Karl Hempel, M.D.

Introduction

Depression may be the most common serious illness a primary care physician sees. It represents about 15 percent of office visits to the primary care physician. Depression is a major public health problem, as more and more people are affected by it. Approximately two to three percent of males and four to nine percent of females have depression at any one time. According to statistics from the National Institute of Mental Health, ten million Americans suffer from depression each year. The annual direct cost of depression is estimated to be 12.4 billion dollars. Indirect cost, which includes time lost from work, is approximately 30 billion dollars. This makes the total cost of depression more than 40 billion dollars per year. Of course, the cost in human suffering is untold. Appropriate treatments could help over 70% of those with serious depression, but unfortunately, not everyone with depression seeks help. Without treatment, symptoms can last weeks, months, years, or even a lifetime. There are approximately 30,000 deaths from suicide in the United States every year. Most suicides are in the elderly. There are all different degrees of depression. Most cases of depression that a family physician sees are not major depressions.

Etiology

Research has confirmed that depression involves a chemical imbalance of the brain. Antidepressants can restore the balance. A person with depression cannot just “snap out of it.” The disease is a multifaceted, complex disorder which affects many different systems of the body. It involves the way people think and act, the way they eat and sleep, and their attitude toward themselves. It is a condition that cannot be wished or willed away. Depressed persons feel down, sad, and hopeless. Often, they feel they may never be happy again and are unworthy of treatment. With this sense of hopelessness, they may wish to die to relieve their suffering. Depression must be taken seriously because it can be fatal.
Depression is believed to be caused by a combination of factors. Research studies suggest there is a genetic predisposition for depressive disorders. Chromosomes 17 and 21 have been linked to depression. Bad life experiences, such as financial hard times, difficult relationships, or marital problems, may trigger a depressive episode that might last more than several weeks. Research suggests that traumatic life experiences may cause permanent functional and structural damage to the brain. Often, the cause of depression is not related to any particular life experience. Patients just feel bad and they don’t know why.
Depression is the result of abnormalities of brain chemistry. There is a shortage of certain neurotransmitters (serotonin, norepinephrine and dopamine) in the brain. It really doesn’t matter whether environmental (bad life experiences) or genetic factors precipitate the abnormal brain chemistry, because treatment is basically the same. When people become depressed there is a tendency to blame the depression on a present or past event in life. They will say they are depressed because they lost their job, or they are going through a divorce. Most people fail to realize that the reason they lost their job, or are having marital problems, is because of the depression that occurred initially. A spouse with a low sex drive, inability to enjoy life, irritability, and constant fatigue is not much fun to be around. This results in marital problems and may eventually result in divorce if it is not treated. Obviously, an irritable salesman, with little enthusiasm for his product and difficulty smiling, is going to suffer a decrease in his sales, and possible loss of his job. Catastrophic life events may certainly result in depression. Interestingly, this type of depression also responds to antidepressant therapy proving that there is an associated neurotransmitter deficiency. This neurotransmitter deficiency was induced by the catastrophic event. Most episodes of depression involve both environmental factors as well as a chemical imbalance. Environmental factors may become worse the longer the patient goes without treatment. This is because the chemical imbalance may create more and more environmental problems (divorce, lost job, poor relationships with friends, etc.). Counseling is very helpful to work on the environmental problems that are frequently associated with depression. Counseling and treatment with antidepressants have the highest success rate in treating depression. Studies have shown that exercise is very helpful in treating depression.  Regular exercise is capable of improving the chemical imbalance. I always recommend exercise in treating depression.
 

Symptoms

The following symptoms suggest depression:

1. Depressed mood most of the day (nearly everyday)
2. Markedly diminished interest in daily activities
3. Significant weight loss or gain
4. Insomnia or excessive sleeping.
5. Agitation or slowing of purposeful movements
6. Fatigue-probably the most common symptom of depression
7. Feelings of worthlessness
8. Diminished ability to think
9. Recurrent thoughts of death
10. Reduced sex drive
11. Inability to enjoy activities that have always been fun in the past

