This is a 51-year-old female patient who reported experiencing anxiety and depressive symptoms intensifying one week before menstruation, lasting 3 - 4 days. Symptoms included extremely low energy, depression, shortness of breath, difficulty focusing, and suicidal thoughts without plans for ten years. The patient also described repetitive thoughts, social withdrawal, and a feeling of being out of control. The patient was initially presented to a mental health clinic about three years ago for a telemedicine visit, exhibiting signs and symptoms of Major Depressive Disorder, including suicidal thoughts. These symptoms worsened prior to menses. Psychiatric treatments focused on managing depression, generalized anxiety, sleep disturbances, and suicidal thoughts. Medications such as Quetiapine and Bupropion were continued to manage depression, anxiety, and sleep disturbances. The patient was referred from the psychiatry clinic for further evaluation because maximum doses of psychiatric medications yielded no therapeutic effects. The patient was diagnosed with Major Depressive Disorder with suicidal ideation and plans.

The patient, a 51-year-old female with Major Depressive Disorder (MDD) and Generalized Anxiety Disorder (GAD), initially showed moderate improvement in anxiety with Sertraline 50 mg daily, but depressive symptoms and premenstrual exacerbations persisted. Increasing Sertraline to 100 mg and adding Quetiapine 25 mg for sleep provided some relief, though daytime sedation required reducing Quetiapine to 12.5 mg. Six months later, Bupropion 100 mg daily was introduced for persistent fatigue and depression, leading to notable improvement in mood, energy, and motivation. After a year, due to concerns about weight gain, the patient transitioned to Bupropion monotherapy, maintaining 100 mg daily with sustained benefits. Temporary dose increases of Bupropion to 150 mg and later 300 mg during premenstrual exacerbations were tried. However, side effects like insomnia and anxiety led to a reduction back to 100 mg, which proved effective long-term.

Throughout treatment, the patient engaged in CBT, group therapy, and self-help techniques such as journaling and mindfulness, which improved her coping skills. Counseling was also provided via BetterHelp, an online platform, and self-help resources like Mind Over Mood were recommended. Regular follow-ups monitored sleep quality and suicidal thoughts, and the patient was encouraged to use the suicide hotline if needed. Psychotherapy, including CBT and motivational interviewing, helped address maladaptive behaviors, though the patient struggled to fully connect her actions with their impact on mental health. Given the partial response, particularly with premenstrual symptoms, she was referred for endocrinological evaluation while continuing Bupropion 100 mg as the most effective dose.

Menstrual History

Contraception

Sexual History

Current Medications

Past Medical and Surgical History

Family History

Social History

The patient lives with her son and his family, including her husband and two children. She is independent in activities of daily living, cooks for the whole family, and walks in a park for 30 to 40 minutes 3 times a week. She quit smoking 30 years ago and denies drinking alcohol or using recreational drugs.

Review of Systems

The review of symptoms was positive for depressive signs and symptoms. All other systems were reviewed and negative.

Physical Examination

Premenstrual Dysphoric Disorder (PMDD)/Major Depression:

The patient’s symptoms are indicative of PMDD, which involves significant mood and anxiety exacerbations linked to her menstrual cycle. Notably, her anxiety and depressive symptoms intensified during the luteal phase, prompting a focus on PMDD management alongside her other psychiatric conditions. According to the DSM-5-TR, PMDD is diagnosed when a patient exhibits at least five symptoms—such as affective lability, irritability, depressed mood, anxiety, loss of interest, fatigue, feeling emotionally overwhelmed, or physical symptoms—during most menstrual cycles over the past year, with at least one of these symptoms involving mood-related issues. In this case, the patient’s recurrent depressive episodes, anxiety, fatigue, and mood swings, particularly during the luteal phase, align with these diagnostic criteria. Her symptoms consistently disrupted daily functioning, especially in work and social settings, further supporting the diagnosis of PMDD.

Since the patient’s laboratory results were unavailable at the initial visit, immediate treatment was initiated, focusing on cellular-level supplementation to address potential deficiencies. The following labs were ordered to assess her overall health: hormonal levels (FSH, LH, Progesterone, SHBG, Testosterone, Estradiol, Estrone, DHEA, Prolactin), metabolic and inflammatory markers (CMP, CBC, CRP, TSH, Free T4, Free T3, Vitamin D, HbA1c, ESR), urinalysis, and genetic testing (MTHFR, TPO-Ab). These tests aimed to identify conditions like hypothyroidism or vitamin deficiencies that could be contributing to her PMDD symptoms. The patient was instructed to follow up in 1 - 2 weeks for test results and further management.

