Vitamin B6, Tryptophan, and Other Serotonin and GABA Influencers - Treatments for Premenstrual Dysphoric Disorder (PMDD)

Fluctuating sex hormones during the menstrual cycle can lead to changes in energy, mood, or physical symptoms, most commonly in the late luteal phase. Though symptoms can start as early as the ovulatory period and carry on until menstruation, as is common in premenstrual dysphoric disorder (PMDD), a severe and distinct disorder in the DSM 5, recognized for its intense cognitive-affective symptoms.^[1]

In addition to depressed mood, marked anxiety, marked affective lability (tearful or increased sensitivity), and persistent anger/irritability, women commonly report hopelessness.^[1] Due to the overlap in symptoms and high comorbidity between depressive syndromes and PMDD, it is thought that the two share common neurological substrates.^[2] Serotonergic dysfunction is a prevalent hypothesis in the etiology of PMDD, especially when considering the efficacy of serotonergic antidepressant medications in PMDD compared to all other classes of antidepressants.^[3] The serotonergic system seems to be most connected, though other neurotransmitters, such as GABA, may also contribute. Considering our current evidence, supplementation with key cofactors required for neurotransmitter synthesis and metabolism may provide an alternative or conjunctive treatment in cases of PMDD-associated depression and mood dysfunction.

Timing and Hormonal Changes

As the onset of symptoms is cyclical, fluctuating estrogen and progesterone was first considered as the instigator in PMDD. However, abnormalities in ovarian hormones have not been reported, regardless of impaired anxiety and mood regulation experienced by these women.^[4] Timing of onset of symptoms is also remarkable: The luteal drop in progesterone right before menses cannot be a direct cause, since symptoms tend to appear right after ovulation. This is a major distinction between PMS and PMDD. Instead, it may be a blunted response to the changes in these hormones that causes mood-related symptoms. Sensitivity of the central nervous system (CNS) to changes in reproductive hormones has been observed in rats and nonhuman primates, as sex steroid hormones have been shown to modulate serotonin transmission.^[3]

Serotonin Antidepressant Therapy

Observations of women with PMDD have shown abnormal levels of whole-blood serotonin and abnormal serotonin platelet uptake.^[5] Therefore, there may be a blunted response to hormones that fail to produce adequate serotonin receptors in women with PMDD.^[6] The most studied treatments of PMDD have focused on the use antidepressants. Selective serotonin reuptake inhibitors (SSRIs) are the gold-standard treatment for PMDD as well as severe-mood related PMS, and they have been shown to increase GABA levels in addition to affecting serotonin concentrations.^[7] Their efficacy in treating PMS and PMDD is roughly 75%, compared to 35% with placebo. Their effect is unique to serotonergic antidepressants including serotonergic tricyclic antidepressants and the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine, whereas other nonserotonergic antidepressants have been completely ineffective for this population of women.^[3] Even more interesting is the efficacy in acute and intermittent dosing of these medications. The use of SSRIs in PMDD are most commonly cyclical, with 14–17 days of use per cycle, with breaks in-between from menstruation to ovulation. The effects are often felt within hours to days. In contrast, when using SSRIs in cases of major depression (not related to hormonal fluctuations or the menstrual cycle), effects can often take weeks.^[1] This leads us to believe that although neurotransmitter receptor dysfunction can lead to the same presentation, increasing neurotransmitter synthesis or exposure to receptors may have beneficial outcomes, potentially enough to cause significant decreases in cyclical symptoms.

The downside to SSRIs are the considerable side effects including nausea, difficulty sleeping, decreased libido, and anorgasmia, which are common during treatment days.^[3][7] For a women who is already experiencing significant symptoms, it may be advantageous to support neurotransmitter function without causing further emotional or sexual distress. Nonpharmaceutical antidepressant treatment would also be required for those unable to take SSRIs, due to contraindications such as reports of suicide and suicidal thoughts in teenagers and young adults.^[8]

Hormones and GABA Function in PMDD

GABA is one of the main inhibitory neurotransmitters in the brain, and it contributes anxiolytic effects.^[9] Supplementing with GABA has been used to help treat patients with anxiety, mood disorders, and epileptic seizures.^[10] Magnetic resonance spectroscopy (MRS) studies investigating GABA and glutamine/glutamate levels have shown reduced levels in women with PMDD in areas of the brain that play integral roles in mood-disorder pathophysiology.^[9] ALLO is a metabolite of progesterone which positively modulates the GABA A receptor. It is hypothesized that low ALLO can lead to increased anxiety, depressive symptoms, and increased stress reactivity.^[1][2]Typically, increased ALLO levels will enhance GABA transmission in response to acute stress. Therefore, a low ALLO may blunt this response.^[1] This effect is demonstrated in the startle response, as ALLO modulates the resulting stress response from loud sudden noises. Women with PMDD seem to have a more profound startle response premenstrually.^[1] This could be linked to the acute onset of anxiety or emotional dysregulation in the luteal phase. Although GABA has been used as a supplement and has benefited those with mood disorders, the research on GABA supplementation in PMDD is currently insufficient.

