[1] Which of the following agents is contraindicated in a patient with epilepsy?

A. Bupropion

B. Fluoxetine

C. Mirtazapine

D. Venlafaxine

[2] The antidepressant action of imipramine is thought to be caused by which of the following?

A. Blockade of prejunctional α₂-adrenoceptors

B. Blockade of prejunctional neuronal norepinephrine and serotonin uptake transporters in the CNS

C. Increased numbers of β-adrenoceptors

D. Inhibition of monoamine oxidase

[3] Which of the following antidepressant agents inhibits hepatic microsomal enzymes to cause clinically significant drug-drug interactions?

A. Fluoxetine

B. Imipramine

C. Phenelzine

D. Trazodone

Answers

[1] A. Bupropion causes seizures in a small but significant number of patients. This number is reduced with use of the slow-release form.

[2] B. Imipramine and other TCAs block prejunctional neuronal norepinephrine and or serotonin uptake transporters in the CNS. Phenelzine and tranylcypromine inhibit monoamine oxidase. The heterocyclic agent mirtazapine blocks prejunctional α₂-adrenoceptors to enhance serotonin and norepinephrine neurotransmission.

[3] A. The SSRI fluoxetine inhibits cytochrome P450 and therefore can significantly elevate the level of other drugs metabolized by these hepatic enzymes.

Pharmacology pearls

SSRIs are the most commonly prescribed antidepressants because of their favorable side effect profile. Sexual disturbances and GI effects are common, however.

TCAs may lead to toxicity as a result of cardiac arrhythmias.

The antidepressant agents are roughly equivalent in their therapeutic action. However, individual patients may respond to, or tolerate, one better than another.

Small beginning doses of many antidepressant agents are usually preferred because with time tolerance may occur to some of their adverse effects.

Bupropion is contraindicated in patients with seizure disorders.

Answer. Your story, unfortunately, echoes those of millions of individuals who suffer from severe, major depression. Some day, you may look back at what happened following your suicide attempt and feel that you were given a second chance to succeed at life. While I don’t have any magic solutions for you, I do want to offer you the perspective I have gained after having treated many hundreds of such patients.

First: Depression is a treatable and reversible condition, even when several therapies or medications have failed. There are still many treatments that could be tried and which I have seen work. It might be frustrating, but not all treatments are beneficial to an individual patient. You should talk to your psychiatrist about both your ongoing feelings of hopelessness and possible trials on some of the newer antidepressants, such as Effexor and Remeron. And, whatever you may have heard about ECT (electroconvulsive therapy), do not exclude this as a treatment option! I have seen ECT work for people who were virtually at death’s door. It is safe and very effective.

Second: In all my years of treating depressed patients and working with their families, I have never seen a single instance in which the family truly felt they would be better off without their depressed family member. That’s right, not once. This belief is virtually always a symptom of severe depression. In fact, suicide is usually a devastating emotional blow to a family, from which recovery is extremely difficult. Some families never recover from losing a loved one in this way.

Third: You are not alone. If you have not yet joined the National Depressive and Manic Depressive Association (NDMDA), I would urge you to do so. They provide support and peer counseling for thousands of individuals with depression; you can call 800-826-3632 for local referrals. You can also contact the National Mental Health Self-help Clearinghouse (800-553-4539). These groups should supplement, not replace, the help you are already receiving. Also keep in mind that the Samaritans provide 24-hour anonymous telephone counseling for suicidal individuals (ask your telephone operator for the number).

Finally, depending on your spiritual and religious orientation, consider some form of pastoral counseling; not as a replacement, but as a supplement to your therapy. I know it may be hard for you to believe there is a light at the end of the tunnel, but I hope you can believe that I believe that. Good luck…

Answer. I am providing you with a list of commonly used antidepressants, as well as their usual doses:

Maintenance Dosage and Tablet Size for Non-MAOI Antidepressants

With respect to non-addictive medications for anxiety, it is first important to realize that the term addiction is defined in many ways. The medications most commonly used in the treatment of anxiety – the benzodiazepines, such as Valium, Librium, Ativan, etc. – are not highly addictive for the vast majority of people who are prescribed them for the right reasons. These agents may be abused or become habit-forming, however, in individuals with a history of alcohol and substance abuse, and, very rarely, in individuals who do not have such problems. The antianxiety agent buspirone (BuSpar) is a good alternative, and is not habit-forming or prone to abuse; however, while buspirone is useful for generalized anxiety, it is not helpful for panic attacks or obsessive-compulsive states.

Sometimes, low doses of the older tricyclic agents, such as doxepin 15-25 mg/day, may be useful for generalized anxiety in patients who are not good candidates for benzodiazepines. If you want more details about available medications for mood and anxiety disorders, you may want to call the NIMH Depression Awareness program.

Answer. I certainly appreciate how frustrating and difficult this situation must be for you, your father, and your family. Most of us have had elderly relatives or friends with depression, and it is truly a terrible illness. While treatment is effective in most cases, your father demonstrates that, unfortunately, this isn’t always so.

Without evaluating your father, I’m not in a position to recommend any specific treatment. But I do have some ideas that you and your father’s doctor may want to discuss.

First, I think establishing the correct diagnosis is crucial. Depression and tiredness are very general terms, and may be due to a variety of underlying medical and neurological disorders, including low thyroid function, repeated small strokes, or medication side effects. Has your father had a complete medical and neurological evaluation? If not, getting him seen by a specialist in geriatric medicine or geriatric psychiatry would be advisable, even though this won’t be easy for you. If there is a medical school Department of Psychiatry near you, this might be a place to start. Or, you can try logging on to www.elderweb for resources.

I don’t know what your father has already taken in the way of medications, but here are some options to consider: bupropion [Wellbutrin], venlafaxine [Effexor], mirtazepine [Remeron], methylphenidate [Ritalin], or a special type of antidepressant called a MAOI. This last option would require careful dietary monitoring and would need to be compatible with other medications your father may be taking. The older tricyclic antidepressants have fallen out of favor, but they may actually be superior to newer agents for elderly depressed patients; e.g., nortriptyline [Pamelor] is worth considering. A number of these agents may also be used in combination (except for the MAOI). A new agent called modafanil [Provigil] is now being used to treat excessive daytime sleepiness in patients with narcolepsy, and is being investigated as an adjunctive treatment for depression, but this has not yet been approved by the Food & Drug Administration for use in depression.

Finally, if your father had only unilateral (on one side of the brain) ECT, a trial of bilateral ECT should be considered. I think it will be critical, however, to find an experienced geriatrician who can at least follow-up on your father’s response from time to time. If your local doctors can’t do this, the Internet now can connect them to a number of experts worldwide. I hope your father finds some help soon.

Since you say you “cycle” into depression, I would certainly make sure that you do not have a cyclical mood disorder, such as bipolar (manic-depressive) disorder. (You did not mention any mood stabilizers in your list of medications, and these might be worth discussing with your psychiatrist.) There are many new medications available for depression, such as venlafaxine (Effexor), mirtazepine (Remeron), and citalopram (Celexa), and the fact that you did not respond well to the ones you mentioned does not mean that you will not respond to these newer agents.

A MAOI (a special type of antidepressant) would also be worth considering. Both ECT (electroconvulsive therapy) and a new technique called TMS (transcranial magnetic stimulation) could be beneficial as well. Any medication should be used in the context of a supportive therapeutic relationship with a mental health professional. You could also benefit from participating in a support group for depressed individuals. And if you have not yet joined the National Depressive and Manic-Depressive Association, I would encourage you to do so. Don’t give up – there is effective help out there!

Answer. You are raising a very important question, which, unfortunately, has not been settled by any good, controlled studies. The pharmaceutical representative is correct that Zoloft has greater dopaminergic activity than Prozac. In theory, this ought to be of some benefit in Parkinson’s disease, but I have seen no comparative studies (e.g., Zoloft vs. Prozac). All agents of this type, called SSRIs, have the potential of worsening tremor and other parkinsonian symptoms; that includes Zoloft, Prozac, Paxil and Luvox.

The problem is, there are few alternatives that have a comparable safety factor in elderly patients. The old tricyclic antidepressants (amitriptyline, nortriptyline) have a beneficial effect in Parkinsonism, because they reduce a brain chemical called acetylcholine. Unfortunately, this same effect can cause dry mouth, blurry vision and often memory impairment. Furthermore, the tricyclics can cause various cardiac problems. Wellbutrin is a nontricyclic, non-SSRI that has had mixed results in Parkinsonism, but is generally quite safe in the elderly. There are still insufficient data on very new agents, such as Effexor or Remeron.

Frankly, if your relative did well on Prozac initially, I would consider a retrial at a lower dose (e.g., 5-10 mg/day or even every other day). Some patients can get an antidepressant effect from Prozac even taking it 3 times per week, since it is so long-lasting. Another option that could be considered is L-deprenyl (if he is not already taking this). This is an agent used for both Parkinson’s and depression. I would suggest a good consultation with an experienced geriatric psychiatrist, working in concert with a neurologist.

Question. I am 19 and have experienced depression for over two years. My doctor recently prescribed Serzone, which caused severe headache, nausea and strangely hot skin. Then he switched me to Paxil, which caused severe nausea and vomiting. I have not returned to my doctor because he assured me the Paxil would not cause me to become ill. I am very nervous about trying further treatment, but I am still depressed. What do you recommend?

Answer. First of all, I recommend gaining some perspective on your problem with medication. It is quite common for patients to have a negative experience with one or two medications, before finding that another one works very well for them. Both of the medications you tried affect mainly a brain chemical called serotonin. This is also found in the GI tract, and sometimes this type of medication can cause nausea, vomiting, etc. I would suggest discussing a trial on Wellbutrin with your doctor, since this rarely causes GI side effects. However, I do not want to assure you of a good response! The only sure thing in the field of medicine is that illness is always a reality, and that hope is always worth having. Some patients may experience mild jitters with Wellbutrin, as well as other potential side effects that you should discuss with your doctor. But most patients tolerate it very well.

Some patients who cannot tolerate one of the SSRIs (Prozac, Paxil, Zoloft, Luvox) still tolerate another, and this is a viable option if Wellbutrin doesn’t work for you. I would start off with very low doses of any SSRI, and increase the dose very slowly. If you did have GI complaints, a medication called ondansetron could be used to counteract nausea. Another option would be a low-dose trial of nortriptyline, one of the older (but very reliable) tricyclic antidepressants. Tricyclics can cause dry mouth, constipation, and occasional lightheadedness, but usually don’t cause nausea, vomiting, or headache. Remeron is a new antidepressant with a low incidence of nausea or headache, and might be tolerated better than the SSRIs, but can be quite sedating. Remeron also has a 1 in 1000 risk of a fairly serious blood abnormality, so it is not a first-line agent.

The bottom line is, there is no perfect antidepressant. In your case the motto should be start low, go slow, with dosage. Finally, if you really do not want to go through multiple medication trials, I would strongly urge you to get involved in psychotherapy, if you are not already. Cognitive-behavioral therapy has a particularly good record in the treatment of depression. Indeed, I would recommend CBT with or without a medication trial. Good luck, and don’t give up!

Question. I have a friend who inhaled gas three times in his youth. He is very smart and has a great memory, but has severe depression. Is there a drug or specific combination of drugs that would help? He has tried Luvox, Zoloft and Paxil.

Answer. Inhalation of cleaning solvents, paint, glue, gasoline, etc. is a significant public health problem and may be a stepping stone to other kinds of drug abuse. For a review, see Westermeyer J, American Journal of Psychiatry, July 1987. While chronic, repetitive inhalation can certainly cause brain damage, memory impairment and trouble concentrating, it is not clear that a few exposures (as with your friend) could produce either significant brain damage or a persistent mood disorder, such as depression. Major depression has been reported as part of the early phase of abstinence from inhalant abuse and may respond to standard antidepressant and psychotherapy.

There is some question as to whether psychiatric symptoms in the context of inhalant abuse is due to the chemical per se or to preexisting, perhaps genetic tendencies (e.g., one Japanese study suggests that psychotic symptoms in inhalant abusers are often associated with a family history of schizophrenia). Thus, in your friend’s case, I wonder if he might have developed depression regardless of the exposures to gas. In any case, his failure to respond to three antidepressants does not mean that he requires some special treatment, beyond those used for resistant depression from any cause. He may benefit from combination strategies (e.g., Prozac plus a tricyclic or Ritalin), from newer agents (such as Effexor or Remeron) or from electroconvulsive therapy. I would advise him to get a good psychopharmacology consultation from someone specializing in mood disorders. Psychotherapy, of course, should also be a part of the treatment.

Question. I have had several bouts of depression in my life. Over the past six months, I have had recurrent periods of despondency and hopelessness. Medication has helped, but has also resulted in total loss of libido, fatigue and a lackluster interest in life. I want off the drugs. I am asking my doctor to evaluate me to determine if there could be a medical basis for my fatigue and depression, and then I want to find someone to help manage my care. What do you think?

Answer. My first suggestion is exercising caution about discontinuing medication for your depression. If you have had recurrent periods of despondency and hopelessness over the past six months, as well as several bouts of depression, I would seriously consider staying on some type of antidepressant medication. Yes, it is important to rule out underlying medical causes for depression and fatigue. Checking thyroid function, B-12 and folic acid would be a start, along with a physical exam. However, it is possible that your symptoms of despondency and hopelessness need to be distinguished from loss of libido and blahs. The first two symptoms may represent unresolved depression. The other symptoms may also be due to depression, but could represent treatable side effects of your medication. Long-term use of Prozac and similar medications can occasionally produce a state of apathy or lack of emotional reactivity that differs from clinical depression. Prozac-type medications (though good antidepressants) may also produce sexual dysfunction.

It may be tempting to get off all medications, but I would work with a skilled psychopharmacologist to examine alternative medications (e.g., a small amount of Ritalin) which can often jump start Prozac-type medications that have petered out over time, as well as reduce sexual dysfunction. Wellbutrin may also have this effect when added to Prozac. Alternatively, Wellbutrin alone may be helpful with depression without causing fatigue and sexual dysfunction. Sometimes, a slight reduction in Prozac dose can actually improve outcome in some patients, perhaps accompanied by an augmenting agent, such as methylphenidate. Other medications to consider include Effexor, Serzone and Remeron, which may have lower rates of sexual dysfunction than Prozac. However, Serzone and Remeron are quite sedating.

Depression, unfortunately, tends to be a recurrent illness and if an individual has had three or more bouts of major depression, the risk of a relapse is high without ongoing medication. This is not to underplay the role of psychotherapy, which I consider very important in treating depression. If you are not already seeing a psychiatrist, I suggest you try finding one who has experience with the pharmacologic treatment of depression. Getting a referral from your doctor would be a good start.

Answer. Unfortunately, the scenario you describe is not uncommon with Remeron. Significant weight gain occurs in at least 10% of patients and probably more. Other side effects with Remeron include increased appetite (15% of patients), drowsiness (36%), dry mouth (10%) and constipation (6%). There is also a rare blood disorder that can occur in about 1 in 1000 patients (agranulocytosis), though that figure may be an overestimate. It is always difficult to advise a patient who is otherwise feeling good on a medication, but is gaining a great deal of weight. There is no easy solution to this. It is important both to reduce dietary fats/sugars and to increase one’s daily exercise. It’s also important to make sure that the patient’s thyroid is not underactive. But even after doing these things, many patients do not lose the weight they have put on. Unless your wife’s weight gain puts her into the obese range, I would not advocate use of the new weight loss medications such as fenfluramine and phentermine; I think these can have their own risks when used long term.

It might be possible to reduce the dose of Remeron slightly and to try augmenting it with another antidepressant that does not promote weight, such as Wellbutrin or Ritalin. However, these combinations have not been studied systematically. I do recommend getting some dietary counseling from a registered dietitian. You would be surprised how many high-fat foods people eat without being aware of it. And anything your wife can do to increase her exercise, even adding 15 minutes of walking each day, will help keep off the pounds.