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Curbside Consults






Q: I have a 37-year-old woman with chronic depression since adolescence. She seems to have a baseline of mild depression with 1-2 depressive exacerbations per year lasting several months. She also has anorexia nervosa, and although she is currently at normal weight, she still purges after eating when depressed. She has been tried on multiple SSRIs, with or without antipsychotic augmentation and also with lithium augmentation, but has never had a significant response to medicines. She is now on nortriptyline with dose titrated to therapeutic drug level, but that has not clearly worked any better. She has never had any manic symptoms, or mixed states, just different levels of depression and the eating disorder. Family history includes mother with anxiety, sister with possible bipolar 2 and another sister with anxiety. What are your thoughts regarding diagnosis and treatment?


PL: The key to this case is the family history of genetics in the sister. If the DSM claims are correct (which they are not), bipolar genetics are supposed to be separate from unipolar genetics. Thus in a person with supposed unipolar depression ("MDD"), you should not see bipolar genetics. If you do, either the bipolar genetics is wrong, or the patient does not have unipolar depression. Those are your two options. Assuming the bipolar genetics are correct here, then the patient does not have "MDD." Or, more correctly, the whole concept of "MDD" is false. In other words, the whole distinction between bipolar and unipolar depression as two different diagnoses or diseases is wrong, and they are two subtypes of the same disease, manic-depressive illness (MDI). (See PL.com for elaboration). Either way, the bipolar genetics tells you that should not insist on the "MDD" concept, implying the use of antidepressants instead of mood stabilizers.

Given the STARD results, the likelihood of response to nortriptyline or any antidepressant now is at most 15%. So failure is not surprising.

In this case, what has not been done is to stop antidepressants entirely, and use only mood stabilizers, just as would be recommended for bipolar depression. This is what PL would recommend, since unipolar depression and bipolar depression are seen as the same illness, MDI. Instead of lithium "augmentation," you could give lithium alone. Or you could give lamotrigine alone, or carbamazepine alone. Given the eating disorder, lamotrigine and carbamazepine would be alternatives that would not cause weight gain and/or exacerbation eating disorder. One of these mood stabilizers could then be combined with a dopamine blocker with depressive symptom benefit, like aripiprazole or lurasidone.


1/5/2021


This curbside consult on bipolar illness and the autism spectrum is more a comment from a colleague, with brief PL comment:


Comment: I’m a psychologist is private practice. The population I treat includes a high preponderance of clients with hyperthymic and bipolar disorders. I’ve been working successfully with a treating psychiatrist and I pride myself in having a deep respect for family genetics and psychopharmacology when working with clients. I’ve noticed over 20 years of practice that it can be very difficult to stabilize manic or hypomanic conditions with traditional mood stabilizers, or even with some of the newer antipsychotics, when there is also an autism spectrum genetic line running through the family. Treatment seems to be very challenging, even if the client shows no autistic features or symptoms. In these cases, typical mood stabilizers like lamictal, trileptal, lithium, etc., seem to seriously exacerbate depression, create intense sedation, or lead to social withdrawal. I’m interested in whether you have had similar experiences and what your recommendations are for stabilization in these client populations. I would much appreciate any advice or relevant research information.


In all of the five cases that I’ve treated long term over the past ten years, these clients have been the most challenging to stabilize and return to full functioning. Just to be clear, none of these clients had autism spectrum symptoms or diagnoses. However, it was clear in four of the cases that one parent ( and another family member, I,e., brother, grandparent, or child) did or could have easily qualified for an Asperger diagnosis. Why I am so invested in understanding this population is because of how much suffering their symptoms and medication side-effects caused each of them. All are now stable and fully functioning, but only after years of trials, and many medication failures.


As I noted, typical anti-seizure, mood stabilizers, and older atypical antipsychotics did not work and increased suffering from side effects. Often the side effects included social withdrawal and lethargy. So, using classic med protocols extended the amount of time it took to get to the use of the newer atypical antipsychotics, which were most effective in treating these clients. Often it was also necessary to add a stimulant to get to a high functioning level in which social interaction was tolerated and even enjoyed.


I’d be most grateful to get connected with other clinicians who have also struggled in treating this population to see if they’ve experienced similar challenges and results.


PL: Your observation is very interesting. I haven’t had the same experience as you but I haven’t treated many patients on the autism spectrum. I think your observation is likely correct and the question is what it means. Perhaps the “bipolar” illness in this setting is different than primary psychiatric bipolar illness, and rather secondary to another neuropsychiatric cause? I’ve thought so in relation to other settings, such as manic states with cerebral palsy or other developmental conditions.


