Depression etiology: Hypothalamic-Pituitary-Thyroid Axis Dysregulation

We are almost done building up the discussion about potential causes or contributing factors for depression. This post will focus on the role of the thyroid. 

Evidence Supporting Thyroid Dysfunction In Depression

It’s well established that thyroid dysfunction is associated with depression. Some evidence to support the theory that thyroid function is linked to depression includes a significant number of depressed patients who are hospitalized have a diagnosis of hypothyroidism (around 10%), thyroiditis is more common in mood disorders, patients with rapid cycling bipolar disorder are more likely to have hypothyroidism, and triiodothyronine (T3) is used as a augmentation strategy for difficult to treat depression.

One of the things we need to do prior to making a diagnosis of depression is to rule out potential medical causes. Looking for the following signs and symptoms, as well as laboratory testing can be helpful in assessing thyroid function.

The following symptoms are common in Hypothyroidism

  • Fatigue 
  • Cold intolerance 
  • Impaired memory and concentration 
  • Constipation 
  • Weight gain 
  • Shortness of breath 
  • Hoarse voice 

The following Signs may be present

  • Dry skin 
  • Cool extremities 
  • Hair loss 
  • Low pulse rate 
  • Delayed deep tendon reflexes 
  • Carpal tunnel syndrome 

Lab Testing and Physical Exam

Lab testing for TSH levels is the best initial test. It may need to be repeated in a few weeks to ensure the levels are truly elevated. Another way to help make the diagnosis is order a free T4 blood level to determine if this is subclinical hypothyroidism. If a lump or a mass is felt on thyroid during physical exam diagnostic imaging may be required. The presence of antibodies against thyroid peroxidase (Anti-TPO) provides evidence to support autoimmune thyroiditis as the cause of hypothyroidism.

Treatment For Hypothyroidism

Treatment includes hormone replacement. The long-acting form of thyroxine is called levothyroxine. A psychiatrist will likely recommend the primary care provider manage the diagnosis and treatment. 

Final Comments:

The need to treat depression while the work-up for hypothyroidism is occurring will depend on the clinical picture. Generally, I would prefer to wait until the hypothyroidism is treated adequately, but this is not always possible. 

Depression etiology: Hypothalamic-Pituitary-Adrenal Axis Dysregulation

Elevated cortisol levels over 24 hours have been observed in patients with MDD. Cortisol is a steroid hormone in the glucocorticoid class of hormones. It’s released in response to stress and low-blood glucose. It functions to increase blood sugar, suppresses the immune response, and aids in the metabolism of fat, protein, and carbohydrates. 

In studies a test called the dexamethasone suppression test (DST) has been used to assess cortisol release in depressed patients. Nelson and Davis used this test in patients with depression. They found that 41% of those with MDD with melancholia and 64% of those with MDD with psychotic features either had decreased suppression or were non-suppressors of serum cortisol. They determined that the utility of this test in routine clinical practice is limitted due to low sensitivity and specificity. 

There is a theory that may explain HPA axis dysregulation in depressed patients. Patients who are depressed, may have a dysfunction in the ability of cortisol-glucocorticoid receptor complex to enter the cell. This will disrupt the negative feedback mechanism which tells the body to stop producing cortisol. The result is increased cortisol levels because there is nothing indicating to the body enough cortisol has been produced. 

Elevated cortisol levels appear to be dependent on the current state of the person. If the person is depressed, levels will be elevated. Once the depressive episode has resolved or the person has been effectively treated with antidepressants the HPA axis appears to normalize. 

Inflammation and Depression Revisited

What is Inflammation?

It can be defined as the body’s natural response to infection or injury. Inflammation can be a good thing and is essential for survival. We also know that chronic inflammation is bad. It’s known to contribute to heart disease, cancer, and neurodegenerative disorders. 

What can we say about depression and inflammation?

Some patients with depression have elevated inflammatory markers. In cardiology, C-reactive protein (CRP) is used as a marker to help predict the risk of cardiovascular disease. Obesity is known to be correlated with inflammation and can result in elevated CRP. The standard American diet contributes to both inflammation and obesity. CRP has also been used in psychiatry, but it’s less clear how to use this to predict risk or severity of depression.

