine. De Montigny et al. (1999) reported a 58% response rate (e50% improvement from baseline on the 21-item HAM-D) and a 28% remission rate (e75% improvement) in 152 patients with TRD. Patients had been switched to venlafaxine therapy after failure to reach an adequate response in at least an eight-week trial on another antidepressant. It was suggested that because venlafaxine has more serotonergic than noradrenergic activity, venlafaxine might be expected to be more beneficial in nonresponders to TCAs and MAOIs than SSRI nonresponders. The most common adverse events reported with venlafaxine were headache, insomnia, nausea, constipation, diaphoresis and xerostomia.
Switch to mirtazapine. A study by Fava et al. (2001) showed that SSRI nonresponders exhibited a 48% response rate and SSRI-intolerant patients exhibited a 53% response rate to mirtazapine. Response rates did not differ significantly between patients who were switched immediately from the SSRI to mirtazapine and those who were first given a four-day SSRI-washout period. In this study, mirtazapine also improved sexual functioning in several patients who had had SSRI-induced dysfunction. The adverse events most commonly reported by the mirtazapine-treated patients were somnolence, increased appetite, headache, weight gain, dizziness and nervousness.
To Augment or Switch?
The decision to augment or switch drug therapy should be based primarily on the patient's degree of clinical response as well as the presence and severity of adverse effects. Augmentation may be considered for the patient who has been on an adequate dose and duration of an antidepressant and has had good tolerability, but has shown only partial response. Augmenting allows patients to continue to reap whatever benefits they have from their original drugs but with the additive or synergistic benefits of the augmentor (Nelson, 2000).
In contrast, switching therapy should be considered for patients who have shown inadequate response to their current therapy or for those who experience intolerable adverse effects (Fava, 2000). Switching also offers simplicity of drug therapy compared to use of multiple drugs with augmentation strategies.
Posternak and Zimmerman (2001) compared the strategies of switching and augmentation in patients with TRD. They concluded that switching antidepressants was somewhat less effective than augmentation, although the difference was not statistically significant.
Given the very limited number of treatment option studies, the choice of augmentor or switch agent must be based upon several considerations. These include history of past drug response, adverse-effect profile differences, concomitant medical disorders and concurrent drug therapy.
Nonpharmacological Options
Electroconvulsive therapy (ECT) is a highly effective treatment for psychotic depression and severe refractory depression. Unfortunately, there continues to be a stigma associated with ECT despite its safety under medically monitored conditions, its efficacy and its more rapid onset of effect (Olfson et al., 1998). The Texas Medication Algorithm Project consensus panel recommends ECT after three ineffective treatments for major depressive disorder without psychotic features (Crismon et al., 1999). Generally, ECT is a very safe treatment. The chief side effects are transient confusion and memory impairment (APA, 2000).
Psychotherapy is a treatment option that may be used either alone or in combination with pharmacotherapy for enhanced patient response. Types of psychotherapy include cognitive-behavioral therapy, interpersonal therapy and behavior therapy.
Light therapy with a 10,000 lux intensity light box for 30 minutes per day directly upon the patient's face has been studied for first-line therapy in subsyndromal winter "blues," as well as for adjunctive therapy in chronic major depressive disorder or dysthymia with seasonal exacerbations (APA, 2000). Side effects can include headache, eye strain, irritability, insomnia and occasionally hypomania.
Vagus nerve stimulation (VNS), a treatment option for treatment-resistant seizure disorder, was recently evaluated in TRD (Rush et al., 2000). Escalating amounts of output current were administered to patients' left vagus nerves via an implantable and multiprogrammable pulse generator for 10 weeks. Approximately 40% of patients experienced a positive response, and 17% had a full remission of symptoms. An open, naturalistic follow-up study (Marangell et al., 2002) was conducted to determine whether the initial promising results of the acute-phase study would be sustained for an additional nine months. Longer-term VNS treatment was associated with sustained symptomatic benefit and sustained or enhanced functional status.
