Posted by JadeKelly on January 15, 2009, at 12:43:16
In reply to Re: I want to switch from nortriptyline to desipramine » JadeKelly, posted by JadeKelly on January 15, 2009, at 12:27:28
Diagnosis and Treatment of Refractory Depression
Sheppard Pratt Psychiatric Lecture Series, February 1999
by Dr. David Goodman[Spring 1999; Vol.26 No. 1]
I had the honor of being invited to present an update on pharmacologic treatment of refractory depression. For this presentation, refractory depression was defined as a patient who has been on adequate dosing trials of at least 6 to 8 antidepressant combinations and failed to adequately respond. For the purpose of diagnosis, it is important to remember that a patient uses the term "depressed" or "anxious" as a descriptor of mood, and not a diagnosis. It is the clinician who needs to enumerate the patient's symptoms in order to substantiate a clinical psychiatric diagnosis. Although we may speak about depression as a clinical diagnosis, in fact, depression is a mood phase which can be seen in major recurrent depression or bipolar disorder. Diagnostic accuracy is essential in determining effective treatment. Many unsuccessful treatments have been started prematurely without an accurate assessment of symptoms and conclusive diagnosis.
Symptoms of clinical depression are well-known amongst physicians and mental health professionals. However, diagnostic confusion arises when patients present with depressed mood accompanied by anxiety and/or agitation. There seems to be increased focus on the treatment of depression with anxiety, as many pharmaceutical companies attempt to establish their antidepressant in this area. However, anxiety with depression is distinctly different from depression with agitation. Anxiety is accompanied by worry, a sense of impending doom, general fearfulness and usually no significant insomnia. In contrast, agitation is characterized by physical restlessness, irritability, an internal sense that the "motor is revved," and significantly decreased sleep. It is important to make this distinction because agitation occurring with depression may reflect an underlying bipolar diathesis. This diagnostic distinction becomes important because bipolar patients in depressed phases are typically less responsive to antidepresants without a mood stabilizing agent when compared to the antidepressant response of major depressed patients.
In a study of 50 inpatients by Ghaemi, et al, it was found that bipolar disorder was severely under-diagnosed. Forty-two percent of the bipolar patients had carried other diagnoses. Of the 42%, 90% of them carried a diagnosis of unipolar depression. Therefore, that which we call refractory depression may in fact be a patient with a bipolar disorder who is only partially responsive to any antidepressants they have been on.
Since mental health professionals are probably most familiar with the selective serotonin re-uptake inhibitors, the five U.S. SSRIs were reviewed. The kinetics and active metabolites of fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine were discussed. Linear kinetics applies only to sertraline and citalopram. The presence of food seems to have no clinical effect on SSRI absorption. The only two SSRIs with clinically active metabolites are fluoxetine and sertraline. Citalopram is the latest SSRI in the U.S. market. Specific kinetic and clinical features were reviewed. Citalopram seems to have the lowest inhibitory effect on the P450 system in in-vitro studies. This has lead clinicians to believe that it probably has fewer possible drug-drug kinetic interactions. In addition, it is the most highly selective serotoninergic antidepressant as judged by the ratio of dopamine re-uptake affinity to serotonin re-uptake receptor affinity.
There are five key clinically relevant psychopharmacologic concepts that are important in the poly psychopharmacologic treatment of refractory patients.
1. Drug-drug interactions: Pharmacokinetics (changes in drug absorption, distribution, metabolism, and excretion) versus pharmacodynamics (when two drugs act at the same or interrelated receptor site). A clinician must decide in which of these two categories a patient's side effects occur because this will determine how drug doses are modified.
2. Genetic polymorphism: There are five isoenzymes which are particularly relevant in psychiatry. Two of these isoenzymes 1A2 and 3A4 have no genetic polymorphism, that is, there is not much variation from 1 patient to another in the metabolism of substrates through these isoenzymes. This is in contrast to 2C19 and 2D6, for which the slow versus fast metabolizers exist. There are ethnic and racial differences. Approximately 20% of the Japanese and 4% of Caucasians are slow metabolizers for 2C19 substrates. Approximately 7% of Caucasians, but only 2% of Asians are slow metabolizers for 2D6 substrates.
3. The clinical onset of drug-drug interactions: The inhibition of drug metabolism and decrease in drug clearance causes an elevation in serum levels. The clinical effect of this elevation is usually seen in 2-5 half-lives of the drug whose metabolism is inhibited. However, when a drug's metabolism is induced and serum levels fall, the clinical effect is not seen for several weeks. Therefore, if you know the temporal relationship between a drug and the onset of side effects, you might be able to deduce whether metabolic inhibition or induction has taken place.
4. The clinical relevance and differences between in-vitro versus in-vivo study results: Isoenzyme inhibition, seen in-vitro, takes into account only a parent drug. The in-vivo studies will take into account inhibitory effects of any metabolites. This was seen when comparing three SSRIs with desipramine blood levels. So although we may be able to extrapolate clinical information from in-vitro data, it should not be presumed as conclusive.