Evidence for the treatment of patients with depression and inflammation

The current recommendation to determine if significant inflammation is present, is to order a high-sensitivity CRP test. The exact cutoff value to indicate significant inflammation is not clear. Somewhere between 1 mg/L and 3 mg/L is a reasonable reference range. We can look to the literature to guide us. There are a few randomized controlled trials available. One such trail in the American Journal of Psychiatry compared escitalopram (Lexapro) to nortriptyline in 241 patients. Patients with high CRP > 3 mg/L did better on Nortriptyline and patients with low CRP 1 mg/L did better on escitalopram (GENDEP Trial). Another trial looked at the use of bupropion (Wellbutrin) as augmentation for 106 patients with major depression currently on escitalopram. Bupropion improved depression for those with a CRP > 1 mg/L (CO-MED Trial). A common factor is both nortriptyline and bupropion have an effect on dopamine. The precise reason that increased dopamine levels seems to improve depression in patients with inflammation is unclear. However, this provides some evidence and can inform treatment decisions.

Pharmacotherapy for patients with depression and inflammation

  1. Nortriptyline: If the patient has a CRP >3 there is evidence to support the use over SSRIs specifically escitalopram from GENDEP Trial
  2. Bupropion: For patients with CRP >1 or obesity augmentation with bupropion may improve depressive symptoms. 
  3. Lurasidone: commonly used to treat bipolar depression, has some evidence to support its use when CRP > 2 
  4. Pramipexole: has some evidence to support its use in animal models, and off label use in treatment resistant depression

Final Notes

I do not believe all of these new insights into inflammation and depression are ready to be considered standard of care in psychiatry. For patients struggling with obesity, are treatment resistant, or had a poor response to initial antidepressant treatment may benefit from ordering a CRP level and letting it help guide medications choices. Like most things in science more research is required, but inflammation remains an interesting target for depression treatment. 

What to Expect When You Visit the Psychiatrist: Part One

The initial psychiatric interview is the beginning of an important relationship. Many things will be determined in the first encounter by both the patient and the psychiatrist. At times this can feel overwhelming. A large amount of information must be gathered, processed, and incorporated into a cohesive treatment plan. This series of posts is designed to shed some light on the process, and reduce the anxiety associated with undergoing a psychiatric evaluation. 

The interview consists of five key parts: (1) introduction, (2) opening, (3) the body, (4) closing, and (5) termination. A good psychiatrist will blend these sections into each other, so it feels more like a conversation than a formally structured interview. 

Part 1: The Introduction

This is an important phase and begins as soon as the psychiatrist and patient see each other. The primary goal is to engage the patient and get them comfortable before asking sensitive questions. Like other first encounters the patient will form an impression of the psychiatrist which will shape the rest of the interview and treatment process. 

One way to ensure patient comfort is to address anything in the office setting that can be altered prior to starting the evaluation. For example, closing a shade due to light from the window shining directly on the patient’s seat. Another example would be offering a drink of water or tea before starting. A simple gesture of kindness goes a long way in helping the patient feel comfortable in the setting. 

The psychiatrist should then proceed with a formal introduction and offer a few details about himself or herself. One fear many patients have is a friend or family member finding out that they are under the care of a psychiatrist. It’s always a good idea to clarify and ensure confidentiality. Confidentiality is strictly maintained with the exception two primary scenarios (may vary by state). If a patient informs the psychiatrist of a plan to kill themselves or someone else, there is a duty to warn and protect the patient. 

Once these parts are complete a brief description of how the interview process works is in order. 

An example of this interaction may occur as follows:

The purpose of today’s interview is to learn about your concerns and the types of stressors you are dealing with. As the interview progresses, I will get a better idea of the primary concerns. We will then transition to some background questions about your family, medical health, schooling, and any previous psychiatric care you received. At the end of the discussion we can work together on a treatment plan. This process will take approximately one hour. Do you have any questions before we get started?

We want to convey two things to the patient, (1) a sense of understanding about the interview process to reduce fear, and (2) altering the patient to the fact that many questions will be asked, and it will take a fair amount of time. 

The structure of the introduction is not set in stone and may be modified. It should take around five to seven minutes to complete. 

In the next post we will tackle the opening of the interview process. 


Diagnosis Depression: Sleep Dysregulation

One of the most common symptoms found in multiple psychiatric disorders is sleep disturbance. In fact, sleep disturbance is one of the criteria for the diagnosis of major depression. This post will offer an explanation of some of the changes observed in the sleep patterns of depressed patients.

Much of this information comes from sleep studies in patients who have a diagnosis of major depressive disorder. Without getting too technical there are two primary types of sleep, non-rapid eye movement sleep (NREM) and rapid eye movement sleep (REM). The NREM sleep can be broken down further but for the sake of simplicity we will consider these two categories. 

