Answer. I would need to know more about your medication regimen; i.e., do you take the 200 mg of Serzone as a single dose or in two or three doses? At what times of day? If you are now taking the Serzone as a daytime dose, I would try shifting most or all of it to bedtime. Splitting up the total dose into 2 small (25 mg) doses and taking the remaining 150 mg at bedtime might work for some patients, without compromising efficacy. If you are already taking the Serzone in this way and are still feeling heavily sedated all the time, there are two equally reasonable options, in my view:

1. Switch to a less sedating agent (e.g., fluoxetine [Prozac] or sertraline [Zoloft]); or

2. Add a small amount of a stimulating agent to the Serzone, such as methylphenidate (Ritalin), bupropion (Wellbutrin) or caffeine. Caffeine, however, may exacerbate anxiety in some patients.

Some patients may tolerate an alternating schedule of, say 200 mg of Serzone one day, 150 mg the next, etc. Have you tried cutting down the Serzone by just 25 mg/day? It may be that if you can cut it down to the point that you no longer feel so drowsy, a small amount of Wellbutrin (e.g., 37.5 mg per day) could be added to augment the Serzone’s antidepressant effect–Wellbutrin does not have very good antianxiety properties. If the first option is used, I would start very low with the Prozac or Zoloft dose, in order to avoid initial worsening of anxiety; e.g., 5 mg per day of Prozac or 12.5-25 mg of Zoloft. You might need to buy a pill-cutter.

Which path to take would depend, in part, on whether you wanted to accept he risk-benefit ratio of a second (augmenting) agent, vs. the risk-benefit ratio of trying a new and hence uncertain, medication. My general rule is “build on strength.” Try to work with and around the first successful agent, if possible. By the way, are you certain that your TSH is now normal? (In most labs, below 4.5-5.0.) Borderline hypothyroidism can certainly contribute to low energy and delay antidepressant response.

Answer. I admire your tenacity, after all these complications with your treatment. So, let’s go through each of your questions and see if it leads to some treatment options to discuss with your doctor. First, I think buspirone augmentation can be helpful, particularly if there is an anxiety component to the depression. In fact, there are studies showing that buspirone alone, and in high doses (at least 50 mg/day) has antidepressant properties. Pindolol studies have yielded mixed results, and this may vary from SSRI to SSRI, but I think the risks are so minimal that it might be worth trying in your case. Other medications to consider as augmenters to SSRIs would include methylphenidate (Ritalin), which works well, in my experience, but could be overstimulating to you (if it were used, I’d start with 2.5 mg per day and hold it there for a week). Alternatively, you (with your doctor’s approval, of course) could try stopping the tyrosine for a week or two, then re-starting it. Sometimes this strategy works with the SSRIs as well, though some patients may experience mild-to-moderate withdrawal symptoms (flu-like symptoms) when a short-acting SSRI (Paxil, Zoloft) is suddenly stopped–so a tapering period might be better, followed by 1-2 weeks off, then a restart.

Another option would be to add a dopamine agonist, such as pergolide. I have seen this help in one case of very resistant depression. Here, too, I’d start low, and go slow with the dose. The combination of the MAO-B inhibitor selegiline (L-deprenyl) in combination with phenylalanine (another amino acid precursor) has been reported helpful. To use L-deprenyl, you must be off Zoloft for at least two weeks. You did not mention Serzone…if you haven’t tried this, it could be used in low doses in combination with the Zoloft, or as a single agent in much higher doses. Or, Serzone could be used in combination with most of the other agents mentioned above, except an MAOI. I don’t know if you’d consider treatment in Canada, but they do have a unique MAOI up there–moclobemide–that is not available in the States. It might work for you, even though two previous MAOIs did not. Moclobemide can usually be obtained via a cooperative arrangement between your doctor and one up in Canada. Then, there’s always St. John’s Wort, but we know so little about how well this works, or if it can be combined safely with standard antidepressants, that I can’t really recommend it.

Since you have been through the pharmacologic ringer, I think you should at least consider something that we know does work, and that is ECT. This is a safe and very effective treatment for major depression, and can be used on a maintenance basis.

As to the mechanism of “poop-out” – the undignified name says a lot about our state of knowledge. It doesn’t really fit the usual definition of tolerance since dosage increases may or may not help (with tolerance, an increase in dose virtually always – by definition – brings about a renewed response). Dopamine depletion from the SSRI is plausible, and goes along with the observation that some patients who experience this fading out of SSRI effects also experience a sort of emotional flattening and decreased response to rewarding stimuli (e.g., sex, good times, etc.). Since the reward system is mediated in large part by dopamine, this all hangs together. That may be why methylphenidate (Ritalin), which has dopamine enhancing properties, sometimes restores the SSRI response. On the other hand, the apparent success of pindolol – which basically unlocks the valve on the neuron that produces serotonin – suggests that serotonin slow down may underlie this loss of SSRI effect. I don’t think it is a pharmacokinetic effect in most cases. I do wish you and your doctor the best in dealing with your problem, and don’t give up!