5. Drugs can be metabolized through multiple isoenzymes: It is important to be apprised of the substrate's major pathway when looking at spreadsheets of substrates and isoenzymes. Both imipramine and propranolol run through four isoenzymes. Clozapine runs through three isoenzymes. If you are not familiar with the major metabolic pathway, you may presume clinically relevant drug interactions where none exist and thereby avoid potentially useful drug combinations.
As had been mentioned earlier, diagnostic accuracy is essential in treating depressed patients. Patients who are depressed and bipolar should avoid tricyclic antidepressants because of a tendency to increased cycling frequency and worsen the pharmacologic response of the illness.
With the drive to identify depression in primary care, the issue of diagnostic accuracy in the consideration for bipolar disorder seems to have been lost. Although we might say that SSRIs do not increase cycling frequency, it took 25 years before we determined that tricyclic antidepressants increase cycling frequency. Who is to say what we will decide 20 years from now. Therefore, the prescription of these medications should be used judiciously and with diagnostic accuracy.
Pharmacologic algorithms have suggested that clinicians change from one class of antidepressant to another class of antidepressant if a patient fails to respond. Although this makes sense at face value, it wasn't until recently that we had research in this area. The response rate if you switch from a TCA to a TCA is approximately 22%. Switching from a TCA to an SSRI produces a 45% response rate. Switching from an SSRI to a TCA produces a 62% response rate. However, the question to be answered is, what is the response rate when you switch from one SSRI to another SSRI. Keep in mind that the SSRI structures are completely different. I have often said that what we know about these drugs we can stuff in a thimble and what we don't know about these drugs can fill a library. There is one study by Jaffe, et al, which took a look at response rates when switching from one SSRI to another. In general, he found a 50% response rate when changing from one SSRI to another. Therefore, it is important not to discard the whole class of SSRIs simply because the patient failed to respond to one. It is also well established that patients developing side effects on one SSRI may very well tolerate an alternative SSRI.
I reviewed the typical adjunctive agents used in refractory depression. In Pharmacotherapy, 4th Generation of Progress, there are reviews of response rates for adjunctive agents. Twelve studies of lithium augmentation to TCAs produced a response rate of 56%. Twelve reported T3 potentiation to TCAs showed a response rate of 40%. The addition of fluoxetine to TCAs in two studies showed a response rate of 47%. The addition of MAOIs to TCAs in ten studies produced a response rate of 54%. As you read this, you may notice a very untraditional drug combination, that is MAOIs with TCAs. Yes, there are several papers supporting the use of these agents without severe drug reactions.
Historically, the use of MAOIs has been infrequent, despite the fact that overwhelming research supports their benefit. Years ago, the dietary restrictions seemed to be so severe that clinicians worried that the patient would inadvertantly eat a restricted food, have a severe hypertensive reaction and suffer a stroke or heart attack. However, as the years have gone on, experts have revised and simplified the MAOI dietary restrictions. The current restrictions are very workable for most patients. Many patients who are judged to be refractory have never been on MAOIs. Clinicians who fail to use MAOIs eliminate a very effective class of agents.
To further complicate the treatment, MAOIs can be used with stimulants and TCAs. Although there are severe warnings and contraindications, there is a body of literature supporting their combined use. My clinical experience in about 8 patients, has been fairly rewarding. I stress that no physician should consider these drug combinations before the patient has been tried on the typical and traditional drug combinations. The MAOI combinations should be used by a clinician familiar with the literature and in patients who are trustworthy. It is important that patients monitor blood pressure and pulse as dosages of MAOIs and stimulants or tricyclics change. For those clinicians wishing to gain more experience in this area, I recommend Clinical Advances in Monoamine Oxidase Therapies, edited by Sidney Kennedy, MD, published by American Psychiatric Press, Inc. In this book, there is a report of nine trials with over 1,000 patients on MAOIs-TCA combinations, with no death or severe toxic events. Three open trials and 3 chart reviews showed treatment responses between 65-80%. These are remarkable response rates given the fact that patients have been severely refractory to other agents.
When using MAOIs, it is important to know the recommended wash-out period from other drugs. In general, when going from an MAOI to an SSRI, 4-5 weeks needs to be allotted.
When changing from a TCA, buproprion, SSRI to MAOI, a 2-week wash-out period is recommended. Keep in mind, that if you change from one MAOI to a second MAOI, there is also a 2-week wash-out recommendation. These recommendations are conservative and experienced clinicians have published reports of drug switches with shorter periods of wash-out.
Perhaps the most critical factor in the treatment of depressed patients is the provision of hope. It is important for the clinician to be diagnostically committed and hopeful that a successful treatment alternative will be identified. As noted, there are a number of pharmacologic alternatives beyond traditional recommendations. Those clinicians treating refractory depression should become familiar with the breadth of pharmacologic options. When patients believe that there is something else to be tried, it allows them to better tolerate their depression, demoralization and frustration.
Dr. David Goodman, is an Assistant Professor of Psychiatry at The Johns Hopkins University, School of Medicine, and is in private practice at Greenspring Station in Baltimore County.
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