1) Premenstrual Dysphoric Disorder (PMDD)/Major Depression:

2) Hypothyroidism:

3) Vitamin D Deficiency:

4) Perimenopause/Hormonal Imbalance:

5) MTHFR Gene Mutation (Gene A and Gene C):

The patient was diagnosed with PMDD and started on a treatment regimen that included the following supplements:

These supplements were introduced based on their documented benefits in managing PMDD symptoms and improving overall mental health in women. Given that the patient’s labs had not yet been performed, initiating treatment at the cellular level was essential to address potential deficiencies that could exacerbate her symptoms.

Research suggests that Vitamin B6 plays a crucial role in serotonin production, which can help alleviate depressive symptoms in women with PMDD. Studies have shown that Vitamin B6 supplementation can reduce irritability, depression, and anxiety during the luteal phase of the menstrual cycle [4] . Adding a Vitamin B complex ensures that other B vitamins, such as B12 and folate, are available to support overall brain function and energy levels, further helping to stabilize mood in women with PMDD [5] .

Vitamin D deficiency has been associated with mood disorders, including depression, and research indicates that maintaining adequate Vitamin D levels may help reduce the severity of PMDD symptoms [6] . Vitamin D, combined with Vitamin K2, plays an essential role in calcium metabolism, supporting bone health and promoting hormonal balance. This is particularly important for women in perimenopause, whose fluctuating hormones can exacerbate mood disorders [7] . Vitamin D supplementation has been linked to improved mood and reduced depressive symptoms, making it a critical component of the treatment plan for PMDD.

Omega-3 fatty acids, particularly EPA and DHA, have anti-inflammatory properties that benefit both physical and mental health. In women with PMDD, Omega-3 supplementation has been shown to reduce depressive symptoms and improve overall emotional well-being [8] . Omega-3s help regulate neurotransmitter function and reduce inflammation, which can play a role in mood stabilization and anxiety reduction.

Magnesium glycinate is beneficial for managing PMDD due to its role in regulating neurotransmitters and reducing symptoms of mood instability. Magnesium helps alleviate anxiety, irritability, and depression by supporting serotonin production, a key neurotransmitter that influences mood [9] . Additionally, magnesium glycinate has been shown to reduce physical symptoms of PMDD, such as menstrual cramps, by relaxing smooth muscles [5] . It also improves sleep quality, often disrupted in PMDD, promoting better overall emotional well-being [10] . Unlike other forms of magnesium, glycinate is easily absorbed and less likely to cause gastrointestinal side effects, making it a preferable long-term treatment option for women with PMDD [11] .

Beyond PMDD and major depression, several differential diagnoses were considered:

1) Polycystic Ovary Syndrome (PCOS): Characterized by menstrual irregularities, hyperandrogenism, and metabolic issues, PCOS can exacerbate mood disorders [14] .

2) Adrenal Dysfunction: Conditions like Addison’s disease or Cushing’s syndrome can present with mood disturbances due to cortisol imbalances [15] .

3) Perimenopausal Transition: Hormonal fluctuations during perimenopause can lead to significant mood changes, including anxiety and depression [16] .

4) Subclinical Thyroid Disorders: Both hyperthyroidism and hypothyroidism can influence mood, and autoimmune thyroiditis was considered [17] .

5) Iron Deficiency Anemia: Iron deficiency, particularly in women with heavy menstrual cycles, can contribute to fatigue and mood disturbances [18] .

The patient’s transition from Premenstrual Dysphoric Disorder (PMDD) to perimenopause introduces significant changes in hormone regulation, particularly declining levels of progesterone and testosterone, both of which play a critical role in mood stabilization, energy levels, and overall well-being [2] . PMDD is already characterized by mood disturbances linked to the luteal phase of the menstrual cycle when progesterone levels fluctuate. As perimenopause progresses, these hormonal fluctuations become more pronounced, contributing to emotional and physical symptoms such as mood swings, fatigue, irritability, and sleep disturbances [1] .

