Part 1-Depression

How common are psychiatric problems with Cushing’s, and what problems do Cushing’s patients have?

In some studies, as many as 90% of Cushing’s patients suffer from depression. In part, this is due to actual chemical changes in the brain from high cortisol. The depressing effect of having a serious and impairing illness may also contribute to depression. High cortisol levels also can be experienced by the body as anxiety, and insomnia is extremely common in patients on steroids and with high cortisol states. Elevated, agitated mood, like in mania, can also be seen in a minority of patients, and some actually hallucinate and have psychotic symptoms. Problems with concentration and memory are common and may improve or continue after recovery, depending upon the severity and length of the Cushing’s symptoms.

What treatments are there for Cushing’s patients’ psychiatric problems?

Ultimately, the most important treatment is control of the cortisol level. Thus, surgery or radiation are needed for most patients with Cushing’s Disease and Cushing’s Syndrome due to adrenal tumors. On a temporary basis, medications, such as ketoconazole, metyrapone, and aminogultethimide, have been used to lower high cortisol levels due to tumors and may be helpful in alieviating some of the psychiatric symptoms associated with the high cortisol state.

Most patients will also use and benefit from standard psychiatric treatments, including psychotherapy and medication. Medications may be helpful for the treatment of depression, anxiety, sleep, energy, and mood swing states. Until cortisol issues are resolved, including both high cortisol states and cortisol withdrawal, results may be less than for patients not ill with Cushing’s, and some patients respond differently to medications than they would with normal cortisol levels.

What is the best treatment for depression?

Psychotherapy has proven benefit for depression. All patients with a serious medical illness should consider the use of psychotherapy in coping with their disease. Psychotherapy can help with depressed mood, anxiety, and handling the loss of functioning and strain on relationships which are caused by Cushing’s.

All antidepressants achieve about equal rates of response in treating depression. There are slight differences between them which can be significant to the patient. Patients with anxiety do best with an “SSRI” (serotonin type of anti-depressant). Patients most concerned about fatigue can benefit from Wellbutrin (or a combination of an SSRI and Wellbutrin if anxiety is also present).

How long does it take for antidepressants to work?

It is a myth that a patient must wait a month for an antidepressant to work. Most people experience some benefit in 1-2 weeks. If a person hasn’t improved at all in 3 weeks, the dose should be increased or the medication changed, according to latest research findings.

Can anti-depressants make someone worse or cause suicide?

Some patients’ reports of increased suicidal behavior on anti-depressants have resulted in drug companies’ being required to caution all potential consumers about this concern. No actual causal relationship has been proven. What is clear is that the suicide rate in children and adults is lower when depression is treated and that anti-depressants help depression, probably in all age groups, although there is less supporting data for their efficacy in children. Patients with diagnosed or undiagnosed bipolar illness may experience agitation or increased mood swings when treated with antidepressants without concomitant use of mood stabilizers. All patients on psychiatric medication should be monitored periodically with in-person visits with prescribing practitioners as well as phone contacts.

Is there anything that helps loss of libido or sensation caused by some anti-depressants (SSRIs)?

Ginkgo Biloba 120 mg 1 or 2 times a day has demonstrated benefit for a majority of patients. A month’s trial is a reasonable time to see some effects. Ginkgo is available over-the-counter in drugstores and healthfood stores. Wellbutrin, the antidepressant, may improve sexual functioning when combined with SSRI antidepressants. Buspar, an anti-anxiety medication, has also been used for this purpose with success in some patients. Viagra and Cyproheptatide (Periactin), a serotonin blocker, may provide some temporary and immediate effect to enhance sensation when taken an hour before sex.

Do antidepressants cause weight gain?

The only antidepressant which never causes weight gain is Wellbutrin. Only a minority of people gain weight with other antidepressants, but certain ones are more likely to cause weight gain, like Remeron, Paxil, and older antidepressants called the “tricyclics”, such as Elavil. Some who gain weight catch it early by noticing an increased appetite. Others put on weight gradually over time by a slowing of the metabolism. These people may continue eating the same but gradually find themselves gaining. Some people actually lose weight on antidepressants because they are more motivated to control diet and to exercise and because anti-depressants lower anxiety and can reduce anxiety-driven eating.