Vitamin B6

It is understood that B vitamins—such as vitamin B6, vitamin B12, and folic acid—all play a role in neurotransmitter synthesis and metabolism, and are widely used for cases of depression and premenstrual mood disorders. GABA is synthesized by the rate-limiting enzyme glutamic acid decarboxylase (GAD) which requires vitamin B6, also known as pyridoxine hydrochloride or pyridoxal-5´-phosphate, as an essential cofactor.^[11] There are over 100 known reactions that are dependent on vitamin B6, most of which are involved in amino acid and neurotransmitter synthesis.^[12] B6 is required to convert tryptophan into serotonin, and is essential for the synthesis of dopamine, norepinephrine, GABA, and melatonin.^[12] A recent systematic review suggested that 50 to 100 mg of B6 can relieve PMS symptoms by more than twofold compared to placebo.^[13] It has been suggested that 50 mg of vitamin B6 per day could help decrease emotional premenstrual symptoms.^[14] For clinical application, vitamin B6 shows potential as a treatment option in premenstrual-related mood issues, though no greater response has been seen with doses larger than 100 mg.^[13]

Calcium Carbonate

A few high-quality studies have used calcium for premenstrual mood symptoms. In a study of 33 women with premenstrual symptoms, 1000 mg calcium carbonate was given daily for 3 months, followed by 3 months of placebo. 73% of the women reported a decrease in their symptoms (including negative affect) while taking the calcium, compared with 15% who were taking placebo.^[15] A multicentre trial including 466 women with moderate to severe PMS, experiencing symptoms of depression, irritability, anxiety, aggression, or crying spells, were randomized to take 1200 mg of calcium carbonate daily, or placebo for 3 cycles. No improvements were noted after one cycle, but after three cycles, there was a 48% reduction in total symptoms scores compared to baseline.^[16]

Tryptophan

Tryptophan, within the diet or as a supplement, can easily cross the blood-brain barrier (BBB). Diets that are deficient or low in tryptophan have been implicated in exacerbation of premenstrual symptoms.^[3] Therefore L tryptophan may be used as a supplement or via the diet to support serotonin synthesis and decrease mood symptoms. This was tested in a study where 6 g of L tryptophan was given daily for 17 days, starting at ovulation, and showed benefit in significantly reducing symptoms of PMDD.^[17]

Inositol

Once considered as “vitamin B8,” inositol is a signalling molecule, associated with multiple neurotransmitter receptors, well known for its antidepressant activity. A meta analysis of inositol for depression and anxiety disorders reported that inositol was superior to placebo in reducing the cyclical depressive symptoms of PMDD.^[18] In a study, subjects were given a dosage of 4 g of myo inositol three times daily for 6 menstrual cycles; they showed significant improvements as reported on the Hamilton Depression Rating scale and the Penn Daily Symptoms Record scale.^[19] It has been suggested that inositol’s antidepressant activity is mediated by the serotonergic system, which may explain its efficacy in PMDD, but not other depressive disorders.^[18]

Conclusions

There are multiple factors to consider in cases of PMDD, and as such, combination therapy may present a better option than monotherapy. The cyclical nature of PMDD symptoms is likely attributed to dysfunctional neurotransmitter metabolism in response to normal hormonal fluctuations during the menstrual cycle. Several components have been implicated in the aetiology of PMDD, including synthesis and transmission of serotonin and GABA, sensitivity to allopregnanolone (ALLO), and calcium homeostasis. Therapeutic dosing of individual therapies—such as 20–100 mg vitamin B6, 12 g daily of myo inositol, 1000–1200 mg calcium carbonate daily, and luteal dosing of L tryptophan—have been shown to reduce symptoms of PMDD. The key may be in combination therapy: Using a synergistic approach to promote proper serotonergic function with therapies such as B6 with inositol, magnesium, GABA, or L tryptophan may yield better results than monotherapy. However, this theory remains to be tested. Regardless, these therapies should be considered as alternatives to SSRIs, especially in patient populations that are unable to use or tolerate SSRIs.