Curbside Consult Questions

We have seen a number of patients with treatment resistant major depressive disorder who have come to us started on an antidepressant augmented with quetiapine XR 300 mg at dinner and aripiprazole 2-5 mg in the morning by another physician. This seems like irrational polypharmacy to me and I have not found even a single case report supporting it. Is there any reason to even think of using this combination?

It is never a good idea for a patient with treatment resistant depression to have multiple prescribers, particularly if the left hand does not know what the right hand is doing.  Sometimes the combination of quetiapine and aripiprazole happens when transitioning from quetiapine augmentation to aripiprazole augmentation, or vice versa and would be therefore justified as a short term bridging strategy.  If the two prescribers did not know that the other one was giving a different antipsychotic for augmentation, as seems to have happened in your example, this may not be the case.

Other times, there may be lack of efficacy with one of the agents, so a prescriber knowingly adds a second agent to the first in an attempt to get a good response. Finally, it is possible that the patient cannot tolerate a higher dose of either agent so a prescriber knowingly gives tolerable lower doses of two agents simultaneously.  In all these cases there are at least three drugs involved, since the two antipsychotics are presumably augmenting an SSRI/SNRI. In none of these examples here does the three drug/two simultaneous antipsychotic augmentation idea seem to be a very good one or an evidence-based one.  Certainly it makes no sense to try such a 3 drug combo until each antipsychotic was tried on its own at adequate dose and for adequate period of time.  And I wonder if in your cases of seeing this practice whether the patient did not have a trial of something else that makes far more sense, like SNRI/mirtazpine (California rocket fuel) combo, or an MAOI monotherapy.  These days, I am only using two drug antipsychotic combs for treatment-resistant psychosis associated with violence. 

Stephen M. Stahl, MD, PhD
Adjunct Professor, Department of Psychiatry,
University of California, San Diego School of Medicine
Honorary Visiting Senior Fellow, University of Cambridge, UK

 

A young woman with bipolar depression is receiving olanzapine 10 mg, fluoxetine 20mg and ridazyn 25 mg. The computer of the family physician announces a problematic interaction. Is the fluoxetine-ridazyn interaction problematic, or perhaps not because of the low dose of the ridazyn, or is the computer problematic?

There are no significant interactions between low dose Ridazin (thioridazine) and fluoxetine plus olanzapine. Of course, there are additive effects of the two antipsychotics on the D2 receptor but, with the very low dose of thioridazine used, there is little worry. For side effects, there is additive sedation between the two antipsychotics as well as potential additive effects in lengthening the QTc interval. Regarding fluoxetine and thioridazine, there are no known significant pharmacokinetic interactions. For both the QTc effects as well as possible pharmacokinetic effects, one would not expect clinically relevant concerns given the thioridazine dose. So, in answer to your question, in this situation, the computer is problematic.

Michael Gitlin, MD
Professor, Psychiatry and Biobehavioral Sciences,
University of California, Los Angeles (UCLA) School of Medicine
Director, Adult Division and Director, Mood Disorders Clinic,
UCLA Neuropsychiatric Hospital

 

I have a new client, 66-yrs-old with depression and Parkinsons disease. He was unable to give me any history but this is what I have put together from his PCP: he has been on Prozac (fluoxetine) 40mg adequate trial, Lexapro (vilazodone)10mg not sure for how long, Zoloft (sertraline) unknown dose and time, Wellbutrin SE (bupropion)150 mg BiD unknown time and trazodone unknown dose and time. He is currently on Remeron (mirtazapine) 15 mg. He is also a throat cancer survivor. Is there a medication that is more helpful for someone with mild memory impairment and depression comorbid with Parkinson's disease?

This is a difficult patient who has resistant depression as he has failed to respond to 3 SSRI, an NDRI, and possibly a SARI type antidepressant. He is on a low but therapeutic dose of a NASSA antidepressant (mirtazapine) now. His depression is complicated by Parkinson’s disease. It is unclear if his mild memory problems are age associated, early Parkinson’s Dementia, or executive dysfunction from depression.

Like all resistant depressions, I attempt to look at (1) what classes of antidepressants and their pharmacodynamic properties have already failed so as not to repeat redundant mechanisms of action (2) what are the target impairing symptoms for the patient as I feel that certain antidepressants may facilitate certain transmitter systems that affect brain areas responsible for said target symptoms… In this case we have depressed affect and memory problems in a patient who is dopamine deficient due to Parkinson’s disease (at least in the nigrostriatal dopamine pathway).