Can growth hormone help with depression?

Research on this particular topic is lacking, but, for those people who are shown (by insulin tolerance test) to be growth hormone deficient, replacement (by daily injection) may produce a variety of benefits, including an improvement in energy and overall well-being.

What happens during cortisol withdrawal?

Cushing’s patients may experience cortisol withdrawal when surgery successfully removes tumors which increase cortisol. Cortisol withdrawal may occur when a patient is being tapered off of replacement hormones following surgery while awaiting recovery of the hormone system which regulates cortisol. This system, the hypothalamic-pituitary-adrenal axis, may take months or years to recover after removal of a tumor.

People experiencing cortisol withdrawal often feel extremely fatigued and have severe muscle and joint pain. In an extreme case, the body experiences a crisis in which a person has nausea, dizziness, severe fatigue, and may actually be at risk of death. This is a medical emergency and should be treated with immediate higher-dose steroids.

Depression is the most common psychiatric symptom of cortisol withdrawal. It is likely partly chemical and partly a result of a person’s extreme difficulty functioning due to the cortisol withdrawal symptoms. These symptoms are thought to occur because the body’s tissues have grown used to a higher level of cortisol (such as that brought about by Cushing’s tumors) and they go into a reaction state when that level is brought down suddenly by surgery or cortisol-blocking agents, such as ketoconazole. The best treatment is slow taper, but many people going through cortisol withdrawal use psychiatric drugs as well as pain medications for the muscle and joint pain. Steroid hormones (hydrocortisone, prednisone, solucortef) should be stopped only under the guidance of a physician, who can conduct tests to make sure the person is making enough cortisol on their own.

How do you know whether you need psychiatric help?

All seriously medically-ill patients merit psychiatric support. Psychotherapy helps people cope better and function better. Psychiatric medications help with many symptoms which come from medical illnesses like sleep disturbance, depression, fatigue, and anxiety. Cushing’s patients should not hesitate to seek counseling or psychiatric care.

Psychotherapy can also help relieve some of the stress on close relationships which Cushing’s presents. Psychotherapy offers a place where all sorts of feelings and suffering can be freely shared and relieves the burden from being placed solely on spouses and loved ones.

Where can you get help?

Medical doctors who care for Cushing’s patients often have worked with psychiatrists and psychotherapists and may be able to recommend a practitioner. People with HMO insurance plans can contact the mental health providers listed with their insurance and receive care at reduced rates. Almost all teaching hospitals which have medical schools and psychiatry departments have a psychiatric residency clinic where psychiatrists-in-training provide quality care. These doctors are often willing to learn about medical illnesses and are happy to have patients who provide real-life experience with uncommon diseases. Psychiatric residency clinics usually charge on a reduced or sliding-scale rate. They can be reached by calling the Department of Psychiatry at any teaching hospital with a medical school or psychiatric residency program.

What’s the best take-home message about mental health and Cushing’s?

Appreciate all you have that is good. Seek out the good in all experiences and all around you. Use the opportunity of being ill as a chance for new learning and new experience. Have fun with your life (and your illness) whenever and wherever you can!

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Part 2 – Anxiety, Fatigue and Insomnia

What is the best treatment for anxiety?

High levels of cortisol, whether due to disease or steroid medication, may cause anxiety. Many different categories of medications are available to treat anxiety. Again, the most important treatment is lowering the cortisol level.

Valium (diazepam), Ativan (lorazepam), Xanax (alprazolam), Klonopin clonazepam), and other benzodiazepine-type drugs offer short-acting relief (several hours’ action) with the main side effect of tiredness and potential problems of dependence and withdrawal.

Buspar (buspirone) can be helpful for generalized anxiety and less likely to cause sedation. Buspar does not have the addictive problems of the tranquilizer drugs. Buspar has not demonstrated effectiveness for panic attacks.

Atypical neuroleptics, like Risperdal and Seroquel, used in high doses for the treatment of psychosis can be used in small doses for the treatment of anxiety, agitation, elevated mood states, and sleep.

Neurontin and anti-convulsants may also be helpful for anxiety. Each drug has its own characteristics and potential side effects, and thus close medical followup is indicated.