In an open pilot study of VNS in 60 patients with TRD, Sackeim et al. (2001) found the response rate ranged from 30.5% to 37.3%, depending on the rating scale used. The most common side effect was voice alteration or hoarseness. This is an interesting alternative strategy for TRD that requires further study.
Conclusion
For major depression, the new standard of practice requires treatment that leads to remission of symptoms and a return of occupational and social functioning. Most nonresponse is explained by inadequate treatment, treatment nonadherence, comorbid medical or psychiatric disorders, or failure of an individual drug or treatment method. Strategies for these patients involve identification of the causative factor and correction of it whenever possible.
For the remaining patients with TRD, there are many options including multiple pharmacological mechanisms, VNS, psychotherapy and ECT. Most patients with major depression have the potential to achieve full remission of symptoms.
References
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Posted by Mark H. on November 27, 2002, at 18:43:45
In reply to Update on hard to treat depression strategies, posted by Bill L on November 27, 2002, at 13:32:31
The cited article states: "At least eight weeks at a full therapeutic dose is necessary to evaluate the efficacy of an antidepressant (O'Reardon and Amsterdam, 2001), and treatment must continue for an additional four to five months (American Psychiatric Association, 2000)."
Fortunately, these two statements are completely untrue for many of us who have suffered from treatment-resistive depression and have found effective relief with the right medications during much shorter trial periods.
Unfortunately, there are doctors who will assume they are doing the right thing by following the advice of this article, while their patients become progressively worse during the 2-1/2 months or more that it takes to reach and maintain the full therapeutic dosage for an "adequate trial."
Further, if an antidepressant works for someone who has treatment-resistive depression, then of course it is going to be continued, not just for months, but possibly for years. TRD is, by definition, a long-term chronic illness. If an antidepressant doesn't work, however, continuing it for an additional four to five months past an already miserable trial period is inexcusable.
I can only speak for myself as a patient, but here is what worked for me:
1.) If a medication makes my depression worse, I won't continue to take it. My experience has been that giving it more time only further deepens my depression.
2.) I won't continue to take any medication that helps initially but poops out after a few days or weeks. Again, my experience has been that giving it more time does not improve my depression.
3.) Anti-depressant and adjunctive medications that work for me generally work very rapidly, with significant relief coming either immediately or within a few days of reaching therapeutic dose. These are also the same medications most likely to continue to be of benefit to me over an extended period of time (5 years and counting at this writing).
I realize that different people react to medications differently, and I caution the reader not to generalize from my experience. However, I think it is far more humane, effective and sensible to try several different antidepressant medications and adjunctives in relatively shorter rotations, looking for those that provide early relief (or at least some improvement), before resorting to long-term trials for major treatment-resistive depression.
It's also important to recall that most occurrences of "ordinary" depression resolve on their own within two to six months, which might account for the efficacy of those medications that appear to be effective only when given an "adequate" trial period and then are continued for an additional four to five months.
The concept of the "adequate trial" in TRD may give physicians some comfort and relief from the anxiety of dealing with patients who do not improve immediately -- and for some patients, long-term trials will be necessary -- but for a significant number of patients, it may only needlessly prolong their suffering.
With kind regards,
Mark H.
Posted by Mark H. on November 27, 2002, at 18:51:57
In reply to Update on hard to treat depression strategies, posted by Bill L on November 27, 2002, at 13:32:31
Hi Bill,
I fell into the content of the article and forgot to thank you for posting it. I enjoyed reading it and, except for my differences with the author about the universal need for long-term medication trials, found it to be a reassuring and well written overview.
Many thanks,
Mark H.
Posted by ItsHowdyDudyTime on November 27, 2002, at 19:55:10
In reply to Update on hard to treat depression strategies, posted by Bill L on November 27, 2002, at 13:32:31
I hope this message comes out OK. Im on an old Mac with an old version of AOL 4.0. My two previous posts didnt come out right I dont know what the problem is.
Anyway, I read the article a while back. I was unimpressed with it. It is a long, meandering article full of psychobabble. I disagree with the authors about the definition of TRD. TRD is a rather simple term in the real world and can be defined simply. Any person with severe depression and a correct diagnosis who fails three or more antidepressants each from a different class is probably TRD.