I would suggest on these premises the following:

  1. As he is taking low dose mirtazapine currently that enhances norepinephrine by alpha-2 receptor antagonism and likely aids frontal cortical dopamine and norepinephrine activity by way of serotonergic receptor blockade on brainstem GABA interneurons, his depression and target symptoms may be better treated by titrating this drug to 30 or 45mg per day (completing a full dose range monotherapeutic therapeutic trial)
  2. If this fails, the SNRI class of medications may help. He has failed SRI component antidepressants, but the NRI mechanism should increase norepinephrine in the frontal cortex which may target energy, concentration, memory and thus improve symptoms better than an SSRI. Remember, norepinephrine reuptake pumps in the frontal lobe actually control the reuptake of dopamine too. So using an NRI property may increase dopamine here and help as well. Alternatively, one could return to the bupropion product line (an NDRI) and try the full 400-450mg per dose per usual guidelines as it was likely underdosed at only 300mg per day in this patient’s case.
  3. Finally, selegiline is an MAOi and orally is approved for Parkinson’s disease treatment and preferentially inhibits MAOi-B enzymes thus increasing available dopamine. It is also available as a transdermal patch that is approved for depression and in the brain now inhibits both MAOi A+B allowing simultaneously increased serotonin, norepinephrine and dopamine. It may be possible to better treat this patient’s depression, cognition and Parkinson’s symptoms in one pill/patch. Interestingly, a metabolite derivative of this product is amphetamine-like which are known to promote energy, concentration, vigilance, etc. Of course at high doses this patch is an antidepressant MAOi and certain drug-drug and dietary restrictions must be navigated, but this can be done with reasonable patient and clinician education.

Thomas Schwartz, MD
Associate Professor, Department of Psychiatry
SUNY Upstate Medical University, Syracuse, NY

 

Is there a way, clinically or through the use of laboratory tests, to determine which patients with major depressive disorder would benefit from L-methylfolate addition?

The short answer is “not any that are proven yet.”  The longer answer is “research is in progress and there are some rational if unproven possibilities to guide us.”

First: lab tests for folate.
Since depression can be associated with low folate, it would seem a no brainer to give depressed patients L-methylfolate if their folate were low, but how do you find that out?  Turns out it may not be as easy as it appears at first glance.  That is, measuring folate in the blood tells you what the level of a mixture of various folates are due to recent ingestion of food containing folates.  So, you can actually be folate-depleted in the long term but with a bit of folate in the diet just before the blood test, like a piece of fortified bread which is how bread comes these days, look normal.  Better to study RBC folate or CSF folate levels, but not easy to get these from the lab; yet they reflect longer term folate levels.  Given these difficulties, some suggest measuring homocysteine levels, which are reciprocally elevated when L-methylfolate levels are low, and it is easier to obtain from labs.

Second: genomic tests related to L-methylfolate synthesis.
What if folates and homocysteine are normal?  It turns out that functional deficiencies that do not necessarily show up as changes in metabolites, occur in various inborn errors of metabolism.  These are considered research tests yet, but if you are interested, the genes that regulate folate levels are:
methylene tetrahydrofolate reductase (MTHFR); methionine synthase reductase (MTRR); methionine synthase (MTR); and others.

Some early results from the positive trial shows that those patients who responded to 15 mg folate added on to SSRIs were more likely to have a genetic variant of one of these enzymes. 

Also, there is genetic interaction called epistasis especially for cognition and studied more in schizophrenia than depression for the enzyme COMT and the enzyme MTHFR, another research finding.

Bottom line: stay tuned.  It is likely that genomic tests (some of which you can already get with insurance coverage from Genomind or AssureRX – NEI members get one free test from Genomind) will not tell us what drug will work for sure, but will add to the weight of the evidence when choosing treatments.  These are exciting times, but no clear lab test has yet been replicated and ready to apply in clinical practice to tell you who will be more likely to respond to L-methylfolate.

Clinical features.
Now for one final interesting finding.  Of all the results from the large 15 mg add on study, the one clinical feature that best predicted who was an L-methylfolate responder in that study, was not one of the symptoms of depression.  It was BMI>30.  Interesting, but not clear why obesity may be linked to L-methylfolate response, and needs to be replicated, but you might keep this in mind if you are prescribing L-methylfolate.

Stephen M. Stahl, MD, PhD
Adjunct Professor, Department of Psychiatry,
University of California, San Diego School of Medicine
Honorary Visiting Senior Fellow, University of Cambridge, UK

 

Stimulant medications (ritalin, Adderall) are often cited as useful in treating elderly patients with depression. What is the literature on the use of these agents in other ages?

Stimulants for nongeriatric depression are commonly prescribed, more often as adjunctive agents to antidepressants than as monotherapies. Unfortunately, the data base in support of this approach ranges between limited to negative. For dopaminergic stimulants (methylphenidate, d-amphetamine in various preparations), daily doses used as adjunctive agents vary widely from 10 mg to 80 mg. In the few controlled studies, doses used were somewhat lower than is often prescribed in clinical settings (54 mg or less of extended release methylphenidate).

