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10 Psychopharm Commandments #1

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Antidepressants in mania and stimulants in psychotic disorders get called out in our first psychopharm commandment. 

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Published On: 09/05/22

Duration:  14 minutes,  48 seconds


Ever wonder what happens when you give a patient with bipolar disorder an antidepressant, or a patient with psychosis a stimulant? Find out in this first edition of the 10 Psychopharm Commandments.

Chris Aiken: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. 

Kellie Newsome: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

CHRIS AIKEN: Psychopharmacology is tough work, and not because there are more than a dozen serotonin receptors. We treat an organ we never see, or even palpate, and we depend on the reports of patients who have problems with memory and self-awareness. We’re taught to use collaborative care, but how do we make collaborative decisions with someone who is hopeless, impulsive, or self destructive? It is the blind leading the blind, and we can get lead into some dangerous places if we’re not careful.

KELLIE NEWSOME: Collaborative care is essential, but it needs some guard rails. Otherwise, if the only guidance you have is what makes people feel better, most of your patients will end up on Xanax and Adderall. So in this podcast-series we’ll put up those rails, through the 10 Commandments of Psychopharmacology.

CHRIS AIKEN: I try not to think in absolutes, but there are some lines you just should not cross when prescribing medications that affect the mind. So we’ve laid out 10 absolutes you should not cross in psychopharmacology. You might think our list is somewhat arbitrary and opinionated, and on that you’re probably right. 

KELLIE NEWSOME: In this episode, the first commandment: Do not worsen mental illness with psychiatric medications

CHRIS AIKEN: There are a lot of ways this do-no-harm commandment gets broken, but the two we see most often are with antidepressants in mania and stimulants in psychosis. 

Starting an antidepressant is contraindicated in bipolar mania, relatively contraindicated in bipolar mixed states, and questionable in bipolar depression. 

KELLIE NEWSOME: Wait Dr. Aiken, I get that but why would anyone start an antidepressant in someone who is climbing the walls with mania?

CHRIS AIKEN: Mania can be easy to miss. There was an interesting study done in the 1970’s where they asked patients who were hospitalize for mania what they were suffering from. The most common answer was “depression.” That answer alone will lead you astray! Mania often starts out euphoric and expansive, but after a few days that turns into impatience, a feeling that you just can’t be satisfied. We see people with mania doing so-called pleasurable things – having sex, traveling, indulging in luxuries, but there’s really not much pleasure going on because their reward centers are never satisfied. It’s a restless feeling. Inside, there’s a deep anxiety that they are losing control. It’s not pleasurable at all, and in DSM-5 they removed the word “pleasurable” from the criteria on impulsive behavior.

KELLIE NEWSOME: Nearly half of patients with bipolar disorder are prescribed antidepressants. That’s been the case for decades, and the latest 2022 data on 40,000 patients from Rakesh Jain and colleagues tells us the trend has not changed much. And I can understand why – I mean if the patient is complaining of depression – even if their mental status suggests they have mania – it’s tempting to prescribe an antidepressant. 

CHRIS AIKEN: Yes, even when the patient is hospitalized for a diagnosis of mania, trazodone will often get added in for sleep. Or mirtazapine. But there’s no reason to think these antidepressants are free of manic-potential even in their low antidepressant doses – there are case reports of mania on them in low doses, and I remember one patient who got manic every time they gave him 50mg of trazodone to help his insomnia.

KELLIE NEWSOME: But here’s some encouraging data. The rate of antidepressant monotherapy has decreased by nearly 50% since 1997 – from 20% to 12%. Still, that means 1 in 8 patients with bipolar disorder are given antidepressants alone, something that Rakesh Jain confirmed as well. And we know what happens when antidepressants are used without mood stabilizers. In 2014 a large study compared antidepressant monotherapy to antidepressants with a mood stabilizer in over 3,000 patients with bipolar disorder. The rate of switch into mania was high in the first 3 months after starting an antidepressant – but only in the monotherapy group – their risk of mania went up 3-fold.

CHRIS AIKEN: That was an important study. It was accompanied by an editorial from Eduard Vieta titled Antidepressants in bipolar I disorder: Never as monotherapy. People pay attention to a title like that, and I saw a change at professional meetings. I was at a bipolar conference before the paper came out and they asked the audience if people thought antidepressants were helpful in bipolar disorder. A lot of hands went up.  After that 2014 study, the same question was asked and the number of hands were far fewer.

KELLIE NEWSOME: The commandment here is not to start an antidepressant during mania. That is absolute. But a lot of patients are already taking an antidepressant when they get manic. What do you do then?

CHRIS AIKEN: That’s where it gets tricky, because sudden changes in meds – including antidepressant cessation – can also trigger mania.

