Contraceptives, Hormones, and… Depression?

For many years, researchers have been trying to clarify the association between estrogen, progesterone, and depression. We know that women are twice as likely as men to become depressed (likely due to hormones). We know that changes in the level of estradiol (a type of estrogen) are associated with depression. Furthermore, fluctuating hormones in the days before menstruation are believed to be the cause of premenstrual syndrome (PMS) and can even cause its angrier sister, premenstrual dysphoric disorder (PMDD).

Combined oral contraceptives include synthetic forms of both progesterone and estrogen. These hormones (given in specific doses and at certain times during a woman’s cycle) inhibit ovulation and prevent pregnancy. Interestingly, external progestins (more than endogenous progestins) seem to increase levels of monoamine oxidase, leading to more serotonin breakdown. Degrading more serotonin may lead to depression and irritability. [If you’ll remember from this article, one of the major classes of antidepressants blocks monoamine oxidase. External progestins seem to do the opposite.] 1

Looking back, I remember many of my friends taking birth control in college for the first time. Incidentally, many of these same friends also began to take antidepressants for mood changes or anxiety. After I started my first hormonal contraceptive, I too felt uncontrollably moody. I have always been prone to ups and downs, but certain types of contraceptives have made me feel as though I cannot regulate my feelings.

On to the data. Similar to the research on statins and SSRIs, Denmark has published another large study examining the rates of depression in women who use hormonal contraception. Over 1 million women from ages 15-34 were observed for 14 years. Women who had used antidepressants or who had been diagnosed with depression prior to study initiation were excluded. Both the first diagnosis of depression and the initiation of an antidepressant after starting hormonal contraceptives were tracked and were used to estimate the increased risk of depression with hormonal contraceptives.

The relative risks (RR) of first-use of antidepressants for users of hormonal contraceptives versus women not taking hormonal contraceptives are outlined below.

Combined oral contraceptives 1.2
Progestin-only pills 1.3
Vaginal ring (Nuva Ring) 1.6
Implant (Implanon) 2.1
Levonorgestrel IUD (Mirena) 1.4
Medroxyprogesterone depot (Depot-Provera) 2.7

RR can be understood as the number of “times” more likely you are to experience an effect. For example, an RR of 1.2 means that users of combined oral contraceptives are 20% more likely to use an antidepressant for the first time than women not taking combined oral contraceptives.

Clearly the use of hormonal contraceptives was associated with antidepressant use and also a diagnosis of depression. Interestingly, the relative risk decreased with age (i.e. adolescents had significantly higher relative risks: up to an RR of 3.2 for adolescent users of Mirena). For both age groups, the RR peaked at 6 months of hormonal contraceptive use.

This article should be taken with a grain of salt. Hormonal contraceptives play an incredibly important role in many women’s lives and have provided an independence that wasn’t present before. Women have more control over their health than ever and birth control plays a large role in this gain. Regardless, it is important to be aware of the possible side effects and to make informed decisions about your health care [and to seek help should you need it].


In Pop Culture: Is your birth controlling depressing the hell out of you?


  1. External Progestins and MAO
  2. Association of Hormonal Contraception with Depression 


Sleep Basics: OTC Antihistamines

Many over-the-counter (OTC) medications used for insomnia have primary effects on the H1 receptor. At this receptor, these medications serve as an antagonist; hence the name antihistamine. The H1 receptor is primarily implicated in allergic reactions, so blockade of this receptor decreases the allergic response. Histamine receptors in the central nervous system also have a role in wakefulness; blocking them causes sedation. Studies report that nearly 25 percent of patients with sleep disturbances use OTC sleep aids such as antihistamines, and 5 percent use them at least several nights a week.