A handful of controlled trials have also evaluated nondopaminergic stimulants such as modafanil as adjunctive agents. In these studies, stimulants showed modest efficacy in combating fatigue and, to a lesser degree, depression.

My own clinical experience is more positive, however. A number of patients-especially those with residual fatigue and/or anergia despite at least a partial response to antidepressants- seem to respond to stimulants with more energy and greater initiative. Positive effects are seen very quickly in responders, thereby allowing a very rapid dose finding and efficacy trial. Side effects of stimulants in depressed patients are identical to those seen in ADHD studies. Despite the concerns raised by some cardiologists, a number of recent studies have provided reassuring data on the cardiovascular safety of stimulants when prescribed to adults.

Michael Gitlin, MD
Professor, Psychiatry and Biobehavioral Sciences,
University of California, Los Angeles (UCLA) School of Medicine
Director, Adult Division and Director, Mood Disorders Clinic,
UCLA Neuropsychiatric Hospital

 

Patient Z is 12 weeks pregnant. She meets the criteria of major depressive disorder at this point, but has never been diagnosed nor treated for depression or any other psychiatric disorders. After delivering her first child 15 months ago, she has been experiencing depressive symptoms and irritability. She does not have any family history of any psychiatric disorders. Currently, she has been under stress from marital conflicts and social isolation; Z denies suicidality. Should I use any antidepressant at this point? If so, what drug(s) would be appropriate?

This case of depression is complicated as the patient developed a post-partum depression (PPD) after her first child and she has never fully recovered; this happens in about 10% of PPD cases. She is pregnant now, barely past the first trimester in a chronic depressive state. She is stressed, agitated, and socially isolated. Risk factors for PPD are multiple but poor social support and partner support are key instigators, so her depression will likely worsen post partum when estrogen levels and monoamine levels fall precipitously.

As she is pregnant, clear discussion about in utero antidepressant exposure and post-partum lactation exposure is warranted. In this case, I feel the first option is to discuss psychotherapy, and I feel Scott Stuart’s work on interpersonal psychotherapy (IPT) in post partum depression is ideally suited for this patient and directly addresses the risk factors of poor social support and falls in line with interpersonal theories of depressive etiology.

If IPT fails or she cannot obtain or afford this modality, then an antidepressant may be warranted. If she is going to breastfeed, I like using high protein-bound SSRIs like sertraline or fluoxetine as the protein binding may limit drug crossing the mammilary barrier. Note, there are clearly mother-dyad case reports of some drug reaching the infant but with negligible effects. Even though she is in the 2nd trimester and the baby’s heart has been formed, I would avoid paroxetine just given the legal implications of its cardiac birth defects.

Pregnant mothers are hypermetabolic, so using a full dose range of an antidepressant is warranted and higher doses may have to eventually be lowered post-partum as side effects may then emerge as the patient’s CYP450 metabolism slows. There are warnings that infants may go through SSRI withdrawal or suffer from pulmonary hypertension after delivery. One must weigh the pros/cons of this versus having a mother with severe depression, which carries the risk of preterm delivery, having a low birth weight infant, or having possible cognitive and emotional impairment of the newborn, etc.

Thomas Schwartz, MD
Associate Professor, Department of Psychiatry
SUNY Upstate Medical University, Syracuse, NY

 

Augmentation strategies for patients who are partial responders with MAOI. Can you combine MAOI with aripiprazole (Abilify) or quetiapine (Seroquel)?

This is an important, illuminating and interesting question. If we first assume that we are confident the dose of the MAOI has been high enough for long enough, i.e. high enough to cause significant postural hypotension and at that level for at least 4 weeks, then the quick answer is, yes.

Perhaps it would be more helpful to be clear about the few things. It is not safe to combine with MAOIs, because that list is shorter than many people suppose. MAOIs are almost entirely devoid of pharmaco-kinetic interactions, so they don't affect the blood levels of other drugs (neither do other drugs affect them).

The problematic reactions are pharmaco-dynamic. That is to say, the cumulative end-effect of interactions with other drugs with different mechanisms of action. There are only two significant reactions in this category, that of serotonin reuptake inhibition (SRI) interacting to cause serotonin toxicity, a.k.a. serotonin syndrome; and secondly the indirectly acting amines, like tyramine, and other drugs that similarly act pre-synaptically by releasing neurotransmitter stores (of NE or 5-HT), e.g. ecstasy (MDMA). Reuptake inhibitors, other than SRIs, do not have problematic interactions. There are virtually no therapeutic drugs acting as norepinephrine releasers, since in most countries nasal vaso-constrictors are now the oxymetazoline-related alpha two agonists, rather than NE releasers like pseudoepinephrine & analogues.

