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A Tale of Two (Hundred Twenty Seven) Depressions


The Depression epidemic has reached explosive proportions making it the most common psychiatric disorder in the world. One in four individuals will suffer from major depression at least once in their lives. Although sad and blue feelings are a normal/_uploaded_files/depression-is-a-flaw-in-chemistry.png part of grief or stress, when such feelings persist over a long period of time and become distressing and disabling, a clinical diagnosis of Major Depressive Episode (MDE, Depression) is warranted.

If you have any of the following depression symptoms, especially if they last more than a week or two, there is a good possibility that you are suffering from depression:

  • Sadness or hopelessness;
  • Loss of interest in activities you normally enjoy;
  • Significant weight gain or loss due to changes in appetite;
  • Feeling tired all the time, or feeling that moving is too much of an effort;
  • Inability to sleep, or sleeping too much;
  • Restlessness, inability to remain still;
  • Unfounded feelings of guilt or lack of worth;
  • Problems focusing, remembering things, or making decisions;
  • Thoughts of death and suicide.

As you can see from the above criteria, Depression represents a wide range of clinical entities characterized by loss of interest and enjoyment in previously pleasurable experiences, low mood, sleep and appetite disturbances, and “brain-fog.”

Not only does Depression cause profound mental anguish, it also attacks core biological processes that regulate sleep, appetite, metabolic activity, hormones, glucose control, neurotransmitters, and immunity (collectively known as psycho-neuro-immunology – PNI). These PNI disturbances contribute to heart disease, diabetes, stroke, Alzheimer’s, premature aging, and a doubling of death rates in patients with Depression at any age independent of suicide, smoking, or physical illness. It is for such reasons that the World Health Organization has ranked Depression as one of the leading causes of disability worldwide.

It will not surprise you to learn that a history of early life adversity (ELA) increases your risk for depression as an adult. Furthermore, interpersonal and environmental (“someone you met or something you et”) stressors in adulthood can trigger Depression and influence its severity, course, and response to treatment. Thus, the unremitting stress, calorie-rich/nutrient-poor diets, sedentary lifestyles, and environmental toxins that permeate our lives collide with our genes and early life influences to produce the set of illnesses we call Depression.

Despite greater awareness of Depression, it continues to represent a major healthcare burden for both patients and clinicians. One of the many challenges associated with treating Depression is that each person’s depression is unique and thereby in need of personalized treatment.

/_uploaded_files/227-different-depression-profiles.pngAlthough it is the most common mental disorder in the world, Depression is not a single entity but rather a description of several distinct but overlapping medical conditions each with its own unique symptoms and biological correlates. For example, based on the current classification system (Diagnostic and Statistical Manual of Mental Disorders – DSM), individuals with Depression may have very different combinations of symptoms. Indeed, there are 227 different combinations of symptoms leading to this diagnosis. And yet the tendency in most treatment settings is to treat all of these distinct presentations the same way: with the cheapest generic antidepressant medication insurance will pay for. This is the very opposite of treatment tailored to a person’s specific constellation of symptoms, co-existing medical conditions, early life experiences, unique genetic make-up, and measurable PNI imbalances.

For instance, you can meet criteria for Depression and be unable to sleep or sleep too much, be unable to eat or eat too much, be unable to sit still or be unable to move. Common sense and, increasingly, scientific literature strongly suggests that these vastly different symptom clusters represent vastly different disorders.

This variability in clinical symptoms reflects a similar variability in biological dysregulations among depressed persons.

This clinical and biological variability (also referred to as heterogeneity) has historically hindered efforts to identify genetic, environmental, and biological foundations of Depression. As such, a potentially useful first step in developing customized interventions is the profiling of symptom patterns based on these subtypes. For example, among those persons who presented with the atypical subtype at baseline, 79% still had atypical depression at follow-up two years later.

Highlighting the heterogeneity of Depression, the DSM-V identifies two distinct clinical variations that seem to be the reverse of each other: melancholic and atypical depression. This distinction, based on the different patterns of symptoms, is the focus of this article. These subtypes of depressive disorder have been found to be stable across a two year follow-up supporting the idea that they represent clinically distinct entities.

As we proceed, it should be pointed out that the majority of persons with Depression present with a mix of cognitive, mood, and biologic features that do not fully fit into either of these tidy compartments. That said, it is nevertheless instructive, particularly from a treatment standpoint, to identify Depression from a multidimensional perspective.

In general, evidence suggests that melancholic and atypical depressive subtypes exhibit different biological measures. When comparing melancholic depression versus atypical depression, metabolic syndrome has been found to be increased in those with atypical depression but not in those with melancholic depression. Similarly, when directly comparing 319 melancholic versus 201 atypical depressed patients, Lamers et al. found metabolic syndrome and, in particular, its obesity-related disturbances to be more common in atypical depression.