Here’s how I would handle that. If they started an antidepressant 1-3 months before the mania, the new med is probably causative and can be stopped abruptly. Otherwise, treat the mania with mood stabilizers while slowly tapering off the antidepressant (eg, over 1-4 weeks). The same rule applies in mixed states, only here it’s less clear if antidepressants are harmful or helpful. With that uncertainty in mind, trace the timecourse to figure out which is true for your patient and adjust the antidepressant gingerly.

Antidepressants also cause rapid cycling in bipolar disorder, where patients cycle in and out of episodes every 3 months or faster. Those “episodes” may all be depressions, which makes it difficult to figure out whether the antidepressant is causing them. When rapid cycling is suspected, have the patient track with a mood chart

While the role of antidepressants in bipolar disorder is controversial, it is clear they should never be used without an anti-manic mood stabilizer (eg, more than lamotrigine) in bipolar I. In bipolar II, the research is thinner. They are certainly safer with a mood stabilizer on board, but it is possible that a minority of bipolar II patients (5-15%) do well with antidepressant monotherapy.

KELLIE NEWSOME: Another line you shouldn’t cross is prescribing a stimulant to a person with psychosis. There is not much recent research on this subject, because the question has long been settled: Stimulants worsen psychosis. In 2004 researchers from Wales gathered 54 studies of acute stimulant effects in psychosis and schizophrenia. Most of these were experimental studies that tested a single dose – not clinical trials. Here’s what they found. In patients who were already in a psychotic episode, a single dose of a stimulant worsened the psychosis in 50-70%. In patients with schizophrenia who were no longer in an episode, a single dose of a stimulant brought on a new psychotic episode in 30%. These are powerful effects – enough to warn us away from stimulants in psychosis, and unlike the bipolar studies – where antidepressants usually look safer if they are given with a mood stabilizer – in the case of psychosis it didn’t matter whether the patient was on an antipsychotic or not – they still caused psychosis at the same rate.

CHRIS AIKEN: Both amphetamines and methylphenidate can cause psychosis, but amphetamines are much more likely to. That’s what we learned from recent study in the New England Journal of Medicine. They looked at data on 220,000 teens and young adults treated with stimulants for ADHD. Overall, the rate of psychosis was fairly low, about 2 in a thousand. But I’d bet the real rate is higher than that – this was an EMR review so they only knew about the cases where the provider caught the psychosis and recorded it in the chart. But what really stood out was the stark difference between amphetamines and methylphenidate: The amphetamines caused psychosis at twice the rate of their methylphenidate cousins.

From what we know about the mechanisms, this makes sense. Amphetamines like Adderall and Vyvanse cause a bigger dopamine surge by pumping dopamine out of the neuron, which pretty much identical to the known pathophysiology of schizophrenia. Methylphenidates like Ritalin and Concerta act differently. They mainly increase dopamine by blocking its reuptake.

KELLIE NEWSOME:  The alpha-agonists guanfacine and clonidine have a few studies in schizophrenia, and they seem to help cognition without causing psychosis. But psychosis is possible – though very rare – with the modafinils and Atomoxetine (Strattera), both of which have case reports of causing mania and psychosis, and the jury is still out on the other repurposed antidepressant for ADHD – Viloxazine (Qelbree).

We see people with schizophrenia on stimulants for various reasons – weight loss, energy, concentration. There is no evidence that they help, and not for lack of studies. Cognitive problems are common in schizophrenia, but you can’t diagnosis ADHD in this illness, and stimulants are not the answer.

CHRIS AIKEN: The bottom line: Don’t start an antidepressant in a manic patient, or a stimulant in a patient with psychosis. In schizophrenia, the psychotogenic effects of stimulants are very strong, and antipsychotics don’t even provide much protection against them. In bipolar I disorder, antidepressant monotherapy is never advisable, and in bipolar II disorder it is controversial – you should watch carefully not just for mania but for mixed states and rapid cycling on them. While a non-lamotrigine mood stabilizer may protect against antidepressant-induced mania, but no protection is 100%. However, we don’t recommend stopping antidepressants abruptly if the patient has been on them a long time – especially serotonergic ones – the withdrawal state can send their mood in all sorts of directions – including mania. 

And that brings us to the second commandment: Avoid abrupt cessation of psych meds. 

We’ll pick up there in 2 weeks. Until then, catch us on Thursdays for a a new edition of the Podcast stream – throwback Thursdays. We’re dusting off our old episodes, updating the content, and adding CME credits, starting this Thursday with Sexual Side Effects of Psychiatric Medications. Start earning CME now for this episode through the link on the show notes.


  1. says:

    Hi! I’m curious if adding an antipsychotic to an SSRI is ever advisable as opposed to a mood stabilizer?
    Additionally, are your recommendations any different for bipolar II? Thank you!

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