Routine use of OTC antihistamines such as diphenhydramine (Benadryl) and doxylamine (Unisom SleepTabs and Nyquil) for insomnia is controversial. I know that on inpatient psychiatric hospitals, these medications are frequently used for sleep because 1) they are relatively safe and 2) they are not addictive. However, the evidence supporting the use of these medications for long-term treatment of insomnia is lacking.  Additionally, many OTC antihistamines (especially Benadryl and doxylamine) have effects at cholinergic receptors leading to uncomfortable side effects such as dry mouth, blurred vision, constipation, urinary retention, and more importantly cognitive impairment and possibly delirium 1.

Recent literature has explored the long term implications of use of anticholinergics (one of the more common being OTC antihistamines). A large prospective cohort study demonstrated that greater cumulative use of anticholinergic medicine in people >65 is associated with an increased risk of dementia 2. To quote from the study:

Higher cumulative anticholinergic medication use is associated with an increased risk for dementia. Efforts to increase awareness among health professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time 2.


In cases where use of a medication is controversial; its important to be an informed consumer. Benadryl or Doxylamine? What dose is effective? Is Tylenol PM different than Benadryl? Is Nyquil? Is it okay to take these medications if you’re >65?

With regard to insomnia, diphenhydramine has been studied more thoroughly and is noted with short-term use to lead to improvements on self-reported sleep efficiency and the Insomnia Severity Index, and a decrease in participant-reported number of awakenings 3. Unfortunately, most studies fail to observe significant changes on the polysomnogram for sleep-onset, sleep efficiency, and total sleep time 3. Thus, although you may feel like you’re sleeping better, the data doesn’t show this. Furthermore, long-term use of OTC antihistamines may be futile. In fact, studies demonstrate that diphenhydramine may lose its sleep-promoting effects after just 3 days. Furthermore, when dosed at 50mg versus 25mg (i.e. 2 Benadryl vs 1) participants had significant psychomotor impairment and a decreased level of wakefulness the next morning 3.

The studies on doxylamine are few and far between. Similar to diphenhydramine, studies show improvement with self-reported sleep but not with the polysomnogram 3. The main drawback to doxylamine? It has a longer half-life than Benadryl, and thus is likely to cause more morning impairment than a comparable dose of Benadryl.

Diphenhydramine Doxylamine
Brand Name Benadryl, ZZQuil, Tylenol PM, All Unisom products except SleepTabs Nyquil, Unisom Sleep Tabs
Half-Life 3-9 hours (usually reported as 8) 10 hours
Dosing 25-50mg 12.5-25mg

My recommendation? If you’re having insomnia and you want a quick fix, go with 25mg of diphenhydramine each night for a short period of time (I’d recommend no more than 1 week). If you’re over 65, be extremely judicious with your use of OTC antihistamines. Likely due to their anticholinergic effects, long-term use is associated with an increased risk of dementia. Short-term use is probably okay, but if you continue to have sleepdisturbances after 1 week of use, ask your doctor for a better, more evidence based, long term solution.

  1. New Developments in Insomnia
  2. Anticholinergics and Dementia
  3. H1 Blockers for Insomnia

Sleep Basics: Melatonin

Melatonin is a hormone produced by the pineal gland from the precursor, serotonin. During daylight hours, serotonin is stored and is unavailable for use. As darkness sets in, an enzyme is activated which converts serotonin to melatonin. Through its changing concentration (high at night and low during the day), melatonin plays a significant role in the human circadian rhythm.

After synthesis, melatonin is released into the blood stream and cerebrospinal fluid, where it acts on receptors found in many different targets in the human body including the suprachiasmatic nucleus (SCN) in the hypothalamus. In the SCN, melatonin inhibits the firing of certain neurons, which may contribute to it’s sleep-promoting effects.


Melatonin is produced by the pineal gland (red) and acts on the suprachiasmatic nucleus (green). Image here.