The article could have been summed up as "we dont know that much about treatment resistant depression" and "we dont know much about the neurological mechanisms underlying TRD." Instead, many psychiatrists prefer to just try one SSRI after another or do combinations of antidepressants.
The hard fact of the matter is that there are presently only two real effective treatments for severe TRD. They are ECT and old fashioned MAOIs. Thats basically all psychiatry has to offer the TRD crowd. There are experimental treatments for TRD such as rTMS, VNS implants, hormone replacement therapy for older women and testosterone replacement therapy for older men with low testosterone levels. However many of these experimental treatments dont seem to work as good as the hype surrounding them.
In the end, it always comes back to the basics. ECT and MAOIs. There is very little true neurological type research into the mechanisms of TRD. Instead many Pdocs who are frustrated with refractory and TRD patients, prefer to begin saddling TRD patients with various personality disorders and sometimes "occult," subtle, comorbid Axis I disorders such as soft bipolar, mild psychosis, OCD, etc. This is a dead end and rarely leads anywhere except to alienate the TRD patient and drive a wedge between TRD patients and their Pdocs.
Until psychiatry modernizes itself, develops real medical tests to get to the bottom of people's brain based disorders, there will continue to be very little progress on the all too common phenomenon of treatment resistant depression.
Howdy Doody.
PS I hope this post came out ok
Posted by Denise528 on November 28, 2002, at 13:07:28
In reply to Re: Unintended Cruelty of the Adequate Trial, posted by Mark H. on November 27, 2002, at 18:43:45
Mark,
Just read your note and you summed up my feelings entirely, I just wish the doctors/psychiatrist shared the same views. Can I ask what you are currently on?
Denise
Posted by Squiggles on November 28, 2002, at 13:18:25
In reply to Re: Unintended Cruelty of the Adequate Trial, posted by Mark H. on November 27, 2002, at 18:43:45
Hi Mark,
I think this is good common sense; i particularly
like the "treat temporarily" and "wait and see"
for an improvement naturally; that is rarely done
now. Before psychiatry became "scientific" backed
up by peer reviewed studies, and trials, and
other tribulations, there was something called
a "nervous breakdown".You know that one doctor at the Royal Vic thought
i was schizophrenic when he first saw me; another
was not sure, another got the wrong diagnosis, etc.
etc..... what worked was a match between the drug
and the state - and that could apply to anything.Squiggles
Posted by ItsHowdyDudyTime on November 28, 2002, at 16:46:55
In reply to Update on hard to treat depression strategies, posted by Bill L on November 27, 2002, at 13:32:31
This whole entire article could have been summed up into one sentence. That sentence is simple and straightforward, uncomplicated. The ONLY effective treatments available for TRD are old fashioned ECT and the older MAOIs. That my friend is about it. A few daring psychiatrists who care more about their patients than covering their asses from the DEA are willing to prescribe amphetamines and certain opiates like bupe for TRD patients, however these Pdocs are few and far in between and very rare. But basically it comes down to either ECT and MAOIs...thats it, my friends.
Howdy Doody
Posted by Squiggles on November 28, 2002, at 16:56:52
In reply to To put TRD succinctly..., posted by ItsHowdyDudyTime on November 28, 2002, at 16:46:55
Which one have you subjected yourself to....John?
Squiggles
Posted by SLS on November 28, 2002, at 20:54:39
In reply to Update on hard to treat depression strategies, posted by Bill L on November 27, 2002, at 13:32:31
Zyprexa (olanzapine) is becoming increasingly recognized as being a potent adjunct for bipolar depression and other treatment-resistant depressions (TRD). I am currently experiencing encouraging results with the following combination:
Lamictal 300mg
Nardil 90mg
Zyprexa 5.0mgZyprexa has been combined successfully with the SSRIs. In fact, Eli Lilly, the manufacturer of both Prozac and Zyprexa, has combined these drugs into a single preparation and will likely be approved for the indication of bipolar depression and perhaps later for TRD and psychotic depression.