Moreover, studies have confirmed higher levels of systemic inflammation among those who suffer from atypical depression.

Lastly, compared to both normal control subjects and those who meet criteria for melancholic depression, those with the atypical form of depression are more likely to have lower levels of one’s primary stress hormone – cortisol.

Melancholic Depression


The term melancholic depression is actually a misnomer in that this type of Depression is a state of hyper-arousal of your stress-response system. Intense anxiety is often focused on the self and takes the form of feelings of worthlessness, intrusive memories of past transgressions and failures (real or imagined), and helplessness. Additionally, melancholics are plagued by dread about the future and an ill-defined sense of doom. It does not matter that their self-assessments and emotional memories do not jibe with the reality of their lives; their feelings of personal deficiency permeate and taint every aspect of their thoughts and mood.

Patients with melancholic depression also suffer from insomnia, especially early morning awakening, loss of appetite, and a 24-hour cycle variation in their mood wherein they feel worse in the morning.

Co-morbid Medical Conditions

The melancholic subtype of depression is often associated with specific medical conditions:

  • Obsessive-compulsive disorder (OCD)
  • Panic disorder
  • Muscle wasting (sarcopenia)
  • Premature heart disease
  • Hyperthyroidism
  • Immune suppression with frequent infections
  • Premature bone mineral density loss (osteoporosis)

Psycho-Neuro-Immunological (PNI) Disturbances

The characteristic PNI imbalances seen in melancholic depression are consistent with its symptom cluster and co-morbid medical conditions: increased cortisol, elevated excitatory neurotransmitters (dopamine, norepinephrine, epinephrine), low calming neurotransmitters (serotonin and GABA), sluggish immune function, and suppression of growth and reproductive hormones. 

Atypical Depression/_uploaded_files/atypical-depression-2.png


Although both atypical and melancholic depression are associated with depressed mood and inability to experience joy (anhedonia), atypical depression is in many ways the mirror-image of melancholia. For instance, atypical depression is associated with a distressing sense of emptiness and disconnectedness from others, infiltrated episodically by brief emotional reactions to external life circumstances. In contrast to the unrelenting bombardment of negative memories seen in melancholia, those with atypical depression often seem walled and insulated from their inner feelings. They often experience an emotional and mental weariness and tend to avoid others, believing that contact would expose them to further rejection or be too demanding, tiring, and poorly received.

Biologic (also referred to as neurovegetative) symptoms in atypical depression are the reverse of those in melancholia and consist of lethargy, “leaden paralysis” (the sensation that one’s limbs consist of lead), fatigue, excessive sleepiness, increased food intake with prominent carbohydrate craving, weight gain, and depressive symptoms that get worse as the day progresses.

Only about one-third of patients with major depression present with pure melancholic features while another third present with pure atypical features. The remaining third exhibit mixed features. Those with melancholic or atypical features show a much more severe course of illness than those with mixed neurovegetative features.

Co-morbid Medical Conditions

Like melancholic depression, atypical depression is associated with its own set of coexisting conditions:

  • Chronic fatigue
  • Fibromyalgia
  • PTSD
  • Alcohol and drug abuse
  • Social anxiety disorder
  • Hypothyroidism
  • Obesity
  • Metabolic syndrome
  • Diabetes
  • Heart disease

Moreover, increased appetite and weight gain are closely related to the atypical subtype of depression. Indeed, only atypical depression, not melancholic depression, is associated with an elevated risk of obesity relative to the population at large.

Psycho-Neuro-Immunological (PNI) Disturbances of Atypical Depression

People with atypical depression have significantly higher levels of inflammation, body mass indices (BMIs), waist circumferences, and triglycerides than those with melancholic depression. They often have low cortisol levels, low excitatory neurotransmitters (dopamine and norepinephrine), and elevations of markers of inflammation such as hs-CRP, TNF-alpha, and fibrinogen. Also, consistent with the co-esisting medical problems, they often exhibit abnormal insulin, glucose, and other metabolic parameters.

A Few Comments About Prescription Antidepressants

/_uploaded_files/antidepressant-treatment-emergent-adverse-reactions-tears.pngYear in and year out, antidepressants rank among the most commonly prescribed classes of medications in the world. For example, from 2005-2008, only cholesterol-lowering statins and painkillers were prescribed more often than antidepressants. A 2011 report out of the National Center for Health Sciences (NCHS), Antidepressant Use in Persons 12 and Older: United States, 2005-2008, showed that 11% of Americans 12 and older take antidepressants. Of those who take such drugs, 60% have taken them for 2 or more years, with 14% having taken antidepressant medications for more than 10 years.