A few things we know about melatonin:

  1. Melatonin secretion starts when human infants are 3-4 months of age. This is the same time infants begin sleeping through the night.
  2. Nocturnal melatonin production decreases over the human lifespan. Peak concentrations in 70 year olds are only 25% of the peak concentrations in younger adults and may contribute to sleep difficulties in older adults. (Fun fact: this decrease may be related to the calcification of the pineal gland with time. Calcification = decreased synthetic capability = less melatonin).
  3. Certain substances (i.e. caffeine and ethanol) can lead to decreases in melatonin concentrations. (Recommendations on caffeine and ethanol intake can be found here).
  4. Very dim light (i.e. 100-200 lux) such as that from the darkest of overcast days or from light-emitting devices (i.e. iPhones) can suppress melatonin production and can lead to feeling less sleepy before bed, increased time to fall asleep, and increased grogginess the next morning 1.

As an over-the-counter supplement, melatonin has an indication for treatment of age-associated insomnia (such as elderly people with decreased melatonin production), jet lag, and shift work. Its primary efficacy is for sleep-initiation and has not been show to have significant effects on sleep-maintenance or early morning awakening 2.

We know that melatonin receptors are highly sensitive to desensitization and that supraphysiologic doses of melatonin may lead to this. As such, optimal dosing of melatonin has not been clearly established. Anecdotally, I have had neurologists and psychiatrists recommend a starting dose of 3mg (such as from this preparation), however from my reading and literature review it seems that lower doses may be preferable. UpToDate, a widely trusted medical resource, recommends starting doses as low as 0.3mg, whereas the European Food Safety Authority recommends that “in order to obtain the claimed effect, 1 mg of melatonin should be consumed close to bedtime”3.

The take home? Melatonin is relativey safe, has few to no addictive properties, and has an indication for sleep-onset insomnia. If you have trouble falling asleep, it is reasonable to try a melatonin supplement with a starting dose of 1 mg. LabDoor provides rankings of the top 10 melatonin supplements, and as I have heard from other physicians, the Nature Made brand ranks near the top for product purity and ingredient safety. What do I take? I buy the 3mg Nature Made brand, break it in half, take it 30 minutes before bedtime, and it helps me fall asleep.

Go Outside, It’s Good for You

Everyone knows that spending time outside is “good for you,” but how many of us know exactly how much time we need to spend outside, or what type of outside areas (beaches, forests, or parks) would achieve the most health benefits?

As urban areas attempt to incorporate more green space (think the High Line in New York City), public health experts are attempting to nail down the characteristics of these areas that have the most population-wide benefit.  A recent study published in Nature examined the relationship between the duration of exposure to green space and public health outcomes such as mental health, physical health, and social health.

The study found that with 30 minutes per week spent in a green area people had reduced rates of depression. This was dose-dependent up to 1 hour and 15 minutes (meaning that increased durations were associated with decreased depression). The mental health benefits were present regardless of the intensity of the green space (i.e. low versus high vegetation complexity). This article estimated there would be a 7% reduction in depression prevalence for the population if every person achieved this minimum time.

The point here is short and sweet; get outside and spend some time in a green space (however you define it). It’s good for you!

Eagle's Nest

Photo taken during a time spent outside hiking in Topanga Canyon to Eagle Rock. Link to trail here, highly recommended!

As an aside, I found the idea that vegetation complexity could influence the magnitude of mental health benefits pretty fascinating. Apparently, vegetation complexity may mediate this through increased feelings of restoration (i.e. higher levels of plant, butterfly, and bird species richness have been shown to enhance a person’s feeling of restoration 1) and by possible parasympathetic nervous system activation (which lowers your blood pressure and heart rate) which may decrease your experience of stress 2. Other fun facts, “more people tend to visit public green spaces with moderate levels of vegetation cover (rather than high or low), and vegetation is also likely to influence the perception of safety of an area.” That’s enough nerdiness for today, until next time!