Antipsychotic drugs do not have these properties. The recent exception is ziprasodone which, like some narcotic analgesics (e.g. pethidine), appears to possess sufficient SRI capacity to be problematic (1). Any other new atypical claiming, or having, SRI potency could be a problem for potential sertotonin toxicity precipitation with MAOIs.

References

  1. Rim, CL and Gitlin, MJ, Ziprasidone, monoamine oxidase inhibitors, and the serotonin syndrome. J Clin Psychopharmacol, 2010. 30(4): p. 470-1.

P. Ken Gillman, MB, BS, MRC Psych.

 

I am getting many referrals for youth and adults having anger issues, mind racing at night and fragmented sleep. They also complain of extreme anxiety around crowds with suspicion of been watched. Occasionally they report trust issues and believe they have heard their name when someone is not around. At times, they see some vision at the corner of the eyes which disappears. These issues have dramatically affected their school and/or job performance. There are no major depressive symptoms, delusions or clear hallucinatory experiences. All of these individuals claim experimental and recreational use of marijuana. Family physicians have tried SSRIs to treat these symptoms without any benefit. Some individuals have been placed on olanzapine with good results.

My question is: are we dealing with psychotic features related to marijuana or should these symptoms be treated as an anxiety disorder.

The differential diagnosis should also include psychotic illness, bipolar spectrum disorder and ultra high risk prodromal state preceding onset of schizophrenia. Non-response or worsening to SSRIs/SNRIs plus good response to an antipsychotic is suggestive that this is not a major depressive episode nor social anxiety disorder, but something in the psychotic or pre-psychotic spectrum or bipolar spectrum. Whether a functional psychosis like schizophrenia or a toxic psychosis from drugs is not knowable from the symptoms alone. As you know, marijuana is actually a higher risk substance to precipitate schizophrenia in a vulnerable individual than is a stimulant, although high-dose long-term stimulant abuse in those without high risk prodromes can make anyone psychotic (amphetamine psychosis, for example). All you can do is monitor, and keep an open mind. In answer to your specific question about marijuana, these symptoms can be caused by marijuana but if so, I would be extremely worried that the individual might go on to get schizophrenia. These symptoms I have seen with very bad anxiety disorders/social anxiety so intense that patients almost look psychotic and they improve with SSRI/SNRI plus short-term benzodiazepines, and reconstitute and look very nonpsychotic when they do, a reassuring outcome. However, if they require antipsychotics to quell symptoms, you might be concerned that this is a prodrome of schizophrenia over the coming years.

Stephen M. Stahl, MD, PhD
Adjunct Professor, Department of Psychiatry,
University of California, San Diego School of Medicine
Honorary Visiting Senior Fellow, University of Cambridge, UK

 

I work in primary care. I have a 17-yr-old female who is having sleep and eating difficulties, and is not interested in socializing. She probably has general anxiety as well as depression and has lost about 10-lbs over a few months. What SSRI, if any, would you start this patient on?

First of all, let's assume that her weight and appetite loss is not due to an eating disorder and is likely due to depression and anxiety. Second, you did not mention lethality symptoms so make sure she has no suicidal or homicidal ideas. In regards to prescribing, all antidepressants, anti-epilepsy, anti-smoking and ADHD medications in the U.S. carry some warnings and precautions about increases in depression and/or suicidality. Anything we prescribe, therefore could make her worse and informed consent is needed. Psychotherapy is the treatment of choice in this age group. If that fails or is not available, then a medication may be warranted if her symptoms are causing psychosocial distress. There are two FDA approved products for depression in this age group, fluoxetine and escitalopram. I would start with one of these. Sertraline is approved for OCD in this age group and is a reasonable alternative if the first two are not ideal choices for this particular patient.

Thomas Schwartz, MD
Associate Professor, Department of Psychiatry
SUNY Upstate Medical University, Syracuse, NY

 

Since evidence-based psychiatry does not support MAOIs as first line treatment - for MDD, how do I use these with a far greater degree of frequency given their efficacy, without committing medical malpractice?

This is a question that deserves a longer answer than can be given here.

My first comment is that we must all remember that recommendations derived from evidence-based guidelines should never be accorded ex cathedra status, and can only ever be suggestions, not injunctions. Many are based on low-grade evidence that is not superior to “clinical experience”. All well-written guidelines are preceded by appropriate caveats paying due deference to the necessity of the consideration of individual patient factors and individual doctor suggestions in the final determination of what is advised to be optimal, or preferred or chosen by the patient, in any given situation. There is absolutely no way a deviation from any guidelines can be held, prima facie, to be medical malpractice, nor even below average practice. That is even more so if adequate case records and decision-paths are recorded, and because it is the patient who decides what advice they wish to follow. It is only if such advice and information were grossly inaccurate that a question of medical malpractice could legitimately arise.