Answer. I wish I had some insight that could unify all the various elements of your case, but I’m afraid I don’t. This is partly because of the complexity of your question, and partly because the circumstances as you’ve described them don’t permit a neat pharmacologic “dissection” of the facts, a result of the way you were taking the medications.

First of all, I would have to say that the reactions you describe strike me as uncommon, but that may be because few such interactions have been published, rather than because they don’t occur. However, my guess is that your nervous system is unusually sensitive to either the single agents you list or to some interaction between them. Let’s start with the Ambien. Ambien itself (i.e., taken without any concomitant medications) can, in less than 1% of cases, cause unusual reactions, including visual distortions, aggressive reactions, manic states and panic attacks. We don’t know whether Ambien alone might have given you some problems. Could it have “negated” the effects of the Luvox? I doubt that a single dose of Ambien could have had any significant effect on the total amount of Luvox in your system; however, since both Ambien and Luvox are bound to “carrier proteins” in the blood, it is theoretically possible that the Ambien displaced a large amount of the Luvox from its carrier proteins, caused a sudden (very brief) surge of “free” Luvox in your brain and somehow negated its own beneficial effects.

Something similar can sometimes be seen in patients with obsessive-compulsive conditions, in which the neurotransmitter serotonin is thought to be deficient (as it is in some depressive states). When we give such individuals chemicals that stimulate serotonin receptors in the brain, they sometimes, at first, get worse; perhaps because their serotonin receptors are overly sensitive. Over longer periods of time (i.e., 6-12 weeks) agents like Prozac and Luvox, which also boost serotonin, are thought to gradually “down regulate” the oversensitive serotonin receptors and restore them to their natural state.

So, thinking very theoretically, it is possible that the Ambien displaced the Luvox from its carrier proteins, caused a sudden, brief surge in your nervous system, which overstimulated your serotonergic system for a few days. However, it is also possible that the Luvox and Ambien interfered with each other’s metabolism (elimination) in some way that led to elevated levels of one or both agents. Now, as to antihistamines and decongestants, it is not clear to me whether these agents have caused intense anger and social withdrawal in you when taken alone or only in combination with Luvox. If the former is the case, I would guess that you have an unusual sensitivity to these agents. More specifically, if you have this reaction to medications such as Actifed and Sudafed – but not to diphenydramine – you may have an unusual sensitivity to pseudoephedrine, a stimulant/decongestant found in Actifed and Sudafed. (Diphenhydramine is an antihistamine). Actifed is actually a combination of pseudoephedrine and the antihistamine tripolidine, so it is possible that you react to the tripolidine. I am not aware of any of these antihistamines or decongestants interacting adversely with Luvox; however, two non-sedating prescription antihistamines (terfenadine and astemizole) may have adverse interactions with Luvox, since Luvox may reduce metabolism of these agents.

My suggestion would be to keep a careful record of your reactions to medications and discuss them with a psychopharmacologist; in the mean time, you might want to avoid use of pseudoephedrine-containing medications. By the way, it may be better for your sleep-wake cycle to use the trazodone on a regular basis, in very small doses (e.g., 25 mg), rather than sporadically; it is not habit-forming and the regularity may help stabilize your sleep-wake cycle.

Answer. I am not sure I entirely agree with the premise of your question, though I do think you are on to something. In my experience as a psychiatrist, most severely depressed men, like most severely depressed women, satisfy most of the typical DSM-IV criteria for major depression. There are exceptions, of course, so-called “atypical” depression with its anxious, phobic, somatizing features; hypochondriacal forms of depression; depressive states expressed as chronic pain, etc. But in the main, I have always found the DSM criteria a very useful starting point for diagnosing depression in men or women.

There is some evidence that women experience more depressive symptoms for a longer period of time than do men. But at least one large study found men and women with major depression (Research Diagnostic Criteria) to have quite similar symptom profiles, on the whole.

That said, I do think that men may show some differences in the way they express depression, perhaps reflecting the divergent cultural influences on men and women in Western society. (I can’t rule out inherent biological differences, either). I think men more often fit Peter Sifneos’ description of alexithymia than do women; i.e., the men are often woefully unable to recognize or at least verbalize their feelings. At times, this seems to be part of the macho culture of the “strong, silent type” epitomized by John Wayne. So, as I’m sure you’ve found, when you ask some men if they are depressed, they may shrug their shoulders and say, “No way, Doc! I just wanna kill myself.”