Psychiatric Applications of Psilocybin

Photo Credit Fungi Steve

Psilocybin is a member of the tryptamine class of hallucinogens. It is the active compound found in dozens of mushroom species and is responsible for the typical features associated with “shroom” or “magic mushroom” ingestion. Classic effects of psilocybin ingestion are similar to LSD, and include:



  1. Oceanic boundlessness: the experience of unity while also being boundless
  2. Visionary restructuralization: auditory and visual distortions and hallucinations

These effects, while each fascinating in their own right, are not the topic of today’s post. Rather today, we’re going to focus on psilocybin’s antidepressant effects.

Psilocybin acts directly on serotonin 5HT-2A receptors. Interestingly, blocking, or antagonizing these receptors leads to improvements in parkinson’s disease-induced psychosis (discussed in a separate blog post here). Psilocybin, acting as an agonist at this same site, appears to have potent antidepressant effects.

Research on psilocybin has shown promise in the treatment of end of life anxiety, obsessive compulsive disorder, and smoking and alcohol dependence. A study from 2008 showed that 14 months after a single dose of psilocybin, greater than half of the participants continued to report an increased sense of wellbeing. Now, in a recent article published in the Lancet, psilocybin has demonstrated preliminary efficacy in the treatment of unipolar (i.e. not bipolar) depression.

Twelve patients (6 women and 6 men) with treatment resistant depression were dosed with two oral doses of psilocybin (10mg and 25mg) 7 days apart. Typical recreational doses of psilocybin range from 10-50mg (i.e. 1-2 grams of dried mushrooms, or 20-30 grams of fresh mushrooms). The participants were dosed in pre-decorated (i.e. low lighting) rooms with music playing through high quality speakers. Patients had psychiatrists sit on either side of them and perform psychological support in the form of check-ins, making sure that the patient experienced a mostly uninterrupted “inner journey.”

Incredibly, at one week and at three months depressive symptoms were markedly reduced. Although clearly not a placebo controlled trial, this study demonstrates significant promise for the future of psilocybin as a treatment for depression and may offer hope for those with treatment resistant depression.

Supplements for Depression

As a psychiatrist in LA, I’m always looking for novel techniques and other ways to help my patients. I recently became aware of a meta-analysis published in the American Journal of Psychiatry that showed great promise for Vitamin D, Omega 3 (fish oil), Methylfolate, and S-adenosylmethionine (SAMe) as adjunctive treatments for depression in patient’s already receiving antidepressants.

Many people take multivitamins and cite reasons like “health” but have no idea what the effects could be. These four supplements could actually help improve your depression. In the meta-analysis the only cited adverse effect was minimal digestive upset.

So, let’s talk about each one individually.

First off, vitamin D. We should probably all be taking vitamin D because 1) we know it serves an important role immune function 2) it is required for proper mineralization of bones 3) it may help prevent falls in the elderly and 4)there are very few (if any) side effects. Now, there is new evidence that vitamin D may help treat depression in depressed patients.  To quote the study, the results were positive and significant. A reasonable starting dose? 1000-2000 IU/day. I personally take 2000IU daily.

Second, Omega 3, or fish oil. Omega 3 is another one we should probably all be taking because it positively impacts cardiovascular risk factors through a myriad of methods including acting as an antiarrhythmic, lowering the heart rate, lowering blood pressure, preventing clot formation, and decreasing the level of triglycerides in your blood. This meta-analysis reveals that there is new evidence for a fish oil as adjunctive treatment for depression. A reasonable starting dose would have a combination of EPA&DHA approximating 1gm. This is the brand and formulation I buy.

Last but not least, methylfolate and SAMe. The evidence for taking these without depression is less robust. Both are participants in essential chemical reactions that happen in your body constantly and a deficiency in folate (related to methylfolate) causes anemia. Both showed positive effects when used as augmentation for antidepressant treatment.

The take home? Vitamin D and Fish Oil are rockstars with few to no side effects. This new meta-analysis only further serves to reinforce that these should both be prominent in your diet, either through naturally-occurring sources or as a high-quality supplement.

Article after the jump: Link