It is important to realize that depression is only one possible symptom of the chemical imbalance. A more common symptom is just plain old fatigue or malaise. Many patients that have this chemical imbalance don’t feel depressed or sad. They may have numerous other physical symptoms such as irritability, anxiety, sleep disturbances, low sex drive, abdominal pain, irritable bowel syndrome or headaches. I have found that a very important and consistent symptom of this illness is the inability to enjoy daily life experiences that are normally very pleasant and enthusiastically anticipated. The name of this illness would better be represented if it was called neurotransmitter deficiency. This is because there are so many misconceptions and negative stigma associated with the diagnosis of depression.
Bipolar illness is a less common form of depression and is sometimes difficult to diagnose. It is more likely if you have a family history of bipolar disease. Frequently, patients with bipolar illness will respond only briefly to the traditional antidepressants. Patients have a history of trying many different antidepressants by several different doctors before the diagnosis is finally considered. Patients may have a history of manic attacks where they feel almost too good. The suicide risk is higher. Manic episodes are associated with agitation, inflated self-esteem, decreased need for sleep, racing thoughts and impairment of daily functioning. It is important to let your doctor know if you have had or are having these symptoms. It is treated somewhat differently than regular depression.

Neurophysiology

Antidepressants are not pep pills nor do they produce a “high.” They are not addictive and they are not contraindicated in patients with chemical dependency. To understand how they work, it is first necessary to describe how the brain works. The brain is the master control center of the body. It constantly receives information from the sense organs, analyzes the data, and sends out messages that control body action and function. It is made up of billions of nerve cells called neurons. The neurons produce electrical signals and send them from one cell to another. The neurons communicate with each other through arm-like structures called axons and dendrites. You can think of it as two people shaking hands. At each point of communication, there is a space called the synaptic cleft or synapse (the space between the hands). When a signal reaches the end of the nerve cell axon it causes the cell to secrete a chemical messenger, called a neurotransmitter. The neurotransmitter floats across the synaptic cleft and binds to a receptor on the receiving side. This produces an electrical current. The neurotransmitter is then either destroyed, or is reabsorbed back into the neuron. There are many neurotransmitters, but three are known to be associated with depression. These are norepinephrine, dopamine and serotonin. Depression is caused by a deficiency of one or more of these neurotransmitters.
An interesting research tool has been developed for studying various illnesses including depression. It is called the PET ( Positron Emission Tonometry) scanner. This apparatus can actually evaluate the intensity of brain activity. It has been helpful in showing how depression affects the brain. Depression reduces the intensity of brain activity. It is like the brain is in a state of hibernation.
PET scan of a normal brain                                          PET scan of a depressed patient
The intensity of brain activity can be measured by the colors.  The most activity is the red, followed by yellow, green, and finally blue.  The depressed brain is in a very low activity state almost like hibernation.  You can see why mental concentration is not very good in someone who is depressed.  The PET scanner is used mainly in research and not specific or sensitive enough to be used in everyday medical practices.
Antidepressants work by increasing the amount of neurotransmitters available at the synapse. This ultimately results in improved communication between the neurons.  The PET scanner will take 3-4 months to revert to normal but symptoms may improve in just 10-14 days after the antidepressant is started.
 

Diagnosis

Unfortunately, there is no specific blood test to detect a deficiency of neurotransmitters in the brain. Several blood and urine tests have been tested, but have not proven useful thus far. PET scanning is being done at research centers, but is not widely available. Depression actually causes a decrease in the metabolic activity of the brain. Depression is seen on the PET scan as a color change from the normal brain. Interestingly, after an individual is treated, the PET scan will revert back to normal. The diagnosis of depression is based on ruling out other conditions that mimic depression and the clinical response to antidepressants. It is important to check for an underactive thyroid since hypothyroidism can mimic depression.
If there is no chemical imbalance, the patient will not feel much different after taking the antidepressant. It usually takes 2 to 6 weeks for the medication to work, and many times, a spouse or a friend are the first to notice any improvement.
 

Treatment

Studies have shown that all of the various antidepressants are equally effective if given in adequate doses. The big differences are the side effects. Many of the older tricyclic antidepressants cause drowsiness even in low doses. This makes obtaining an adequate dose difficult. The next class of antidepressants are called selective serotonin uptake inhibitors (SSRI’s). They have less side effects and have become the most commonly prescribed antidepressants. They are very safe even at high doses. An overdose is unlikely to result in death. Unlike the tricyclic antidepressants, they have almost no cardiac side effects.
Below is a list of some commonly used antidepressants and a comment on side effects and when one may be advantageous over another. The generic name is used first followed by a brand name in parenthesis:

1. Fluoxetine (Prozac)-One of the most commonly prescribed antidepressants with few side effects in most patients. The most common side effects are nausea, headaches, insomnia and sexual dysfunction. Many of the side effects will go away in time if continued. Occasionally, the dosage can be reduced and the side effects will go away or decrease. After years of use some people start feeling fatigued. It usually helps to add Wellbutrin when this happens. Prozac is used to treat eating disorders. Several studies have suggested that it is relatively safe in pregnancy. Prozac elevates the serotonin neurotransmitter. It is one of the few antidepressants that usually don’t need to be tapered down when discontinuing it.
2. Sertraline (Zoloft)-This antidepressant has similar side effects to Prozac, but occasionally is associated with loose stools. It might be helpful in someone with constipation.
3. Paroxetine (Paxil)-It is associated with more sedation and, therefore, may be helpful in patients with anxiety. It is also useful in panic attacks. It can occasionally cause weight gain and is helpful in people who have lost weight.  It frequently causes night sweats as do most SSRI’s. It also elevates the serotonin level.
4. Maprotiline (Ludiomil)-May cause dizziness or lightheadedness. It inhibits reuptake of norepinephrine at the synaptic cleft and therefore increases norepinephrine.
5. Bupropion (Wellbutrin, Zyban)-A big advantage of Wellbutrin is the lack of sexual dysfunction. Patients with seizure disorders should not take this medicine. It is occasionally used at low doses in conjunction with other antidepressants in an attempt to decrease sexual side effects. It has been found it to be very successful for smoking cessation.  It is occasionally associated with weight loss.  It increases the dopamine and norepinephrine neuroreceptors.  It is favored in bipolar illness.  Occasionally, it is helpful in ADHD (attention deficit hyperactivity disorder). It is the only present antidepressant that increases dopamine. It is associated with a higher incidence of seizures in patients with bulimia and anorexia so it is contraindicated in these patients.
6. Venlafaxine (Effexor)-This antidepressant increases the norepinephrine as well as the serotonin.  It may work when the SSRI’s have been ineffective. It is now available in a once a day formulation and has less side effects than the old formulation. It is also indicated in generalized anxiety disorders.  This medicine is occasionally associated with weight loss. It should not be stopped abruptly.
7. Duloxetine (Cymbalta)-This antidepressant is similar to Effexor and elevates the serotonin and norepinephrine. It is also used to treat diabetic neuropathy. It is sometimes associated with nausea.
8. Trazadone (Desyrel)-Causes sedation even at low doses. It is frequently used in low doses in conjunction with other antidepressants to help with insomnia.
9. Mirtazapine (Remeron)-It has a completely different mechanism of action than the SSRI’s.  It elevates norepinephrine and serotonin but by a different mechanism than other antidepressants. It is helpful for people that have weight loss because it stimulates the appetite in some patients.  It can be quite sedating.
10. Citalopram (Celexa)-Another SSRI. It has minimal side effects but occasionally can cause sexual dysfunction.
11. Lexapro (escitalopram)-Very similar to Celexa. Ten milligrams of Lexapro is equivalent to 40 mgs of Celexa.
12. Amoxapine (Asendin)-Increases the serotonin and norepinephrine neurotransmitters. Can cause drowsiness, dry mouth and constipation.
13. St. John’s wort-This product is over the counter. Probably worth a try in mild depression. I have been disappointed with the results in general.  Exercise is more efficacious in my opinion.

There are other antidepressants that are very effective. It is impossible to predict what side effects an individual will have. Occasionally, an individual may have to try several different antidepressants to find one that is acceptable.
The medication is usually continued for 12 months before attempting to stop it. If the symptoms recur after stopping the medication, then the medicine should probably be continued for at least another 12 months. In about 30% of patients, the chemical imbalance will never completely resolve on its own. The patient has no choice but to stay on the medication indefinitely or be depressed. Fortunately, there have been no long-term complications from taking antidepressants. The risk of recurrence is 50% after the first episode, 70% after two episodes and 90% after three episodes. Several experts recommend that persons who have 3 or more episodes at any time in their lives should take antidepressants for the rest of their lives as maintenance therapy. If persons are over 50 years old and have their first episode, or over 40 years old and have their second episode, they should be on lifetime maintenance therapy. Sometimes the antidepressants seem to become less effective after several years of use. This seems to occur with chronic depression. It frequently helps to add Wellbutrin to another antidepressant. This combination will increase serotonin, epinephrine and dopamine. There is no one antidepressant that will increase all three neurotransmitters.
Interestingly, aerobic exercise seems to also elevate the serotonin level. It always has a place in the long-term management of the chemical imbalance, but is not usually adequate for the initial treatment except in the mildest of cases. I have noticed that people who are able to develop a regular exercise program are more likely to be able to stop the antidepressant without a recurrence of symptoms of depression.
Electroconvulsive therapy can be very helpful in patients that are suicidal. It has an immediate effect and is quite safe.
 