I frequently use MAOIs as a first line treatment (for MDD). Common reasons for that were the knowledge that the patients’ situation, illness severity and treatment–failure experience was such that they might not return for further care if treatment was not rapidly effective, or if they declined ECT. Also, particularly with tranylcypromine, younger patients, especially, would find it much better from the point of view of both sexual function and lack of weight gain compared to almost any other available option, perhaps with the exception of bupropion (which I found much less efficacious). There are various other advantages of MAOIs. So, “qui audet adipiscitur” (He who dares wins), originally the motto of the British military unit, the SAS (special air service), and adopted by other similar units.

P. Ken Gillman, MB, BS, MRC Psych.

 

I am treating a patient with treatment resistent depression. Lithium + phenelzine (Nardil) was helping him but his kidney functions are affected. Can I replace lithium with quetiapine (Seroquel)? In other words- Is it safe to combine quetiapine and phenelzine?

Certainly it is safe to give quetiapine with phenelzine, but the quetiapine has a different mechanism of action than lithium of course. Theoretically, quetiapine is metabolized to norquetiapine that has norepinephrine transporter (NET) inhibition, that could theoretically interact with an MAOI, so I would monitor blood pressure but not be worried to give this combination. Quetiapine may also help MAOI-induced insomnia if it occurs. In fact, you can give any atypical antipsychotic with phenelzine or any MAOIs although I would be a bit hesitant only with ziprasidone. It is a very weak reuptake inhibitor of 5HT, so it is mostly theoretical, but probably that is the only one maybe not to combine with an MAOI; although I have done it in fact.

Stephen M. Stahl, MD, PhD
Adjunct Professor, Department of Psychiatry,
University of California, San Diego School of Medicine
Honorary Visiting Senior Fellow, University of Cambridge, UK

 

Bipolar depression for either bipolar type I or type II: During the lamotrigine (Lamictal) titration period, any reasonable augmentation strategy for quicker results?

Lamotrigine does need to be titrated slowly to avoid serious rash complications. As it can take several weeks, patients may continue suffering. Some bridging or combination-initiation-treatment strategies could be utilized such as starting a low dose stimulant albeit with some theoretical risk of inducing mania. The best evidence in this class likely exists for the novel wakefulness promoting agents, modafinil and armodafinil. Assuming there is another mood stabilizer present, then the risk of inducing mania would be minimal. Lithium could be started, but its titration is slow. However, it is certainly faster than lamotrigine. The addition of a mood stabilizer (e.g. lithium) is likely more in line with most treatment guidelines. In this respect, quetiapine, quetiapine XR, of olanzapine-fluoxetine combination are both approved for bipolar depression and could be used right away. The negative to these more guideline-oriented approaches might be an increased risk of serious side effects (i.e. TD, EPS, metabolics, thyroid or kidney disease). Sometimes I use nutraceuticals in these cases as side effect risks are likely the most minimal. Using l-methylfolate 15mg/d, SAMe 800mg twice a day, or n-acetyl cysteine 1000mg twice a day may be an option. Clinicians have to weigh the risk-benefit ratio of following guidelines, or not. Using off-label treatments, or not. Finally, lamotrigine is approved for use when a bipolar patient is euthymic and helps to avoid relapse towards either pole. The evidence base versus clinical use is sometimes contradictory whether it acts as an antidepressant monotherapy or adjunctive therapy.

Thomas Schwartz, MD
Associate Professor, Department of Psychiatry
SUNY Upstate Medical University, Syracuse, NY

 

Do you have an algorithm for MAOIs? Ex: patch first, oral selegiline, tranylcypromine, phenelzine?

I am aware that moclobemide is not generally available in the United States. I would only use it if the patient was adamant that they wanted it and I did not think they were really ill or in need drug treatment. That is because I found it was so weakly effective compared to tranylcypromine that it was closer to being a placebo.

I have no first-hand experience of the selegiline skin patch, but from theory and what I hear (see other MAOI questions) it would seem it may be useful, but not as potent as the other non-selective MAOIs. It is very similar to tranylcypromine (TCP) except that it is metabolised into amphetamine, whereas TCP is not. Whether it is sufficiently efficacious (and affordable) to use regularly before trying something like TCP would perhaps depend on the individual patient characteristics, previous history and preference in relation to having no diet restriction. Perhaps in less seriously ill patients who are not confident (or reliable) about managing their diet it would be a possible starting point. It is now becoming possible to use PET scanning to assess human brain MAO activity, and we may soon observe if the selegiline skin patch does in fact achieve brain levels that make it non-selective in the brain but selective in the periphery.