- Scott
Posted by ItsHowdyDudyTime on November 28, 2002, at 23:08:42
In reply to Re: Update on hard to treat depression strategies, posted by SLS on November 28, 2002, at 20:54:39
> Zyprexa (olanzapine) is becoming increasingly recognized as being a potent adjunct for bipolar depression and other treatment-resistant depressions (TRD). I am currently experiencing encouraging results with the following combination:
>
> Lamictal 300mg
> Nardil 90mg
> Zyprexa 5.0mg
>
> Zyprexa has been combined successfully with the SSRIs. In fact, Eli Lilly, the manufacturer of both Prozac and Zyprexa, has combined these drugs into a single preparation and will likely be approved for the indication of bipolar depression and perhaps later for TRD and psychotic depression.
>
>
> - ScottScott, zyprexa can be used for type one bipolar without too many troubles. However for unipolar major depression that is TRD, Zyprexa is not a wise choice. Those afflicted with unipolar major depression tend to not have the higher dopamine levels that schizophrenics and classic type one manic depressives have. Thus we cant tolerate even low dose atypical anti-psychotics very well, much less for long time periods.
Better solutions are needed. Drugs which dont cause dopamine blockade and have acceptable side effect profiles. At the moment of this writing, there are really only two effective treatments for unipolar TRD and those are ECT and MAOIs.
Have you ever considered ECT, Scott?
Howdy Doody
Posted by catmint on November 29, 2002, at 2:20:43
In reply to Re: Update on hard to treat depression strategies, posted by ItsHowdyDudyTime on November 28, 2002, at 23:08:42
Excuse me, but I'm going to rant a little here, if that's ok....
Zyprexa just made me a zombie. Eli Lilly calls it a mood stabilizer *really*!! because I ordered their promotional video tape when it first came out. It is *not* a mood stabilizer, it is more like a tranquilizer. Sure it is useful in acute sitations for BP1 but that's it in my opinion. ELi Lilly wants all BP people on it because they are greedy #*&@s!!!!!!
And now they want to combine prozac and zyprexa in one pill!? That makes me woozy and faint just thinking about it.Don't forget, George Bush Sr. used to be on the board of directors of ELi Lilly!
Thanks,
Amy
Posted by Squiggles on November 29, 2002, at 6:48:14
In reply to Re: Update on hard to treat depression strategies, posted by catmint on November 29, 2002, at 2:20:43
Actually, i suspected that. In my search
on mood stabilizers, i noticed that recently
there have been many studies on "alternatives"
to lithium. Why "alternatives"... well, reasons
are givens such as "some people cannot tolerate
lithium", "it has been found that lithium is
as good as this new drug we've got", "lithium
lead to weight gain"... etc. One thing that
is rarely mentioned in these studies is the
importance of the dose adjustment to individual
for this drug.Nothing beats lithium for mania and bipolar
disorder - nothing - it's the best. The
real scientitist are now looking into the inositol
and glutamate secrets that make this drug so good,
and applying it to many other neurological
disorders, e.g. Alzheimer's and Parkinson's;I wonder if the patent on lithium has not run
out eons ago, and the drug companies are
vulturing in for the kill.Squiggles
Posted by SLS on November 29, 2002, at 19:59:29
In reply to Re: Update on hard to treat depression strategies, posted by ItsHowdyDudyTime on November 28, 2002, at 23:08:42
> > Zyprexa (olanzapine) is becoming increasingly recognized as being a potent adjunct for bipolar depression and other treatment-resistant depressions (TRD). I am currently experiencing encouraging results with the following combination:
> >
> > Lamictal 300mg
> > Nardil 90mg
> > Zyprexa 5.0mg
> >
> > Zyprexa has been combined successfully with the SSRIs. In fact, Eli Lilly, the manufacturer of both Prozac and Zyprexa, has combined these drugs into a single preparation and will likely be approved for the indication of bipolar depression and perhaps later for TRD and psychotic depression.