Conclusion

The correct administration and dosage of antidepressant medication, along with counseling and aerobic exercise are recommended for the successful treatment of depression. Much progress has been made in the study of depression. Fortunately, the disease is now less stigmatized and better understood. There is help and hope for this devastating, common illness.
 

References

http://www.UpToDate.com.
Clinical manifestations and diagnosis of depression
Author
Jeffrey M Lyness, MD
Section Editor
Peter P Roy-Byrne, MD
Deputy Editor
David Solomon, MD
Last literature review version 18.2: May 2010 | This topic last updated: June 7, 2010
Schulberg, HC, Raue, PJ, Rollman, BL. The effectiveness of psychotherapy in treating depressive disorders in primary care practice: clinical and cost perspectives. Gen Hosp Psychiatry 2002; 24:203.
Unutzer, J, Katon, W, Callahan, CM, et al. Collaborative care management of late-life depression in the primary care setting: a randomized controlled trial. JAMA 2002; 288:2836.
Kroenke, K, West, SL, Swindle, R, et al. Similar effectiveness of paroxetine, fluoxetine, and sertraline in primary care. A randomized trial. JAMA 2001; 286:2947.
Geddes, JR, Carney, SM, Davies, C, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet 2003; 361:653.Josey, ES, Tackett, RL.
St. John’s wort: A new alternative for depression? Int J Clin Pharmacol Ther 1999; 37:111.
Williams, JW Jr, Barrett, J, Oxman, T, et al. Treatment of dysthymia and minor depression in primary care: A randomized controlled trial in older adults. JAMA 2000; 284:1519.
Simon, GE, VonKorff, M, Piccinelli, M, et al. An international study of the relation between somatic symptoms and depression. N Engl J Med 1999; 341:1329.
Rose, D, Fleischmann, P, Wykes, T, et al. Patients’ perspectives on electroconvulsive therapy: systematic review. BMJ 2003; 326:1363.
Stewart, WF, Ricci, JA, Chee, E, et al. Cost of Lost Productive Work Time Among US Workers With Depression. JAMA 2003; 289:3135.
Judge, R, Parry, MG, Quail, D, Jacobson, JG. Discontinuation symptoms: comparison of brief interruption in fluoxetine and paroxetine treatment. Int Clin Psychopharmacol 2002; 17:217.
Kessler, RC, Berglund, P, Demler, O, et al. The Epidemiology of Major Depressive Disorder: Results From the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289:3095.(1)
Gorman, J. M. (1990). The essential guide to psychiatric drugs. New York, NY: St. Martin’s Press.
Harvey, A. M., Johns, R. J., McKusick, V. A., Owens, A. H., Ross, R. S. (1988). The principles and practice of medicine. Norwalk, Connecticut: Appleton & Lange.
Kline, N. S. (1974). From sad to glad. New York, N.Y.: Ballentine Books.
Potter, W. Z., Manji, H., Rudorfer, N. V. (1991). The pharmacological treatment of depression. The New England Journal of Medicine, pp. 633-640.
Roesch, R. (1991). The encyclopedia of depression. New York, N.Y. Facts on File.
Talley, J. (1987). Family practitioner’s guide to treating depressive illness. Chicago, Il.: Precept Press.
Wurtman, J.J. & Wurtman, R. J. (1989). Carbohydrates and depression. Scientific American, pp. 68-75.
Frank E, et al. Arch Gen Psychiatry, 47:1093-1099, 1990.
Kupfer DJ. J Clin Psychiatry, 54(suppl)29-33, 1993.
Greden JF. Clin Psychiatry, 54(suppl)39-45, 1993.
George MS, et al. SPECT and PET Imaging in Mood Disorders. J Clin Psychiatry 1993 NOV;54 Suppl:6-13.
Mann J, et al. Demonstration in vivo of reduced serotonin responsively in the brain of untreated depressed patients. Am J Psychiatry 1996 Feb;153(2) :174-182.
Bench CJ, et al. Changes in regional blood flow on recovery from depression. Psychol Med 1995 Mar;25(2) :247-61.
The information provided above is offered as a community service about health-care issues and is not a substitute for individual consultation. Advice on individual problems should be obtained from your personal physician. This information is based on research by the author and represents his interpretation of the literature.