What we notice in sleep studies of patients who suffer from major depression is a much faster onset of REM sleep. The body usually cycles through these stages 4-6 times throughout the night, averaging 90 minutes in each stage. As the night progress NREM sleep decreases and REM sleep increases. A person with normal sleep architecture will enter REM after 90 minutes, in patients with depression this time period is shorter and can be observed on the sleep study results.

Other changes include decrease NREM sleep which can be thought of as restorative sleep. Increased REM density reduced total sleep time, and decreased sleep continuity are also present. 

Any single change in sleep architecture is not diagnostic of major depression. However, taken together decreased onset to REM, increased REM density, and decrease sleep efficiency can separate patients with major depression from a control group. 

Given all of this information, routine sleep studies are not diagnostic for major depression and are not routinely ordered unless you suspect another sleep disorder. 

Hopefully this provides a basis for why questions about sleep in depressed patients are important. The sleep changes also provide some objective evidence of altered sleeping patterns in patients with depression. 

Is Depression A Genetic Disorder?


This is a common and difficult question I get asked. Like everything in psychiatry, the answer is not clear.

When people think about genetic disorders, they tend to think about classic genetic diseases. Some examples would be sickle cell anemia or cystic fibrosis. There is a clear pattern of inheritance with a single gene involved in these diseases

The human genome project set out to sequence the entire human genome. While it accomplished the goal it did not offer the personalized medicine and targeted interventions initially promised. What it did reveal was a more complicated interplay of genetics and environmental factors. Depression is a multifactorial disease and does not have a single gene involved in the disorder. 

Let’s look at some the evidence supporting the genetic influence on the development of depression.

What Can Family studies tell us ?

The first place to look for a genetic link is family studies. This is one reason we obtain a family history in a psychiatric interview.

MDD is common in families. It’s found 2 to 3 times more often in first-degree biological relatives (e.g. mother or father) of individuals with the disorder than the general population. It’s important to note that the influence of genetics on the development of depression depends on the percent of the genome shared by the individuals. For example, first-degree relatives who share 50% of their genome will have a much greater influence than a second-degree relative who shares 25% of the genome.

What can twin studies tell us ?

The second area of evidence that supports the influence of genetics on depression comes from twin studies.

From the data we know for monozygotic twins (identical twins), there is a 50% chance that one twin will develop the trait (e.g. depression) if the other twin has depression. This number decreases to 20% for fraternal twins who only share 50% of their genome. One flaw in many of these studies is the twins were often raised together in the same environment. There is clearly something to be said for the influence of environment. Some researchers believe twins will influence each other’s behavior when raised together. Identical twins have been known to be treated more similar by their parents than fraternal twins. Taken at face value, when a twin with 100% of the same genetics (identical twins) develops depression the other twin is more likely to also develop depression. Keep in mind, they do not always develop depression even if they share 100% of the genome. 

What do adoption studies add?

Adoption studies make an attempt to differentiate the influence of genetics from environmental factors. These studies examine differences in rates of illness among biological relatives as opposed to adoptive relatives. The studies show higher rates of illness among biological parents rather than adoptive parents. This provides some additional evidence to support a genetic influence. 


There is clearly a genetic component to depression. However, it’s a complicated process that involves multiple genes interacting with the environment. This makes identifying a single causal gene difficult and likely impossible. There are people biologically predisposed to developing depression, but not everyone with biological predisposition will go on to develop depression. 

If you found this helpful please like, comment and share your thoughts for future posts on genetics.

Diagnosis Depression: Major Depressive Disorder (MDD) with Seasonal Pattern

With this specifier, the name provides most of the information. There has to be a clearly defined relationship between the onset and remission of depression with the changing of the seasons. For example, a patient becomes depressed in the late fall or winter and their depression remits once spring arrives. This is the most common pattern in clinical practice.

The relationship between the depressive episodes and season is present for at least the prior two years. Furthermore, the number of seasonal episodes is significantly more than nonseasonal episodes. Basically, what this means is there must be an established pattern related to the changing of the seasons for two years.

If the depressive episode is clearly related to another factor (e.g. start of school or change in work stats) the specifier does not apply. 

In the two-year period where the pattern is established there cannot be any nonseasonal episodes. 

