Possible Causes of Hard to Treat Depression

Some people find antidepressant treatment ineffective and their depression very hard to treat. Here are the causes of hard to treat depression.

While no one knows why some people react positively to antidepressant treatment and others don't, there are some factors that appear to play a part in causing hard to treat depression.


People in a stressful environment often will not find complete relief of depression symptoms from antidepressant medication alone. Stress causes changes to the brain's chemicals and affects how the brain works. (See" Relationship Between Anxiety and Depression.)

Examples of stressors include:

  • A death in the family
  • Relationship issues
  • Financial problems
  • A new job

Depression and anxiety therapy can help many people learn to deal with the stress in their lives and help remission become a reality.

Medication Non-Compliance

Medication non-compliance includes taking medications in any way other than prescribed.

Examples of this include:

  • Skipping doses
  • Taking more than prescribed
  • Taking less than prescribed
  • Taking the medication at a time other than prescribed (like taking the medication at bedtime rather than in the morning)

By not adhering to the dosage and schedule set out by the doctor, the medication may not have a chance to work or it may stop working. People may alter their medication schedule for a variety of reasons:

  • Vacation
  • Forgetting to take the medication
  • Thinking they no longer need the medication

If the medication dose or schedule is changed for any reason, it's important to be honest with your doctor about it so your doctor can help get you back on track.

Other Health Problems

Other medical problems can worsen depression or even mimic its symptoms. It's important that all other health-related issues be ruled out if MDD treatment isn't working. Common problems that may cause depression-like symptoms or worsen depression include:

  • Thyroid disorders
  • Vitamin deficiencies
  • Anemia
  • Heart problems
  • Substance abuse
  • Chronic pain

Many of these issues can be ruled out by simple blood tests and once the underlying condition is addressed the issues of depression lessen or disappear completely.

Other Mental Illnesses

Depression commonly occurs alongside other mental illnesses like anxiety or borderline personality disorder. These other mental illnesses may require additional treatment or a change in the way the depression is treated.

For example, some antidepressants are known to have anxiety as a side effect, so these should not be given to someone who is already anxious.

Depressive symptoms also commonly mask some types of bipolar disorder. While individuals experiencing a full-blown manic episode are easy to diagnose with bipolar disorder, those with other types, such as bipolar depression, who are often misdiagnosed with MDD.

Soft Signs of Bipolar Disorder

The DSM-IV describes type I bipolar disorder as having depressive and manic symptoms and type II bipolar disorder as having depressive and hypomanic symptoms. Hypomanic symptoms are much less severe than manic symptoms and can be harder to detect.

Additionally, some doctors believe there are additional "soft signs" of bipolar disorder which in and of themselves do not indicate bipolar disorder, but put together can be suggestive of bipolar depression. Soft signs may also indicate that non-antidepressant treatments are more appropriate. Soft signs of bipolar include:

  • Repeated episodes of major depression (four or more; seasonal shifts in mood are also common)
  • First episode of major depression occurring before age 25
  • A first-degree relative (mother/father, brother/sister, daughter/son) has a diagnosis of bipolar disorder
  • When not depressed, mood and energy are a bit higher than average, all the time
  • When depressed, symptoms are "atypical": extremely low energy and activity; excessive sleep (e.g. more than 10 hours a day); mood is highly reactive to the actions of others
  • Episodes of major depression are brief, e.g. less than 3 months
  • Psychosis (loss of contact with reality) during an episode of depression
  • Severe depression after giving birth to a child
  • Hypomania or mania while taking an antidepressant
  • Loss of response to an antidepressant, i.e. it worked well for a while then the depression symptoms came back, usually within a few months
  • Having tried three or more antidepressants without response

An experienced psychiatrist can differentiate the types of mental illnesses present, but it's important to be completely honest with the doctor about all symptoms so he can have all the facts on which is base his assessment.

APA Reference
Tracy, N. (2022, January 4). Possible Causes of Hard to Treat Depression, HealthyPlace. Retrieved on 2024, May 22 from

Last Updated: January 11, 2022

Medically reviewed by Harry Croft, MD

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