Can fatigue be treated?

Again, treatment of choice is resolution of the primary cortisol disease. Various agents can help with energy and alertness.

Stimulants, like Ritalin, Concerta, and Adderall can help energy and focus. Patients with hypertension should have adequate blood pressure control before using stimulants and be monitored while on them so that blood pressure medications can be increased if necessary.

Wellbutrin, an antidepressant, has an activating an energizing effect but may increase anxiety or cause insomnia.

Antidepressants may help fatigue in that depression, which goes hand in hand with Cushing’s Disease, may contribute to fatigue. All antidepressants are pretty much equal in effectiveness against depression.

Provigil, a drug which is used to improve alertness in sleep disorder patients, may help some forms of fatigue or sleepiness and may soon receive a formal indication for use with medically-ill patients. Provigil has the advantage of not raising blood pressure but may cause insomnia if taken too late in the day.

Sleep medications may help fatigue by promoting restful sleep.

Exercise is well proven to improve energy levels. Cushing’s patients should meet with a physical therapist or personal trainer to design an exercise program which takes into account the muscle-wasting state of Cushing’s, weight issues and potential osteoporosis.

Herbal treatments have been tried but not panned out in research studies. Ginkgo Biloba is often sold for energy effects; in fact, there is research that suggests that it is helpful in countering the sexual side effects of the serotonin anti-depressants (SSRIs).

What treatments are there for insomnia with Cushing’s?

Insomnia is one of the commonest symptoms in Cushing’s. Sleep is disturbed by the excessive cortisol secretion, which causes changes in various areas of the brain involved with alertness, sleep, and the circadian rhythm. It is not uncommon for Cushing’s patients to have too much energy at bedtime and then, after a few hours of sleep, to wake up again charged and ready to go. While some may get more done, others find this energy to be nervous, non-productive energy, which contributes to daytime fatigue and brain fogginess.

Many different medications can help promote sleep.

Over-the-counter medications can be helpful, including Benadryl (diphenydramine), the active ingredient in most over-the-counter sleep aids, melatonin, and valerian root. These can usually be combined with other medications and sleeping pills to promote better sleep.

Prescription sleeping pills, include Ambien (zolpidem), Ativan (lorazepam), Klonopin (clonazepam), Restoril (temazepam), and Dalmane (flurazepam). Tolerance may develop (requiring a higher dose over time), and many experience rebound insomnia upon stopping the medication unless it was very gradually tapered. Rebound insomnia is severe sleep difficulty especially the first few nights after stopping a sleep medication.

Certain antidepressants, like Desyrel (trazodone) Remeron (mirtazepine), and the older tricyclic antidepressants, such as Elavil (amitryptiline), Tofranil (imipramine), and Sinequan (doxepin) are extremely sedating and, in fact, are probably more commonly used as sleeping pills than as antidepressants. They have the advantage of not resulting in tolerance (needing more to get an effect over time). The tricyclic antidepressants also can be helpful at reducing chronic pain.

Neuroleptic medications, such as Seroquel (quetiapine), Zyprexa (olanzepine), and Risperdal (risperidone) can be extremely helpful, both for insomnia and daytime anxiety. Like the antidepressants, a person generally responds to a certain dose consistently over time, although dosage can be increased if medical symptoms worsen due to cortisol increases.

Anticonvulsant medications, such as Depakote (valproate), Tegretol (carbamazepine), Neurontin (gabapentin), and Gabitril (tiagabine) may be helpful for sleep, mood stabilization, pain, and anxiety. These can be combined with all of the above for enhanced effects.

Some medications can cause weight gain; this is hard to differentiate at times from weight gain associated with Cushing’s, but presumably if treated, Cushing’s and thus the use of medication for sleep should be short-term. Once Cushing’s is treated, significant weight loss is not uncommon, and people are often able to drop some or all over their psychiatric medications. Medications likely to cause weight gain include Remeron (mirtazepine), Zyprexa (olanzepine), Seroquel (quetiapine), Risperdal (risperidone), and Depakote (valproate). Some people will lose weight once anxiety and depression are controlled, so potential weight gain is not a reason to avoid a trial of medication. Often, a person will know if the timing of an increase in appetite corresponds with the start of a medication and, if so, alternate treatments can be tried.