For more seriously ill patients, my preference would be to progress to TCP as a first choice unless the patient has marked phobic anxiety type symptoms, in which case it really does seem that phenelzine is the drug of choice (probably via its GABA effect, see (1). It may be (it is still uncertain) that an equi-effective dose of TCP has a slightly greater propensity to cause tyramine reactions than phenelzine (or isocarboxazid) but on the other hand it undoubtedly has less side effects, both serious and minor. Liver damage and seizures related to phenelzine are rare but potentially fatal, and also the incidence of pyridoxine deficiency, weight gain and sexual SEs are frequent and great (1).

References

  1. Gillman, PK, Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors. J Clin Psychopharmacol, 2011. 31(1): p. 66-74.

P. Ken Gillman, MB, BS, MRC Psych.

 

I have a 55-year-old patient with treatment-resistant depression who has gotten no relief from, I think, every approved treatment and combination of treatments. I would like to try ketamine infusions but there is little guidance on technique, let alone data. Any recommendations for this off-label drug?

There is no recommended protocol for clinical use of ketamine; however, the literature you can consult from Zarate’s group at NIMH suggests about 90 minute infusions at subanesthetic/subpsychotomimetic doses. We do these at UCSD for cash payment through David Feifel, MD at the medical center for about $1400 and a few patients have taken him up on it. The problem is what do you do next? They have immediate onset for TRD, for bipolar depression and for suicidal ideation in many but not all, but only last 4 to 7 days after the infusion. Post-treatment with standard antidepressants, with lamotrigine or with riluzole does not seem to sustain the response. What to do? Another idea is Nuedexta, the combination of dextromethorphan plus quinidine approved for PBA pseudobulbar affect, and off-label used for TRD. I have given to about 6 patients and one has had a remarkable life saving response but not the others. Several agents active at NR2B subtypes of NMDA receptors are in clinical testing but none available outside of research protocols. I think this definitely is something we will see more about in the future but other than Nuedexta (obviously off-label) which has NMDA and sigma properties like ketamine, there are not a lot of immediate possibilities.

Stephen M. Stahl, MD, PhD
Adjunct Professor, Department of Psychiatry,
University of California, San Diego School of Medicine
Honorary Visiting Senior Fellow, University of Cambridge, UK

 

Is there a rationale as to why reversible MAOIs would or would not be as effective?

Yes, there are several reasons why selective and/or reversible drugs would probably be less efficacious. I think this is a question about reversible competitive inhibitors of MAO-A (RIMAs), i.e. moclobemide (MOC), but we could also compare the irreversible drugs selegiline (MAO-B selective) and tranylcypromine (MAO-A+B).

Tranylcypromine (TCP), phenelzine and selegiline form an irreversible bond with MAO and totally disable it. MAO function is then largely restored by production of new enzyme from the genetic code. RIMAs, like MOC, are competitive and reversible and are displaced from MAO-A by the endogenous substrate, in this case mainly 5-HT. Therefore, they have a natural ceiling effect, the more 5-HT is increased the more it displaces a RIMA from MAO-A (especially a weakly competitive one like MOC). That is probably why even large over-doses of MOC do not cause serotonin toxicity, and in fact usually present with minimal symptoms of any sort of toxicity.

We still do not really know how MAOIs work, but it seems probable that MAO has to be inhibited almost completely for there to be much effect on monoamine levels. That probably means around 95% inhibition.

Another important point is that metabolism of dopamine, norepinephrine and 5-HT is, to a greater or lesser extent, contributed to by both MAO-A and -B. For dopamine (DA) it is about 50:50. It is thus the case that TCP raises DA levels to a greater extent than does a slightly selective MAO-B drug like selegiline, or rasagiline (more selective). The main reason MAO-B inhibitors have been developed for Parkinson disease is the perceived importance of avoiding the tyramine-mediated pressor effect (“cheese reaction”). What the risk vs. benefit balance is of the larger increases of dopamine (and other mono-amines) produced by TCP vs. lesser increases from selective drugs remains uncertain, and untested, but it may be that TCP is more effective for depression/Parkinson’s than is rasagiline, or selegiline. RIMAs have little or no effect on dopamine.

So, yes, there are definitely very good reasons to suppose that irreversible MAOI-A/B inhibitors are likely to be more effective, and that is what experience teaches us, even if controlled trials are less helpful; compared with TCP, MOC is a weak antidepressant, if indeed it is an antidepressant that all. As far as I recall every single patient I ever cared for who tried MOC instead of TCP got worse and asked to go back to TCP.

