Major Depressive Disorder is defined by the DSM-5-TR as a condition characterized by at least five of the following criteria: 

1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feel sad, empty, hopeless) or observations made by others (e.g., appears tearful).  
2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation). 
3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month) or decrease or increase in appetite nearly every day. (NOTE: In children, consider failure to make expected weight gain.) 
4. Insomnia or hypersomnia nearly every day. 
5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). 
6. Fatigue or loss of energy nearly every day. 
7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick). 
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by their subjective account or as observed by others). 
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide. 

The symptoms also cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.  

Depression is ubiquitous in general medical offices, where 60-80% of cases are initially diagnosed and treated. However, with the time constraints of general medical offices, a routine visit of 10-15 minutes will only yield a cursory revision of the patient’s complaints.  

As a result, a common strategy employed by general practitioners is to prescribe an SSRI, SNRI, or the latest psychopharmacology agent introduced by pharm reps after a quick evaluation that may or may not include the PHQ-9.  

Then, visit after visit, several medication changes quickly occur, with the result that more than 30% of those diagnosed with Major Depression do not reach remission. On average, a “partial responder” is treated for 3-6 months before the good doctor refers the patient to a psychiatrist.  

Upon arrival at a psychiatric office, the first noticeable difference is that a routine psychiatric evaluation lasts on average 60 minutes and covers all relevant elements of the patient’s longitudinal course of illness, family history, personal history, drug use history, etcetera.  A couple of issues promptly become apparent: 

Major Depressive Disorder is a condition correlated with numerous comorbid conditions, endocrines, and metabolic, and must be differentiated from several other comorbid ones.  

For starters, MDD must be differentiated from and the following conditions ruled out: 

• General medical conditions such as Hypothyroidism, Vitamin B12, and D deficiency, which may cause low mood and fatigue. 
• Neurological conditions such as Parkinson’s, Multiple Sclerosis, and Post-stroke depression, which may present first as apathy or fatigue.  
• Autoimmune conditions, such as Systemic Lupus, Rheumatoid Arthritis, which may present initially as mood disturbances.  
• Pancreatic Cancer, which initially presents as depression without a clear precipitant. 
• Sleep disorders, such as Obstructive Sleep Apnea, which often generate irritability and low energy.  

Major Depressive Disorder is also comorbid with several other psychiatric conditions; thus, they must also be ruled out.  

• Anxiety Disorder, which presents or may precede 50% of cases of depression.  
• Substance Abuse, Alcohol, opioid, which is present in 20-40% of cases.  
• Bipolar Disorder, which is comorbid with 10-25% of cases of MDD.  
• Personality Disorder, such as Borderline Personality, which may be comorbid with MDD in 20% of cases.  
• Eating Disorder, such as Bulimia, Anorexia, and Binge-eating disorder, which may be present in 15-30 % of cases.  And,  
• ADHD, which may be comorbid in 10-20% of cases of depression.  

As we can see, a simple complaint of “I am sad, I am depressed” must not just be assumed to be a simple case of depression. Instead, a comprehensive work-up must take place to rule out highly comorbid psychiatric conditions and a whole array of medical, neurological, etcetera which initial symptoms closely resemble depression.  

The importance of acknowledging such reality is due to the high numbers of patients with MDD who do not respond to standard doses of anti-depressants, the high toll of impairment, disability, and even suicide related to depression.  

We must not just treat the patient’s chief complaint but take time and look under the hood and consider other conditions that must be ruled out.  

In the end, “the devil is in the details.”