In addition to these hormonal changes, the patient’s MTHFR gene mutation adds a layer of complexity. The MTHFR (methylenetetrahydrofolate reductase) gene is essential for converting folate into its active form, methylfolate, which is critical for neurotransmitter synthesis, detoxification, and DNA repair. Variants of the MTHFR gene, such as the ones found in this patient, are associated with reduced enzymatic activity, which can impair methylation processes and increase the risk of mental health disorders, including anxiety and depression [13] . Research suggests that individuals with MTHFR mutations may have difficulty metabolizing synthetic folic acid, commonly fortified in food, leading to a potential buildup of unmetabolized folic acid and an increased risk of neuropsychiatric symptoms [13] .

The hypothyroidism diagnosis further complicates the picture, as thyroid hormones play a significant role in regulating metabolism, mood, and cognitive function. Elevated TSH levels in hypothyroidism lead to sluggish metabolism and neurotransmitter imbalances, contributing to symptoms such as depression, fatigue, and cognitive decline [17] . Vitamin D deficiency also plays a pivotal role in brain health and has been linked to depression and impaired cognitive function. Low vitamin D levels reduce the brain’s ability to regulate neurotransmitters like serotonin, further exacerbating the patient’s mood instability [7] .

Additionally, the presence of low testosterone levels—common during perimenopause—can contribute to fatigue, decreased libido, and mood disturbances. Testosterone has been linked to feelings of vitality and well-being, and its decline during the perimenopausal period can worsen the mental health symptoms the patient experiences [19] .

In summary, the patient’s mental health issues are being driven by a combination of hormonal imbalances, genetic predispositions (MTHFR mutation), and deficiencies in essential nutrients like vitamin D. Addressing these root causes at the cellular level is crucial for effective treatment. By understanding the interaction between these factors, we can approach her treatment with a holistic, evidence-based strategy that not only targets her mental health symptoms but also corrects underlying physiological dysfunctions.

The management of this patient involved a multidisciplinary approach that incorporated both pharmacological and non-pharmacological strategies:

Hormone Therapy: The patient was started on bioidentical hormone replacement therapy (BHRT) with topical progesterone (200 mg/1 gram, one-click daily, stopped during menses and restarted after menses) and topical testosterone (5 mg/1 gram, one-click daily) to address hormonal imbalances. Evidence suggests that BHRT may offer a more favorable side-effect profile compared to synthetic hormones, particularly in managing hormonal fluctuations in perimenopausal women [16] .

Thyroid Hormone Replacement: The patient was prescribed NP Thyroid (15 mg, one tablet daily in the morning on an empty stomach) with a plan to recheck TSH levels in six weeks. This treatment is in line with guidelines that recommend maintaining a lower TSH range for optimal symptom control in patients with hypothyroidism [17] .

Vitamin D Supplementation: High-dose vitamin D supplementation was initiated to correct severe deficiency and improve mood symptoms associated with low vitamin D levels. Vitamin D plays a critical role in mental health, and its supplementation is supported by evidence showing improvement in depressive symptoms in deficient individuals [7] .

Psychiatric Medications: The patient continued her current psychiatric medications, quetiapine and bupropion. Additionally, the use of an SSRI, such as fluoxetine, was considered for intermittent dosing during the luteal phase to manage PMDD symptoms. This approach aligns with evidence supporting the efficacy of SSRIs for PMDD when used during the luteal phase [20] .

Lifestyle Modifications: Recommendations were made for regular physical activity, a balanced diet, and stress reduction techniques. These lifestyle changes are essential adjuncts to pharmacotherapy in managing mood disorders and promoting overall well-being.

Patient Outcome: Follow-Up at 6 Weeks

At the six-week follow-up, the patient reported significant improvements in her mood and energy levels. The initiation of thyroid hormone replacement and vitamin D supplementation led to noticeable improvements in her overall well-being. The addition of bioidentical hormone therapy stabilized her mood during the luteal phase of her menstrual cycle, reducing the severity of her premenstrual symptoms. She was able to resume her daily activities with greater ease and experienced fewer depressive episodes. Continued follow-up and potential adjustments to her treatment plan were scheduled to ensure sustained symptom management and overall health improvement.