> >
> >
> > - Scott
>
> Scott, zyprexa can be used for type one bipolar without too many troubles. However for unipolar major depression that is TRD, Zyprexa is not a wise choice. Those afflicted with unipolar major depression tend to not have the higher dopamine levels that schizophrenics and classic type one manic depressives have. Thus we cant tolerate even low dose atypical anti-psychotics very well, much less for long time periods.
Howdy-Doody,My viewpoint was similar to yours for quite a while. However, I have seen over the last few years individuals on Psycho-Babble whom had suffered for years with severe TRD, and whom had never exhibited bipolarity, improve markedly upon the addition of Zyprexa to an SSRI. It makes sense to me that it would perhaps be an equally worthwhile addition to MAOIs, which are, among other things, pro-serotonergic. I have seen at least two people with depression respond to Zyprexa monotherapy. It would be a valid argument that the majority diagnosed unipolar depressives whom respond to Zyprexa are actually occult or soft bipolar or otherwise fit within the spectrum of bipolarity.
For some people, TRD means treatment-refractory. They have tried "everything" and remain hideously depressed. Unipolar or not, I think such a desperate condition would warrant alternative treatments, even if they are encumbered with a greater risks of temporary or permanent side-effects. In the past, such situations have caused people to allow medicine to administer things like megadose insulin-shock, electrical current applied to the cranium (ECT), intense intracranial magnetic fields (rTMS), wire leads grafted to the vagus nerve and served with electric pulses (VNS), and even cingulotomy psychosurgery (the removal of brain tissue).
When Zyprexa first came out, and my doctor suggested I try it for depression, I declined. I was very afraid of EPS, especially nearly-irreversible tardive dyskinesia. However, I no longer have that fear. Zyprexa (and Seroquel) have shown practically no potential for producing tardive-dyskinesia, and the rate of other EPS is relative small. At 5.0mg, I hardly know that I'm taking it.
Quite a few studies are emerging demonstrating that antidepressants + Zyprexa are better than Zyprexa alone in TRD, regardless of depressive disorder. As an aside, Zyprexa infrequently induces mania. Zyprexa might very well end up being the first-line drug for bipolar disorder. It acts as a true mood stabilizer along several fronts:
1. antidepressant
2. antimanic
3. reduced number of episodes
4. few somatic side-effects
4. few cognitive side-effects
5. extremely low risk of tardive-dyskinesia
6. once-daily dosing.> Better solutions are needed.
We were born 20 years too early to be cured and 20 years late enough to be availed any solutions at all.
> Drugs which dont cause dopamine blockade and have acceptable side effect profiles. At the moment of this writing, there are really only two effective treatments for unipolar TRD and those are ECT and MAOIs.I know it seems that way sometimes, but my observations of some (very lucky) people yield many successful alternatives, one of which is to simply take a high enough dosage of an antidepressant for a long enough time. This has been my own experience with the few successes I have had.
> Have you ever considered ECT, Scott?Yes. Thanks for asking.
In 1991 (age 31) I was given a series of 15 treatments. The first 8 were unilateral-left, the rest were bilateral. I experienced a small antidepressant response that lasted six hours or so after the fifth treatment. Despite continuing with bilateral treatments, no further improvements emerged. This might mean very little, however. In a series of correspondences with Max Fink, MD, a specialist in ECT, he told me that a great many things have changed since the time of my treatments, and that it would be unwise to conclude that I am not a responder to ECT. It still lingers out there as an alternative for me.
I guess everything boils down to making an informed assessment of benefit versus risk. Although I have chosen to take Zyprexa, like you, I wish there were a more effective, zero-risk alternative.
Thanks for your suggestions and comments.
So many drugs - so many perspectives. So much pain.
I haven't been following PB closely lately, but I hope all is well with you. If not, I hope for you that Hope remains true and intact.
Sincerely,
Scott
Posted by JohnX2 on December 2, 2002, at 17:00:31
In reply to Re: Update on hard to treat depression strategies, posted by SLS on November 28, 2002, at 20:54:39
Scott,Good to hear your results are encouraging!