It is interesting that you note that the patients themselves did not have autism but you note it in family genetics. It's also interesting that you note that they all eventually recovered fully, which would not be the case with autism itself. I'm not clear why the newer antipsychotics agents would work better than "older" ones (meaning 1990s era, such as risperidone and olanzapine). These are observations that are unique, and I don't believe there is any research evidence for guidance here. But it is worth noting.


11/4/2020


Question from a psychiatric resident:

A 19 year old male patient was transferred to my outpatient care after hospitalization for bipolar disorder. He had been treated in the past with lithium 300 mg/d plus prozac 20 mg/d. He moved and didn't resume lithium, but stayed on prozac. Then he had a manic episode, used marijuana, began to talk fast, was high energy, had racing thoughts, and then became suicidal and was hospitalized. In the hospital, he quickly improved and lithium was added at 300 mg/d. He was transferred to me, and I stopped prozac, since antidepressants had been proven ineffective in bipolar depression.


My supervisor became quite upset, and told me that by stopping prozac, he would have serotonin withdrawal and become suicidal. He told me to resume it immediately. What are you targeting with lithium, he asked? Stop it. What was the right thing to do?


PL: Leston Havens, the great mentor of many in Harvard psychiatry, used to say to residents: "You have to learn to lie to your supervisors." Nod your head, and then do what's right. This supervisor is practicing 20th century psychiatry and 1990s psychopharmacology. It's time to enter the 21st century. You don't need to "target" any symptom; treat the disease! It would be a bad physician to say in a case of pneumonia: "I'm targeting fever and night sweats." Treat the pneumonia! Psychiatrists practice unmedically though, ignoring diseases like bipolar illness and trying to treat symptoms.

Further in a young adult, prozac increases the risk of suicide, not decrease it. In a suicidal young man on prozac, the first thing to do is to stop prozac. Serotonin withdrawal can increase suicidality, but prozac has a long half-life and minimal serotonin withdrawal.

You did the right thing. Now just lie to your supervisor.


6/7/2020


Question: How would PL approach this case and what does it think of the plan taken?


A 14 year old female is in the midst of a likely resolving acute depressive episode (onset spring 2019). Around this one-year mark, neurovegetative symptoms including energy are beginning to improve which is consistent with natural history of the disease. She has bipolar genetics, as a maternal uncle has bipolar disorder; brother also attempted suicide. She is at increased risk for such given her young age of presentation and family history. A SRI may be helpful in the short-term for this acute episode, though it also carries risks of activation, and at this time, as the episode seems to be resolving, is not recommended. Time will reveal whether she may need longer term treatment for prevention of episodes with a mood stabilizer. Of note, her symptoms are on the background of years of low mood which emerged following parents' divorce, though no other trauma, for which psychotherapy is indicated.

Plan: For acute depressive episode, consider SRI (fluoxetine) though will likely not use given resolving symptoms. Continue weekly psychotherapy to process impacts of divorce plus the experience of an acute depressive episode, and to support resolving symptoms.


PL: PL agrees with this overall approach. In the PL view, it’s best not to give SRIs in such cases. You might highlight the suicide risk and change the word “activation” to “mania” or “manic-like worsening”, to be clear on the problem. One could summarize this way:

“This patient with early-onset depression in the setting of bipolar family history has a high likelihood of eventually having a manic episode and thus bipolar illness, which usually begins in late adolescence or by age 20. Also SRIs increase suicide risk in this population, especially with bipolar genetics. For those reasons, antidepressants are best avoided initially….etc”


Follow-up Question: To be clear to generalize the concept, if a clinician ended up treating this same patient (say the episode was not resolving), would he/she be more likely to use an SRI in short-term with careful monitoring, or go ahead w/ dopamine blocker (for short-term) or even mood stabilizer?


PL: This is a tough question. In the US, it has important legal implications. Since clinicians need to be aware of their legal risks, they should realize that they need to justify why they would not do the standard of care, which is what most clinicians do, ie, use SRIs.

So it would depend on the patient’s willingness, but PL would prefer to treat with low dose dopamine blocker, like abilify, or low dose mood stabilizer, like lithium or lamotrigine. But clinicians should make sure they document that they discussed SRIs, and the pros and cons including suicidality, and that the patient agreed with the idea of using something else initially.

