: The man whose antidepressants stopped working

Major depressive disorder is one of the most prevalent disorders we will see in our clinical practice.  Treatment options for MDD can vary greatly contingent on the appropriate psychopharmacologic interventions being adopted for our clients.

Medication nonadherence for patients with chronic diseases is extremely common, affecting as many as 40% to 50% of patients who are prescribed medications for management of chronic conditions (Kleinsinger, 2018). Nonadherence isn’t a new problem.  However, offering clients valuable interventions and education to overcome any potential compliance barriers will help the provider identify any challenges and decide how to achieve mutually agreed-upon goals to improve their health.


1.  Do you ever feel that taking your medications is a nuisance or inconvenience?  Do you have a difficult time remembering to take your medications or forget?

•&νβσπ;&νβσπ;&νβσπ;&νβσπ;&νβσπ;&νβσπ;Developing a medication schedule, It is difficult to come up with a schedule to take medications every day for some patients. Collaboratively we need to come up with a convenient time to take the antidepressant and the other prescribed medication for them to be effective.

2.  Does your prescribed medications and treatment regimen still leave you feeling depressed?  Do you have a difficult time adhering to a prescribed regimen?

•&νβσπ;&νβσπ;&νβσπ;&νβσπ;&νβσπ;&νβσπ;The patient discontinued his Effexor although it appeared to be effective. It is essential to find out the patient’s reason for not following the prescribed regimen and come up with a solution together.

•&νβσπ;&νβσπ;&νβσπ;&νβσπ;&νβσπ;&νβσπ;It is crucial for the patient to take his antidepressants accordingly, as well as not skip or alter the dosage, nor terminate the medication once you start feeling better.

3.  Have the side effects of your medications been difficult to cope with or manage?  Do you sometimes stop taking your medications because of the adverse effects?

  • Sertraline has been prescribed in the past and discontinued several times. The patient experienced side effects of sexual dysfunction and stopped taking.  Encourage the patient to monitor any side effects, physical and emotional changes or occurrences.
  • Stopping medications and treatment regimens prematurely or abruptly have been associated with high relapse rates and can cause serious withdrawal symptoms (Henssler, Heinz, Brandt, & Bschor, 2019).

Important People

Family members and other caregivers bring personal knowledge on the suitability or lack thereof regarding different treatments for the patient’s circumstances and preferences (Smith, 2013).  The patient is married, so I would address additional questions to his wife.  After getting permission to discuss his medical records with his family members, I would ask the wife if she knew what medications her husband was taking?  If she knew why he was taking them?  Informed and engaged patients, invested in their own health care as well as in the improvement of the broader health care system, are crucial to a learning system (Smith, 2013).  Family support is essential for patients suffering from depression where patients are feeling less motivated or forgetful when taking medications.  Asking family members if the patient has been experiencing any side effects or illnesses since starting the medication emphasizes self-centered care and mutually agreed-upon goals (Siminoff, 2013).

Physical Exams and Diagnostic Tests

CC: worst depression and anxiety he has ever felt

HPI: 63-year-old male presents to the clinic stating his antidepressants have stopped working.  The patient has a 13-year history of recurrent unipolar major depressive episodes.  His first 4 episodes were readily treated to full remission and he discontinued treatment each time several months to a year after remitting.  His subsequent episodes came in an ever-escalating pattern, with less and less time between them.  By the time of his fifth episode, he had become treatment-resistant and took two years to get better.

Current Medications: 1 year following first depressive episode: antiarrhythmic, a statin for cholesterol, antihypertensive, aspirin, transdermal Selegilene 6 mg/24hrs after failing multiple SSRI and SNRI treatments plus multiple augmentation strategies.

PMHx: Atrial fibrillation age 42, resolved with medication, hypercholesterolemia, HTN

Soc Hx: Married 33 years, 3 children, nonsmoker, denies illicit drug or alcohol abuse.

Fam Hx: Mother: depression and alcohol abuse; Maternal uncle: alcohol abuse; Son: depression; Daughters: one with mild depression, one with postpartum depression.


The purpose of the physical examination is to exclude any physical causes for the patient’s current mental health issues.  A mental health assessment often includes this evaluation as the PMHNP reviews the patient’s past medical history and current medications, as well as mental disorders within the family.  While asking the patient about any mental health symptoms, it is crucial for the provider to pay attention to their appearance, mood, and speech pattern as it can yield any clues to explaining the symptoms.  Most patients with major depressive disorder (MDD) present with a normal appearance.  Some would describe it as “smiling depression” where the patient appears happy to others while smiling through the pain, keeping their inner turmoil hidden (Coward, 2016).  This type of MDD results from atypical symptoms and many don’t realize they are depressed, nor seek help.  People with smiling depression are often partnered or married, employed and are quite accomplished and educated. Their public, professional and social lives are not struggling (Coward, 2016).  Patients with more severe depressive symptoms often have poor hygiene or grooming and changes in weight.  Patients may experience both psychomotor impairment and agitation.  Impairments can cause issues with muscle function and speech, flat affect and emotions.  Speech patterns may be normal, monotone, or slow lacking content.  Racing thoughts and pressured speech patterns often suggest anxiety or mania (Dailey & Saadabadi, 2020).

Diagnostic Test:

There are several diagnostic tools that can be used to screen for depression.  The Patient Health Questionaire-2 is a screening tool for the diagnosis of major depression in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).  The Beck Depression Inventory (BDI) is a 21-item questionnaire that was first developed in 1961 that cover affective, cognitive and somatic aspects of major depression.  The Geriatric Depression Scale (GDS) is a 30-item depression questionnaire specifically designed for use in older adults to assess the affective and cognitive aspects of major depression (Ng, How & Ng, 2016).