For this specifier to apply, the person must clearly become depressed in the months where day light is reduced (possible mechanism for these episodes), and have remission of symptoms once the days become longer. (this is one example, there are others)

Like, Share, and leave a comment below if you ever felt depressed during the winter months

Diagnosis Depression: Major Depressive Disorder (MDD) with Melancholic Features

I wanted to finish the discussion on the various specifiers for major depressive disorder. In this post I will discuss melancholic features. 

The most distinct feature in MDD with melancholic features is profound loss of interest (anhedonia) in all or almost all activities. This is a common feature in MDD as well, but the loss of pleasure in activities is far more severe. There is also a complete lack of reactivity to anything that would usually be considered by the person as pleasurable. 

In addition, at least three of the following are required: 

  1. Depressed mood that is experienced as qualitatively different from the feeling experienced after a loss. 
  2. Depression that is worse in the morning. 
  3. Awakening at least two hours prior to the usual wake time 
  4. Marked psychomotor retardation (slow movement) or agitation 
  5. Significant anorexia or weight loss 
  6. Excessive or inappropriate guilt 

I think of this specifier as a more profound form of MDD. 

One thing we try to do with modern pharmacology is treat specific symptoms with classes of medication that match the neurotransmitter profile. The medication selection or augmentation strategy may change depending on the symptoms we want to target. For example, fatigue and concentration are largely regulated by norepinephrine and dopamine, so we may choose a medication that targets these neurotransmitters. In this example of melancholic depression sleep and appetite may be the primary issues, we may select a more sedating medication like mirtazapine. I will provide more details on the symptom-based selection of medication for depression in future posts. 

Diagnosis Depression: Major Depressive Disorder (MDD) With Atypical features

I like the DSM-5 and I think it provides us with a conceptual framework for evaluating patients. In clinical practice it’s rare to find patients that fit all diagnostic criteria perfectly. When that does occur it’s nice and makes life easy. 

Major depressive disorder with atypical features is one of those situations. Many patients have some of the symptoms but not enough to clearly make the distinction. Nonetheless, some of these symptoms are common and need to be discussed.

What makes this type of depression atypical?

I like to think of the symptoms as the opposite or reverse of major depression discussed in previous posts. 

A key distinction to look for is mood reactivity in response to positive events. In major depressive disorder nothing usually makes the patient feel happy. They may even present with a restricted, constricted or blunted affect. In the atypical case, these patients can react and show emotion when positive events occur. 

Along with mood reactivity, they must have two of the following features

  • Increased appetite or significant weight gain 
  • Hypersomnia (excessive sleep) 
  • Leaden paralysis often described as a heaviness of the arms and legs 
  • A longstanding pattern of sensitivity to interpersonal rejection 
  • It must be impairing social and occupational function 

When you look at the list above you see why we can think of these symptoms as the opposite of typical major depression.

Hope this post helps to clear up some question about atypical depression. Please like, share and comment. 

Diagnosis Depression: Major Depressive Disorder (MDD) With Psychotic features

In the last post we covered MDD and we introduced the specifiers. In this post I will talk about MDD with psychotic features. 

You may have guessed already, but what separates this disorder from MDD is the presence of delusions, and hallucinations along with symptoms of major depression. Fairly simple, right?

First, we need to define psychotic symptoms. 

In general, we can think about the following symptoms: 

  1. Delusions: which can be defined as fixed false beliefs. Something that the person believes despite evidence to the contrary. 
  2. Hallucinations: A hallucination is a sensory perception in the absence of external stimuli. There are several types including auditory (most common, consists of hearing a voice or several voices), visual, olfactory (smell), tactile (touch), and gustatory (taste). 
  3. Disorganized speech or behavior: This is an indication of the persons thought process. If the person is not thinking in a clear logical manner their though process may be difficult or impossible to follow for an outside observer.  

These psychotic symptoms can be congruent with the depressed mood (content is consistent with depressive thoughts) or mood incongruent (content is not consistent with typical depressive thoughts). Mood congruent psychotic symptoms will consist of depressive themes such as guilt, death, poor self-worth, and punishment. Mood incongruent symptoms include things such as delusions of control, thought broadcasting, or thought insertion. Both mood congruent and incongruent themes can occur in the same episode.  

Another key point is the psychotic symptoms only occur during a depressive episode. They are not present when the patient is not depressed. Once psychotic symptoms appear with an episode of depression, they tend to be present on subsequent episodes. 

In the next post we will cover atypical features of depression. Please like, comment, and share the content. Feel free to offer suggestions for future posts. 

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