Another option would be to use a low dose SRI that would be a near-placebo, like 10 mg of citalopram, and then use aripiprazole or low dose mood stabilizer with it. Then one could taper the SRI if she improves later and leave her off if she remains well. That way clinicians would be more protected legally as well.


Follow-up outcome: I saw her again today 2 months from the initial evaluation with significant neurovegetative symptoms and suicidal ideation around the 1-year mark since onset of her current depressive episode. She looks much better now, smiling, showing me her dog waving at me, "more hopeful about my life." And she wasn't given the idea a daily medication was needed, but rather is feeling good about her mastery of things in psychotherapy. I'm glad to not have started medication and followed the 'natural course' to guide treatment.




5/18/2020


Question:

I am a psychiatrist in private practice. A common situation I find myself in is this - a patient (usually, but not always, a young woman) is referred to me by their primary care physician, who has started them on an antidepressant (usually for the first time, and usually an serotonin reuptake inhibitor, SRI). The patient has failed to improve, prompting a psychiatric assessment. The history reveals past episodes of probable hypomania and/or cyclothymic temperament, and of course there is often a family history of bipolar illness or recurrent severe depressive illness.

What is your usual approach to these situations? Generally I will offer patients a choice of lurasidone, lithium, or lamotrigine (although I am aware that the evidence of the acute antidepressant efficacy of lamotrigine is quite limited), with a plan to taper and cease the antidepressant at a later date. I have found that, following a description of the relative risks and benefits of the three medications, people will most often opt for lamotrigine (especially young women). And, in my clinical experience, those in this group who opt for lamotrigine will often end up doing very, very well. Furthermore, many of these people are adamant that the antidepressant is having an acute effect, despite my clear advice that it the evidence for its acute efficacy is very limited.

Should I be advocating for lithium or lurasidone (or something else) more strongly, despite my clinical experience of lamotrigine in this context being highly favourable? And should I be more aggressive in tapering antidepressants early on?

PL: This scenario is increasingly common in the experience of the PL editor also. Once you begin to look for affective temperaments, you begin to see it everywhere. What used to be "MDD" and "GAD" or "ADD" or bipolar spectrum or type II bipolar illness often turns out to be cyclothymia. Mood temperaments explain a lot. If someone has cyclothymia, for instance, she will have mild constant mood swings, not severe enough to diagnose bipolar illness - but it's there. She will be anxious frequently, as mood symptoms go with anxiety. She won't be able to concentrate most of the time. And cyclothymia predisposes to depressive episodes, so she will have depressive episodes now and then. Antidepressants are more likely to cause mania/hypomanic switches in such persons also. And yet the baseline cyclothymic temperament seems to respond well to simple interventions like low-dose lithium or valproate. Full doses often are not needed. In contrast, such patients fail or do not respond fully to multiple trials of full dose SRIs and/or amphetamines. In some cases, such patients also seem to respond to low dose dopamine blockers, like aripiprazole.


In this field, the research exists to tell us what's wrong and how to diagnose it. The research is not there to tell us what to do in any definitive way. There are some observational reports on low-dose lithium and valproate, and that's it. That doesn't mean that low dose dopamine blockers might not work, or that lamotrigine might not work or even carbamazepine. We don't know. When we don't know, the bad news is that you cannot be told what to do. And the good news is that you cannot be told what to do. So the PL view would be to follow your clinical observation here and continue to use lamotrigine if it seems helpful, carefully of course, with low and slow dosing.

Regarding the patient experience that antidepressants are helpful, the placebo-controlled randomized studies in bipolar illness prove that this is natural history, not drug effect, and the patient conclusion is correct clinically (they're better) but false scientifically (they're not better because of serotonin reuptake inhibition). The best approach is not to prescribe the antidepressant at all so as not to have to explain why it should be stopped. Although even here, the research is not clear in mood temperaments. What we know for now is that antidepressants can cause mania; we don't know if they're effective or not. Again, not a reason to prohibit them, but certainly a reason not to assume they should be used.


Follow-up: [From the clinician who initially asked the above question] Interestingly the patient I had in mind when I wrote to you originally has ended up responding very well to low-dose lithium (in combination with lamotrigine). The more I got to know the patient, the more obvious it became that she had fairly clearcut bipolar disorder, and not “just” cyclothymia.