Laboratory studies such as a CBC blood or urine tests may be ordered.  For example, anemia or B-12 deficiency can cause fatigue, lack of energy and depression.  Thyroid-stimulating hormone (TSH) is often ordered when screening for depression.  Hypothyroidism is commonly found in depressed individuals.  Electrolytes, including calcium, phosphate, and magnesium levels should be evaluated.  Supplementation with magnesium has been shown to decrease symptoms of depression in patients with mild to moderate depression (Tarleton, Kennedy, Rose, Crocker & Littenberg, 2019).  If a nervous system problem is suspected, a magnetic resonance imaging (MRI), an electroencephalogram (EEG) or a computed tomography (CT) scan may also be ordered.

Differential diagnosis

  1. Hypothyroidism: is often associated with altered cognitive function and depression.  A 2018 study found that about 45% of people with depressive disorders and 30% of those with anxiety also have autoimmune thyroiditis (Siegmann et al., 2018).
  2. Bipolar Disorder
  3. Generalized Anxiety Disorder

Pharmacological agents and dosing

This patient had several recurrent unipolar depressive episodes.  By the time of his fifth episode, he had become treatment-resistant and took two years to get better.  Adding Seroquel to his treatment regimen could have prevented a fourth or fifth episode.  Seroquel works by blocking dopamine 2 receptors, reducing positive symptoms of psychosis and stabilizing affective symptoms (Stahl, 2014b).  Psychotic and manic symptoms can improve within 1 week, but it is recommended that the patient wait 4-6 weeks to determine the drug’s efficiency.  Many bipolar patients may experience a reduction of symptoms by half or more, unfortunately, this patient experienced excess daytime sleepiness.  If Seroquel is ineffective in treating the patient, I would consider adding olanzapine.  Olanzapine works by blocking dopamine 2 receptors, reducing positive symptoms of psychosis and stabilizing affective symptoms (Stahl, 2014b).  The initial dose of olanzapine is 5–10 mg once daily orally; increase by 5 mg/day once a week until desired efficacy is reached; the maximum approved dose is 20 mg/day.


There are no specific contraindications related to the patient’s ethnicity when prescribing Seroquel or Olanzapine.  However, I would use caution with both medications in cardiac patients because it can cause orthostatic hypotension and this patient is already taking antihypertensive medication.  A lower dosage may be sufficient when treating manic/mixed episodes (Stahl, 2014b).

Check points

When adding any new medications, it is recommended that the patient follow up within 4-6 weeks after starting the prescribed regimen.  The patient will need to be monitored for any improvements in his symptoms, as well as any adverse reactions or side effects he may experience.  Obtaining baseline and checkpoints at follow-up appointments for weight/BMI, fasting triglycerides, blood pressure, and fasting serum glucose with Seroquel.  Quetiapine may increase the risk of diabetes and dyslipidemia, weight gain, dizziness, and sedation (Stahl, 2014b).  Olanzapine is approved for long-term maintenance of the bipolar disorder.  Zyprexa should be used with caution in patients with conditions that predispose to hypotension and it may increase the effect of antihypertensive agents (Stahl, 2014b).

Lessons learned

The National Institute of Mental Health estimates that approximately 15.7 million adults in the United States have depression (NIMH, 2014), making depression one of the most common disorders you will treat in practice.  Improving adherence requires an active process of behavioral change, which is nearly always a challenge.  It requires education, motivation, tools, support, monitoring, and evaluation.  Many factors can potentially contribute to a drug’s efficiency.  The prevalence of depression is increasing, representing an important public health problem (Tarleton et al., 2019).  The treatment method that ultimately leads to an acceptable level of improvement in depressive symptoms for any individual is unpredictable.  Combining antidepressant medication with therapy and self-help measures can often be more effective than taking medication alone.  Finding the right treatment options may take time.


Coward, L. (2016). NAMI. Retrieved from https://www.nami.org/Blogs/NAMI-Blog/September-2016/What-You-Need-to-Know-About-Smiling-Depression”

Dailey & Saadabadi. [Updated 2020 Jan 14]. Mania. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK493168/

Henssler, J., Heinz, A., Brandt, L., & Bschor, T. (2019). Antidepressant Withdrawal and Rebound Phenomena. Deutsches Arzteblatt international116(20), 355–361. https://doi.org/10.3238/arztebl.2019.0355

Kleinsinger F. (2018). The Unmet Challenge of Medication Nonadherence. The Permanente journal22, 18–033. https://doi.org/10.7812/TPP/18-033

Ng, C. W., How, C. H., & Ng, Y. P. (2016). Major depression in primary care: making the diagnosis. Singapore medical journal57(11), 591–597. https://doi.org/10.11622/smedj.2016174

Siegmann E, Müller HHO, Luecke C, Philipsen A, Kornhuber J, Grömer TW. (2018). Association of Depression and Anxiety Disorders With Autoimmune Thyroiditis: A Systematic Review and Meta-analysis. JAMA Psychiatry.2018;75(6):577–584. doi:10.1001/jamapsychiatry.2018.0190

Siminoff L. A. (2013). Incorporating patient and family preferences into evidence-based medicine. BMC medical informatics and decision making, 13 Suppl 3(Suppl 3), S6. https://doi.org/10.1186/1472-6947-13-S3-S6

Smith, M. D. (2013). Best care at lower cost: the path to continuously learning health care in America. Washington, D.C.: National Academies Press.

Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY: Cambridge University Press.

Stahl, S. M. (2014b). The prescriber’s guide (5th ed.). New York, NY: Cambridge University Press.

Tarleton, E. K., Kennedy, A. G., Rose, G. L., Crocker, A., & Littenberg, B. (2019). The Association between Serum Magnesium Levels and Depression in an Adult Primary Care Population. Nutrients11(7), 1475. https://doi.org/10.3390/nu11071475

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