P. Ken Gillman, MB, BS, MRC Psych.

 

Do you think that the numerous references to underlying receptor actions of antidepressants in particular adds any benefit when deciding clinically what antidepressant might be advantageous in treating a specific patient? It seems that patients simply respond better to a given antidepressant after trials with several antidepressants until the optimal outcome is achieved. A recent trial suggested escitalopram (Lexapro) was just as effective as venlafaxine and mirtazapine in depression recovery. I believe the adverse event reporting was important to the outcome of the study as well. What do we do?

For first line treatment, it seems to matter little what you give, so most give something cheap and with fewer side effects. Now that Lexapro is generic as escitalopram, that may be it. Cipriani et al published a meta analysis suggesting that escitalopram, sertraline, venlafaxine and mirtazapine had the best efficacy and sertraline and escitalopram the best tolerability with sertraline the best cost until escitalopram became generic. The real question is what to do if first line agents fail. Most of us, including me, use an SNRI, now venlafaxine because of it has the most experience of how to dose and is now generic. Also, the favorite combinations are an SSRI with bupropion for lack of efficacy and an SSRI with trazodone for residual insomnia. If these don’t work, there is the augmentation with expensive atypical aripiprazole, and the now-generic but side effect-laden yet effective quetiapine. Most of us forget MAOIs but that is a bad idea to forget as an option for an expert psychopharmacologist. I use them frequently in my practice because most of my patients are not first-line and it seems few clinicians know how to use MAOIs so treatment-resistant depression comes to me without trials of MAOIs. If bipolar spectrum (most of my patients in this category do not have full manic past episodes), lamotrigine, lithium, quetiapine, and if not effective modafinil, pramipaxole, or another atypical especially lurasidone 20-60 mg or asenapine 2.5 – 5 mg may be useful. In a pinch I have tried the oral ketamine-like agent Nuedexta combination of dextromethorphan/quindine. Don’t forget TMS transcranial magnetic stimulation if covered by insurance.

Stephen M. Stahl, MD, PhD
Adjunct Professor, Department of Psychiatry,
University of California, San Diego School of Medicine
Honorary Visiting Senior Fellow, University of Cambridge, UK

 

What time frame is needed to know if a patient is or isn't responding to treatment with an MAOI?

The question that necessarily precedes this one is: how do we know that we have reached an adequate dose? Theoretical reasons, and some practical experience, suggest that MAO needs to be inhibited very strongly, perhaps to around 95% in order to get the full benefit. Very few laboratories offer platelet MAO inhibition studies, perhaps we should demand that more of them do. It seems very probable that the next best measure (which probably correlates with MAO inhibition), is the degree of postural hypotension patients exhibit (subjective symptoms of faintness are unreliable). It is impossible to explain this fully in the context of short response, but those interested may find the graphs that are posted on my website illustrating this blood pressure change helpful. Monitoring of sitting and standing blood pressure (with two consecutive standing measurements) is essential when using these drugs. When the degree of postural hypotension becomes significant, a drop of ~20 mmHg or so in systolic BP, but not sufficient to cause disabling lightheadedness and faintness, then the dose is adequate. A significant degree of adaption to postural hypotension occurs over time, such that if the dose is maintained for 14 days the degree of blood pressure drop is significantly lessened.

Once that dose has been reached how long it takes to notice a response rather depends on who is looking, and for what. If you concentrate on anergia and anhedonia you will see significant improvements more rapidly than if you concentrate on subjective symptoms (especially anxiety). In patients demonstrating even minor degrees of psychomotor retardation improvements in volume, speed and tone of voice, and reactive facial expression, these improvements are frequently observable within days (the word “animation” is perhaps the most satisfactory single descriptor). Substantial improvement in energy levels are likely to be noticeable within 10 to 14 days (of reaching a proper therapeutic dose). It is remarkable how many patients do not report subjective improvement for longer periods.

Note: When phenelzine is used for chronic anxiety allow 2-3 months for improvement.

P. Ken Gillman, MB, BS, MRC Psych.

 

Are the new pharmacogenomic assays of any clinical utility? If so, when would one be of greatest benefit in making a treatment decision?