Regards,
J
> Zyprexa (olanzapine) is becoming increasingly recognized as being a potent adjunct for bipolar depression and other treatment-resistant depressions (TRD). I am currently experiencing encouraging results with the following combination:
>
> Lamictal 300mg
> Nardil 90mg
> Zyprexa 5.0mg
>
> Zyprexa has been combined successfully with the SSRIs. In fact, Eli Lilly, the manufacturer of both Prozac and Zyprexa, has combined these drugs into a single preparation and will likely be approved for the indication of bipolar depression and perhaps later for TRD and psychotic depression.
>
>
> - Scott
Posted by SLS on December 2, 2002, at 22:06:08
In reply to Re: Update on hard to treat depression strategies » SLS, posted by JohnX2 on December 2, 2002, at 17:00:31
>
> Scott,
>
> Good to hear your results are encouraging!
>
> Regards,
> J
>
Hi John.It's nice to see you again.
I should have known it was too early to post good news. I don't feel bad, but I don't feel as well as I did during my first week on Zyprexa. I have tried Zyprexa three times. All three times, it has produced a significant improvement for about a week to ten days before plateauing and fading. If nothing else, I am consistent. Damned brain. I'm going to keep the Zyprexa, though. I believe in it.
Right now, I'm taking:
Lamictal 300mg
Nardil 90mg
Zyprexa 5.0mgI have a doctor appointment Wednesday. I think he will be in favor of dumping Nardil. However, I won't feel satisfied that it was fully explored until I try adding desipramine 300mg. I don't expect it to work, since Nardil + desipramine, while helpful, has represented a bit of a dead-end. Who knows? Unfortunately, almost no one.
I'll let you know what happens Wednesday.
:-)
A smile just for the hell of it.
I hope all is well with you.
- Scott
Posted by MarkCSF on January 22, 2003, at 23:56:51
In reply to Re: Update on hard to treat depression strategies » JohnX2, posted by SLS on December 2, 2002, at 22:06:08
> >
> > Scott,
> >
> > Good to hear your results are encouraging!
> >
> > Regards,
> > J
> >
>
>
> Hi John.
>
> It's nice to see you again.
>
> I should have known it was too early to post good news. I don't feel bad, but I don't feel as well as I did during my first week on Zyprexa. I have tried Zyprexa three times. All three times, it has produced a significant improvement for about a week to ten days before plateauing and fading. If nothing else, I am consistent. Damned brain. I'm going to keep the Zyprexa, though. I believe in it.
>
> Right now, I'm taking:
>
> Lamictal 300mg
> Nardil 90mg
> Zyprexa 5.0mg
>
> I have a doctor appointment Wednesday. I think he will be in favor of dumping Nardil. However, I won't feel satisfied that it was fully explored until I try adding desipramine 300mg. I don't expect it to work, since Nardil + desipramine, while helpful, has represented a bit of a dead-end. Who knows? Unfortunately, almost no one.
>
> I'll let you know what happens Wednesday.
>
> :-)
>
> A smile just for the hell of it.
>
> I hope all is well with you.
>
>
> - ScottScott:
Hey, I am taking the same regimen as you, except for a difference in doses. I take:
Lamictal 150mg
Zyprexa 10mg
Nardil 60mgI have also had the exact same experience with Zyprexa. It works wonders for a couple weeks then fades away. Ive started it twice and had the same results. Though, the first time I tried it I didnt have the Lamictal on board and had a pretty extreme bout of hypomania, though I must admit it felt really good even though I was staying up all night and just getting a few hours of sleep. Was just wondering, since we seem to have the same reaction, if youve had any luck with anything since you last posted to this thread. I pretty much just started the Nardil (about a week) but havent noticed anything significant. Especially not like the Zyprexa, that stuff just flips a switch somehow within a few days for me. I also believe in the Zyprexa and want to keep it even though it makes me sleep way too much. My dx is somewhere in the Bipolar II/Cyclothymia category. Thanks for your thoughts..
-Mark M.
This is the end of the thread.
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