More recent data, though preliminary, indicate that these numbers are on the rise; indeed some surveys suggest that antidepressant drugs are now the most common class of medication prescribed in the United States.

In spite of the widespread use of antidepressants, 2 out of 3 patients still have many of these symptoms. In fact, only about half of those taking antidepressant drugs experience any reduction in their symptoms, while nearly 90% of users suffer from significant side effects: these may include fatigue, sexual dysfunction, weight gain, insomnia, and emotional flattening.

The biological side effects of antidepressants are well known: weight gain, fatigue, nausea, constipation, and sleep disturbance.

Now, a newly published study indicates that cognitive, interpersonal, and emotional side effects may be even more common than these more familiar physical symptoms.

In the largest survey of its kind, 1829 depressed patients from New Zealand prescribed antidepressants over the past five years were questioned about the frequency of side effects they had experienced.

According to the investigators, the results of this research study, conducted by the University of Auckland and published in the journal Psychiatry Research, demonstrate that interpersonal and psychological side effects of antidepressant medications “appear to be alarmingly common:”

The study found:

  • 62% of people reported experiencing sexual difficulties
  • 60% reported feeling emotionally numb
  • 52% reported feeling not like myself
  • 42% reported a reduction in positive feelings
  • 39% reported caring less about others
  • 39% reported feelings of suicidality
  • 55% had withdrawal effects

Moreover, 8 of the 20 adverse effects were reported by more than half the participants.

Such adverse reactions might be tolerable if they actually worked better. Unfortunately, study after study suggests that on average, prescription medications work only about 1/3 of the time. For example, one of the largest studies of its kind, the STAR*D trial, summarized in the graphic below, demonstrated that only one in three patients with depression achieved remission. Two thirds of subjects remained symptomatic and consequently had a greater risk of relapse and functional impairment.


In short, antidepressants tend to cause more problems than they solve. There is a simple explanation for this: depression is itself a symptom, rather than a separate issue. Decades of research have revealed that a number of physical disorders often cause system imbalances which produce depressive symptoms; these conditions cannot be resolved through the use of antidepressants. In order to effectively treat the problem, it is critical to isolate the underlying cause or causes through laboratory testing.

We at Integrative Psychiatry are NOT against the use of antidepressants; we prescribe them all the time. We are, however, against one-size-fits-all cookbook psychiatry. Rather, we customize treatment interventions - whether those be meds, lifestyle, supplements, medical foods, or some combination thereof - based on your specific symptoms, genetic profile, life experiences, unique biochemistry, medical history, and personal preferences.

This approach becomes even more desirable when the downside risks, the TEARs of antidepressants, as this new study illustrates, become more evident.

Using this approach, antidepressants would work more often if they were prescribed based on your unique symptom profile (melancholic versus atypical), the coexisting medical conditions, and the specific PNI imbalances (neurotransmitter, hormonal, adrenal, and immune), all of which are part of our routine evaluation.


In summary, because of the significant variability among depressive presentations (227 different symptom combinations), it is imperative to determine what type of depression you suffer from before treatment is started. It is for this very reason we so strongly recommend thorough evaluation of your symptom profile (atypical versus melancholic), your co-existing medical conditions, and your unique psycho-neuro-immunological (PNI) disturbances. This is also why we meaure PNI mediators including neurotransmitters, adrenal function, and reproductive hormones.

We practice what we preach: "Test Don't Guess."

Our most popular Neuro-Adrenal Profile from Pharmasan Labs and NeuroScience. Get yours today.


Better yet, call for an appointment - Toll Free:(800) 385-7863. We look forward to hearing from you.



Adverse emotional and interpersonal effects reported by 1829 New Zealanders while taking antidepressants. Read J, Cartwright C, Gibson K. Psychiatry Res. 2014 Feb 3. pii: S0165-1781(14)00083-3.

Clinical patterns and treatment outcome in patients with melancholic, atypical and non-melancholic depressions. Gili M, Roca M, Armengol S, Asensio D, Garcia-Campayo J, Parker G. PLoS One. 2012;7(10):e48200.

Data-driven subtypes of major depressive disorder: a systematic review. van Loo HM, de Jonge P, Romeijn JW, Kessler RC, Schoevers RA. BMC Med. 2012 Dec 4;10:156. doi: 10.1186/1741-7015-10-156.

National patterns in antidepressant treatment by psychiatrists and general medical providers: results from the national comorbidity survey replication. Mojtabai R, Olfson M. J Clin Psychiatry. 2008 Jul;69(7):1064-74.

Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Gold PW, Chrousos GP. Mol Psychiatry. 2002;7(3):254-75.

Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile. Penninx BW, Milaneschi Y, Lamers F, Vogelzangs N. BMC Med. 2013 May 15;11:129.


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