A good night’s sleep is essential for mental health. Treating sleep may not totally relieve daytime anxiety and mood states resulting from high or low cortisol, but it an important building block of well-being.

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Part 3: Concentration and Memory

What can be done to improve concentration and memory problems with Cushing’s?

Resolution or control of cortisol issues may help normalize these functions. Treatment of depression may also help. Stimulant medications, like Ritalin, Adderall, Concerta, Metadate, methylphenidate, dextroamphetamine, have demonstrated benefits on concentration, attention, and organization. They may help with memory if memory impairment is affected by loss of concentration.

Caution should be used with patients who have high blood pressure.

Are the memory and concentration impairments caused by Cushing’s reversible?

The brain does not function normally in any respect in a high-cortisol state. Research done by Monica Starkman et al at the University of Michigan demonstrated actual decreased brain volume in certain areas of the brain associated with elevated cortisol levels, stress, or both. One area of the brain most affected is the hippocampus, an area critical in memory. Normalization of cortisol levels does produce some reversal of this low-volume state, and some who have had Cushing’s find significant improvement of their cognitive function when they are cured.

Unfortunately, many continue to have some degree of difficulty with brain function, even a year or more after successful treatment. It is sometimes difficult to assess the level of loss and recovery in that there are age-related memory deficits which are normally-occurring, and depression due to having serious medical illness can also cause problems with memory and focus.

Are there any treatments for memory loss and concentration?

The first treatment is eliminating the high cortisol levels by treating the cause of Cushing’s Syndrome. Improvement in cognitive functioning will likely occur in time.

Stimulant medications, like Ritalin and Adderall, can help with concentration, and through this means sometimes help also with memory, in that a person who focuses longer may have more time for input to the memory areas of the brain. These medications are safe unless a person has heart disease or uncontrolled high blood pressure.

The antidepressant, Wellbutrin, has attention and focusing effects as well as anti-depressant effects, and Cushing’s patients may benefit from all of these. Energy level also improves with Wellbutrin, although some patients experience this increase as anxiety, and thus dosage levels must be geared to the best overall effect.

Provigil (modafinil) can be given for fatigue related to medical conditions and may help with alertness, concentration, and overall functioning and is not thought to be problematic for blood pressure or cardiac function.

A variety of herbal and alternative substances have been marketed for concentration problems, though without the level of research documentation which leads to recognition as legitimate treatments.

<3>Are the memory and concentration impairments caused by Cushing’s reversible?

The brain does not function normally in any respect in a high-cortisol state. Research done by Monica Starkman, M.D. et al at the University of Michigan demonstrated actual decreased brain volume in certain areas of the brain associated with elevated cortisol levels, stress, or both. One area of the brain most affected is the hippocampus, an area critical in memory. Normalization of cortisol levels does produce some reversal of this low-volume state, and some who have had Cushing’s find significant improvement of their cognitive function when they are cured. Unfortunately, many continue to have some degree of difficulty with brain function, even a year or more after successful treatment. It is sometimes difficult to assess the level of loss and recovery in that there are age-related memory deficits which are normally-occurring, and depression due to having serious medical illness can also cause problems with memory and focus.

A few helpful hints….

Not all internists, endocrinologists, and family doctors are familiar with the treatment of concentration and memory problems. Certainly it makes sense to accept initial treatment for all symptoms of Cushing’s, including depression, anxiety, insomnia, and concentration problems from one’s treating physicians. Patients should not hesitate to pursue further expertise from psychiatrists if concentration and memory continue to be problematic after trial of antidepressants or anti-anxiety agents, whether effective or not. Even when depression is ongoing, use of focusing agents described above may offer a significant quality-of-life improvement. Cushing’s is a complex illness, and the use of multiple treatments may be just what it takes to achieve quality of life. Go for it!

Author: Dori Middleman, M.D. (Summer/Fall 2004)

Editor’s Note: Dori Middleman, M.D. is a child and adult psychiatrist in private practice in Merion, PA. Dr. Middleman has experienced Cushing’s herself and can be contacted by emailing the CSRF.