Great question, complicated answer. NEI members can get a free test from Genomind to test drive this idea in one patient. Insurance is actually reimbursing some tests especially the cytochrome P450 enzymes. Testing is also available from other companies like AssureRx. A number of assays are now commercially available and emphasize P450 enzymes, and a number of neurotransmitter related genes, and are probably most advanced for treatment resistant depression application, and more for treatment than for diagnosis in general in psychiatry. The most common genes available for testing are:

CYP 2D6, 1A2, 2C9, 2C19, 3A4/5
SERT (the serotonin transporter), variation associated with poor efficacy and poor tolerability;
5HT2A receptor gene;
5HT2C receptor gene
CACNA1C, calcium channel gene
DRD2 dopamine receptor gene
ANK3 signal transduction cascade
COMT catechol O methyl transferase enzyme’s gene
MTHFR Methylene tetrahydrofolate reductase

Not enough space here to explain these, but in brief, these are probably best established to help guide selection of treatment, not to guide diagnosis; and the best data are in treatment resistant depression where some of these gene variants predict poor efficacy or poor tolerability.

However, no gene tells you everything about a patient to dictate any specific treatment. This is about the balance of the evidence where the genomics help you make a decision and help make you more confident (and the patient more confident) about your decision.

Stephen M. Stahl, MD, PhD
Adjunct Professor, Department of Psychiatry,
University of California, San Diego School of Medicine
Honorary Visiting Senior Fellow, University of Cambridge, UK

 

I have a young adult male who was recently hospitalized for severe major depressive disorder with psychotic features. His family reports the onset of depressive symptoms approximately one month prior to a near fatal overdose. They report he became more isolative and stopped eating and socializing with friends and family; the family is originally from the Middle East and are very close. His parents described vegetative symptoms as well. He reported a great deal of anxiety and guilt because he was not as far along in college as his relatives and did not have a girlfriend. He explained that culturally there is a lot of pressure on young adults to succeed in college, and find a partner and marry. He was spending most of his time in his room sleeping but reported never feeling rested and waking frequently with worry.

Of note is that this young man had septic shock with multi-organ failure approximately 1 1/2 years prior to this depressive episode. He had to learn to walk and talk again and actually returned to college to study as an engineer. He is very bright. MRI and neuropsychological testing returned normal. However he has had more anxiety and trouble assimilating in the college community since the hospitalization for septic shock. He spent five days as an inpatient in the psych ward following his stay in ICU, during which mirtazapine was prescribed. He has improved on mirtazapine but is feeling tired and "doped up during the day".

I have added buproprion and titrated to 150mg and have lowered the mirtazapine to 15mg. He is improving and interacting more with the family but continues to present with avolition, blunted affect, problems with concentration, worry and guilt. He denies any psychotic symptoms and/or suicidal or homicidal ideation. He denies a sustained period of insomnia or racing thoughts, although he is guarded and there may be more there. I have only seen him on two occasions but his therapist reports that the patient described problems with anxiety in school and was having trouble with his courses prior to the original hospitalization for sepsis. Labs including B12, folate, vitamin D, TSH, CBC/diff and CMP are all normal and the patient's weight and appetite are improved. There is a family history of MDD and this relative is prescribed Fluanxol 3mg daily and doing well.

His father is a retired pharmacist and would like me to prescribe a medication in the United States that is close to Fluanxol. I have done some research and discovered this medicine contains flupenthixol which is a low dose neuroleptic and used to treat anxiety, depression, inactivity, asthenia and lack of initiative. It is in the thioxanthine group which is structurally similar to phenothiazines.

I would like to provide his father with more information but I cannot find much about this medication. I do not believe adding thiothixene would be a wise decision at this time. I would like to stay the course as the patient is improving. He is working with a therapist and beginning to open up. If he plateaus or if mood lability persists then I would considering adding a mood stabilizer or second generation antipsychotic. Do you have any recommendations and can you tell me if there is a compound similar to Fluanxol available in the US.

Very interesting case. Up to the point that you said he had septic shock, I have an almost identical case. I wonder whether your patient, with a family history of depression responding to the conventional antipsychotic flupenthixol, is pre-psychotic or prodromal for a psychotic illness, even schizophrenia. However, most of the description above sounds like a fairly severe unipolar depression. If you have developed sufficient rapport, inquire about whether he has auditory hallucinations or any other psychotic symptoms. Both the patient and the family may be quite guarded about that but I would have a high index of suspicion and this may come out over time or with continued rapport and questioning. Otherwise, tell the father that you can give the son an antipsychotic but the risk of tardive dyskinesia in a young person means a modern version of flupenthixol is either the atypical antipsychotic aripiprazole (soon to be available also in depot form in the US) or quetiapine. If the patient has less than complete resolution of symptoms, I would not hesitate to give someone like this either aripiprazole or quetiapine augmentation. He may now have an organic component to his illness if the septic shock affected the CNS in any way.

Stephen M. Stahl, MD, PhD
Adjunct Professor, Department of Psychiatry,
University of California, San Diego School of Medicine
Honorary Visiting Senior Fellow, University of Cambridge, UK

Top of Page