PL: This is an important point too. Sometimes we underestimate the symptoms, and the patient may underreport, and then we are dealing with standard bipolar illness, not a mood temperament. Other times, we overreport the mood or associated anxiety or cognitive symptoms, and usually it is labeled "MDD" or "ADD" or "GAD"; then it is misdiagnosed altogether and the underlying mood temperament is missed.


5/14/2020


Anecdote: On the inpatient unit, I educated our team that a recent increase in sertraline (Zoloft) may have worsened the delusions and auditory hallucinations in a patient with bipolar depression.

PL: Sertraline has dopamine reuptake blockade, which is potent, and thus could cause or worsen delusions or hallucinations. Another reason why SRIs are not "selective" (hence not "SSRIs").


5/12/2020

Question: How would PL approach this case and what does it think of the plan taken?


A 14 year old female is in the midst of a likely resolving acute depressive episode (onset spring 2019). Around this one-year mark, neurovegetative symptoms including energy are beginning to improve which is consistent with natural history of the disease. She has bipolar genetics, as a maternal uncle has bipolar disorder; brother also attempted suicide. She is at increased risk for such given her young age of presentation and family history. A SRI may be helpful in the short-term for this acute episode, though it also carries risks of activation, and at this time, as the episode seems to be resolving, is not recommended. Time will reveal whether she may need longer term treatment for prevention of episodes with a mood stabilizer. Of note, her symptoms are on the background of years of low mood which emerged following parents' divorce, though no other trauma, for which psychotherapy is indicated.

Plan: For acute depressive episode, consider SRI (fluoxetine) though will likely not use given resolving symptoms.

Continue weekly psychotherapy to process impacts of divorce plus the experience of an acute depressive episode, and to support resolving symptoms.


PL: PL agrees with this overall approach. In the PL view, it’s best not to give SRIs in such cases. You might highlight the suicide risk and change the word “activation” to “mania” or “manic-like worsening”, to be clear on the problem. One could summarize this way:

“This patient with early-onset depression in the setting of bipolar family history has a high likelihood of eventually having a manic episode and thus bipolar illness, which usually begins in late adolescence or by age 20. Also SRIs increase suicide risk in this population, especially with bipolar genetics. For those reasons, antidepressants are best avoided initially….etc”


Follow-up Question: To be clear to generalize the concept, if a clinician ended up treating this same patient (say the episode was not resolving), would he/she be more likely to use an SRI in short-term with careful monitoring, or go ahead w/ dopamine blocker (for short-term) or even mood stabilizer?


PL: This is a tough question. In the US, it has important legal implications. Since clinicians need to be aware of their legal risks, they should realize that they need to justify why they would not do the standard of care, which is what most clinicians do, ie, use SRIs.

So it would depend on the patient’s willingness, but PL would prefer to treat with low dose dopamine blocker, like abilify, or low dose mood stabilizer, like lithium or lamotrigine. But clinicians should make sure they document that they discussed SRIs, and the pros and cons including suicidality, and that the patient agreed with the idea of using something else initially.

Another option would be to use a low dose SRI that would be a near-placebo, like 10 mg of citalopram, and then use aripiprazole or low dose mood stabilizer with it. Then one could taper the SRI if she improves later and leave her off if she remains well. That way clinicians would be more protected legally as well.



5/8/2020


Question:


A 21 year, female in mid-March 2020, had a severe manic episode. She had been diagnosed two years earlier. She was hospitalized for 3 weeks and stabilized on Latuda (Lurasidone) 80 mg qhs – as she refused any mood stabilizer. She won’t take Lithium as she claims it left her numb and “ a robot.” She won’t take Lamictal for uncertain reasons. I’ve been adding Tegretol (carbamazepine) and it has been very, very useful. Everything has quieted down, pretty nicely. She’s now on 250 mg qam and 500 mg qhs, where we’ll stay until getting a carbamazepine level next week. She continues on Latuda 80 mgs qhs, which is her “go to” drug during most of 2019 (when she was moderately stable) and a drug she has a lot of faith in. Curbside questions:


  1. Do you worry about an interaction between Tegretol and Latuda that is problematic? The combination over these past several weeks seems to be quite good.

  2. Should the Tegretol level be a “trough” level – early in the morning, before her morning dose of Tegretol?

  3. Should I wait until we hit your suggested “target level” of Tegretol, of 8, before reducing the Latuda?

  4. At the “target level” should the Tegretol dose continue to be split, a.m. & p.m., or can it all be moved to the qhs dose?

PL: