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: In today's episode, you'll learn how to assess and manage perimenopausal symptoms, including hormone replacement therapy and novel treatments like clonidine, saffron, and l-methylfolate. But first, a preview of the CME quiz. The answer is in the research update at the end.

1. According to a recent meta-analysis, what percentage of children diagnosed with ADHD also have obstructive sleep apnea?

A. 10%

B. 21%

C. 44%

D. 62%

Pearl Number 7: Watch for worsening in the perimenopause

KELLIE NEWSOME: Last week, we talked about hormonal swings that worsen psych disorders during the luteal phase, the two-week window before menstruation. Today’s episode is not about hormonal swings but their decline. Many psych disorders also worsen during menopause, as estrogen starts its gradual decline. Once they stabilize in the low range, things get better, but in the meantime, you can expect to see more depression, concentration problems, and even relapses of schizophrenia in middle-aged women.

CHRIS AIKEN: Here are some specifics. Depression is two to four times more common around menopause. Bipolar depression also worsens during menopause, but mania does not, and there’s a message there. Depression tends to be caused by slow changes that grind people down over time, like chronic stress, while mania is triggered by rapid changes like the sudden rise in spring sunlight, postpartum hormones, starting or stopping medications, or traveling in an airplane across more than 2 timezones. ADHD also worsens during menopause. In a survey of 600 women with ADHD, 98% reported worsening during menopause, and many women without a prior ADHD diagnosis complain of brain fog. Binge eating rises too. Whether anxiety peaks in menopause, however, is less clear, so if you’re a psychiatric researcher there’s a gap in need of data.

KELLIE NEWSOME: In schizophrenia, women have two risk windows where psychosis can worsen: one is shared with men, in the late teens, and one they face alone, around menopause. The likely cause is the decline in estrogen's neuroprotective effects on dopaminergic systems.

CHRIS AIKEN: Estrogen influences many processes in the brain: GABA, serotonin, dopamine, norepinephrine. It affects neurogenesis, inflammation, and the stress hormones of the HPA axis. But the brain adapts, which may explain why women do better once the low levels have stabilized. It's the transition that is risky, the perimenopausal period when estrogen is falling and fluctuating unpredictably, and that can take years.

KELLIE NEWSOME: Perimenopause lasts an average of seven years.  It typically begins in the late 40s, though some women start it in the 30s. Menstrual cycles become less frequent and more irregular. Hormone levels decline without plateauing. You know when perimenopause is over because the definition is clear: defined as a full year without a period.

CHRIS AIKEN: Here’s another thing to watch out for during perimenopause. For some women, premenstrual dysphoria comes back or starts anew, especially when the menopausal transition is abrupt, like when it’s induced surgically, or by estrogen-blocking treatments for breast cancer like tamoxifen. In our next pearl, we’ll look at the practical question: So if falling estrogen is driving the depression, could restoring it treat it?

Number 8: How to treat perimenopausal psychiatric problems

KELLIE NEWSOME: The first-line treatments for perimenopausal depression are the same ones many take for in other depressive episodes: SSRIs and SNRIs. They address both mood symptoms and vasomotor symptoms — hot flashes and night sweats. Among the SSRIs, paroxetine, escitalopram, and citalopram have the most data in this population. Among the SNRIs, desvenlafaxine and venlafaxine.

CHRIS AIKEN: Vortioxetine and other serotonergic agents are also likely to help. But the non-serotonergic antidepressants — bupropion, for instance — probably don't address the vasomotor symptoms. Gabapentin is another option, particularly when insomnia is prominent. Another good option for perimenopausal insomnia is melatonin.

KELLIE NEWSOME: One practical note: if a patient responded to a particular antidepressant before, that's usually the best place to start again. The evidence base for specific agents here is thin, so prior response is a better guide than the clinical trials. And if your patient has bipolar disorder, skip the antidepressant — they can cause more agitation or rapid cycling.

CHRIS AIKEN: When antidepressants don't work or aren't tolerable, hormone replacement therapy, HRT, is an option, for unipolar and likely for bipolar as well. HRT is an attractive option because it addresses the underlying cause, but the supporting studies are few and small.

KELLIE NEWSOME: Here's what the evidence tells us about HRT. For women without clinical depression, HRT improves well-being, energy, and cognition, along with physical benefits: relief from hot flashes, night sweats, vaginal dryness, and weight changes. It also lowers the risk of diabetes and osteoporosis. That’s a lot of benefits across a pretty big evidence base, but the treatment nearly got cancelled by a large observational study.

CHRIS AIKEN: A 2002, the Women's Health Initiative reported increased risks of breast cancer and heart disease with HRT. Prescriptions dropped sharply, and clinicians grew reluctant to recommend it. But subsequent studies challenged those findings. HRT may protect the heart, particularly when started early in the menopausal transition. The picture is still evolving. Risks depend on a woman's individual history, the type of hormones used, and how long they are used. During treatment, you need to watch for complications like excessive bleeding, fibroid growth, and blood pressure changes. Most psychiatrists aren't equipped to weigh and monitor those risks, so I recommend women get this treatment from an OB-GYN.

KELLIE NEWSOME: When it comes to treating clinical depression with HRT, the data is much more thin. We have two small randomized controlled trials enrolling a total of 84 perimenopausal women. Both used HRT as monotherapy. Both were positive. Response and remission rates ran between 65 and 70 percent. Both used transdermal estrogen — a patch rather than a pill. Transdermal delivery gives steadier blood levels, which might be important for stabilizing mood. In both studies, the patch combined estrogen with progestin to protect the uterine lining from cancer. A third randomized trial found that starting transdermal HRT early prevents depressive symptoms. This one was larger, enrolling 172 women in the early phase of menopause. Compared to placebo, HRT cut the risk of future depressive symptoms in half, especially in women with recent stressful life events.

CHRIS AIKEN: In schizophrenia, transdermal HRT also treats and prevents psychotic relapses. For active treatment of psychosis, the effect size is small, 0.3, and supported by four randomized trials. Another option in schizophrenia is raloxifene, brand name Evista. This is a medication that modulcates the estrogen receptor modulator. It’s approved for osteoporosis in menopausal women, and it’s also approved for breast cancer prevention.

KELLIE NEWSOME: Raloxifene for schizophrenia? I’ve never heard of this one. Is this another novel med with an intriguing but impractically small trial?

CHRIS AIKEN: That’s what I thought when I saw it in a 2023 paper called, “Evidence-Based Recommendations for the Pharmacological Treatment of Women with Schizophrenia.” They are saying it’s ready for prime time, and they cited 8 randomized trials, one of them large, and 3 meta-analyses. 

KELLIE NEWSOME: OK, so if you’re treating schizophrenia, look up raloxifene and learn how to use it. Then give us a call and we’ll interview you for the podcast. But if you think HRT is indicated, we’re not recommending you write for it. Contact the OB-GYN directly. Explain that psychiatric treatments haven't been sufficient and ask whether HRT is an option. They'll weigh the risks and follow the medical effects.

CHRIS AIKEN: Here are the contraindications that the OBGYN is going to mull over: a history of estrogen-sensitive cancers — breast, ovarian, uterine — may rule out HRT. So does unexplained vaginal bleeding or a history of blood clots, pulmonary embolism, stroke, or conditions that raise stroke risk like uncontrolled hypertension or elevated triglycerides. If anyone’s counting, there’s a lot more than 14 pearls in this series, because we’re still on number 8 and we’ve already covered five treatments and two perimenopausal disorders.

KELLIE NEWSOME: Dr. Aiken, I think you’re the only one who is counting.

CHRIS AIKEN: OK, I’ll stop. But what about other disorders that worsen around menopause — bipolar, ADHD, or bulimia? For these, we have no direct clinical trials, but some medications and supplements have separate lines of evidence that we can patch together to make a treatment plan.

1. First, consider clonidine for perimenopausal ADHD. Clonidine improves perimenopausal symptoms like hot flashes and palpitations, and it also treats insomnia and ADHD. 

2. L-methylfolate for perimenopausal depression. True, there aren’t studies of that exact presentation, but this vitamin treats depression, and it did improve sexual function in a randomized trial of  perimenopausal women, so worth considering.

KELLIE NEWSOME: And finally, Saffron. This one actually has the evidence, but often gets overlooked because it’s an herb. But saffron has 3 large and 17 randomized trials in mild to moderate major depression, all of which are positive, and a few are in perimenopausal women. Saffron also treats symptoms relevant to the perimenopause: sexual dysfunction, sleep quality, and it has small trials in ADHD. The dose across all of these trials is 30 mg/day. A reliable brand is the patented Affron — spelled without the S — it was used in clinical trials and licensed to other manufacturers. Dr. Aiken keeps a list of lab-tested products at chrisaikenmd.com/supplements.

Research Update

KELLIE NEWSOME: Is it ADHD, or sleep apnea, or both? That's a tough differential, and today's research update tells us how critical the question is. It's a meta-analysis by Bryan Leow and colleagues from the Journal of Attention Disordersthat estimates the rate of sleep apnea in children with ADHD.

CHRIS AIKEN: Last year, I saw an estimate of 25%, which woke me up, because that suggests around a million children in the US might be taking stimulants for an airway problem. The new estimate is higher. Across 11 studies involving 903 children, 44% of kids with ADHD also had obstructive sleep apnea. Flip it around, and 28 to 43% of children with sleep apnea met criteria for ADHD. The limitations: It’s a small dataset, and most of the studies involved younger children age 7-11.

KELLIE NEWSOME: The mechanism is straightforward. Sleep apnea fragments sleep and drops oxygen levels overnight, impairing attention, impulse control, and behavior — the same symptoms we see in ADHD. Adults are also affected. We have less data, but about 20 to 30% of adults with ADHD have sleep apnea, and the rate approaches 50% if we broaden the criteria to include all sleep-disordered breathing. There's a key difference between the two age groups. In adults, the main treatment for sleep apnea is CPAP or BiPAP. In children, enlarged tonsils and adenoids are often the culprit, and we clear the airways by removing the tonsils: adenotonsillectomy.

CHRIS AIKEN: Some children may have both ADHD and sleep apnea — but surgery is still a reasonable first step. After adenotonsillectomy, half of children no longer met criteria for ADHD at one-year follow-up, and scores on an ADHD rating scale dropped 30%, from 32 to 21.

KELLIE NEWSOME: Methylphenidate can also work, but it doesn’t get at the underlying problem. In studies of sleep apnea, this stimulant improved inattention, but not the sleep-disordered breathing, and one study found that stimulant use slightly worsened the apnea index. Stimulants also add extra stress to the heart, which is a major cause of death in sleep apnea. Here's a pearl you can use in practice right now. Atomoxetine is approved as Straterra for ADHD, but this noradrenergic med also opens up the airways and improves the hypoxia index in sleep apnea. If you suspect sleep apnea in a patient with ADHD, get them to a sleep study, and for medication, atomoxetine is a reasonable place to start. Next week, we’ll look at a new study of atomoxetine in sleep apnea.

CHRIS AIKEN: Based on this study, I'm going to start screening for sleep apnea in every patient with ADHD. For adults, the STOP-BANG questionnaire is a good screening instrument. For children, the standard is the Pediatric Sleep Questionnaire. Both are free. You'll find them in the link in the show notes, or go to chrisaikenmd.com, click Research Updates, and search for "sleep apnea" – you’ll find the study on sleep apnea in ADHD with a link to the Pediatric Sleep Questionnaire.

KELLIE NEWSOME: Learn more about hormonal therapies for depression in Dr. Aiken's book, Difficult to Treat Depression. The audio version is on sale now for $14 at Amazon. It covers estrogen therapies for women, testosterone for older men, zuranolone for postpartum depression, and high-dose thyroid for treatment-resistant depression.