Even the Frank et al study found some differences between men and women; e.g., women reported more appetite and weight increase, more somatization, and showed greater levels of expressed anger than men. The women also took longer to respond to treatment. Re: alcoholism and sociopathy, there is a school of thought that views these conditions as “the man’s way of expressing depression”. However, I don’t think there is compelling empirical evidence for this; e.g., most studies of alcoholism and depression have found that these are independent disorders. For more details on this interesting issue, you may want to see the chapter by Wolk & Weissman in the American Psychiatric Press Review of Psychiatry, volume 14, 1995. Good luck with your research!

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 appreciate that this is a painful situation for you, but I am a bit unclear as to what, precisely, is causing your lives to become more out of control each day . First of all, I would be interested to know what the psychiatrists said about your son, besides that he is a mad or sad child. Did they feel that he is clinically depressed or in need of an antidepressant? If not, what did they recommend? Did they feel that your son was reacting normally to a very difficult situation?

Clinical depression is certainly a different condition from being angry and upset over the very difficult issues in your lives. I do not believe it would be warranted to expose your son to the side effects and risks of an antidepressant medication simply on the basis of his genetic loading, though that, indeed, is a risk factor for clinical depression. It would really depend on the symptomatic picture your son is presenting, which is not provided in your question. Symptoms such as marked irritability, aggressive behaviors, deterioration in school performance; or more classically depressive symptoms, such as poor sleep, poor appetite, expressions of hopelessness, guilt, low self-esteem or suicidal statements, might persuade me that a trial on Prozac is appropriate.

If you and your son are now involved in counseling/psychotherapy, I think you are already taking the right step. If not, it certainly sounds like both of you could benefit from therapy. You might also look into support groups for both you and (separately or together) your son. I think such groups can often be more helpful than individual therapy. If you believe strongly that your son merits a trial on an antidepressant, I would suggest an evaluation through the child psychiatry department of a teaching hospital or medical school. You may also wish to contact to the American Academy of Child and Adolescent Psychiatry at 3615 Wisconsin Ave. NW, Washington DC 20016 or call (202) 966-7300 for resources, booklets and referral sources in your area. Good luck.

Answer. There is a good deal of interest in the use of herbal remedies for the treatment of depression, as well as in the use of naturally-occurring precursors (building blocks) of various brain chemicals, called amino acids. The most persuasive literature on herbal treatments involves the use of St. John’s Wort (hypericum perforatum); this is reviewed in an article by Ken Bender in the October 1996 Psychiatric Times. German researchers recently published an analysis of 23 trials of this herb, in a total of over 1,700 patients with mild to moderate depression, and concluded that it is superior to placebo and comparable to standard antidepressants, while producing fewer side effects; however, there is very little in the American literature on this and I would reserve judgment regarding severe or psychotic types of depression.

Many studies have suggested that amino acids – which are naturally occurring building blocks of proteins – may be useful as adjunctive treatments of depression. L-tryptophan, phenylalanine and tyrosine have all shown some promise, though few controlled studies exist. (L-tryptophan was removed from the U.S. market some years ago due to a contaminant.) If you want more information on natural approaches to illness, you may want to subscribe to the Review of Natural Products, published by Facts and Comparisons, 111 West Port Plaza, Suite 300, St. Louis, MO 63146-9811. But remember, the word “natural” does not always mean safe. Many herbs and plant substances found in health food stores – and not approved by the FDA for use in any illnesses – contain compounds that can produce serious side effects. Thus, it is important to check with your doctor before setting out on any kind of self-medication venture using natural products.

Answer. Well, the media are often ahead of the scientists on these things, but I must say I am very skeptical about the 5-HTP story (although I did not see the Prime Time piece). By the way, 5-HTP is the precursor chemical for serotonin, which as you probably know is the neurotransmitter heavily involved in depression, appetite regulation, pain perception and sleep. In the first place, very few clinicians, to my knowledge, are prescribing or recommending 5-HTP to patients, at least among psychiatrists. Thus I suspect we are hearing about a handful of “testimonial” cases rather than seeing the results of methodical research or even clinical case reports. In fact, I didn’t find a single clinical case report or recent controlled study of 5-HTP for the uses you mention in the professional literature within the past 5 years!

However, there was one report in the British Journal of Psychiatry (July 1985 pp. 16-22) comparing the L isomer of 5-HTP with a classic antidepressant called tranylcypromine (termed an MAO inhibitor). These patients had not responded to several antidepressant medications, including SSRI-type antidepressants like Luvox (fluvoxamine). Of 17 patients given L-5-HTP, none responded. In contrast, 15 of 26 responded to tranylcypromine. The authors concluded that L-5-HTP was not therapeutically effective in such refractory patients. Of course, the possibility remains that milder cases of depression may respond to 5-HTP.

A precursor of 5-HTP, tryptophan, was used for many years as a sleeping aid, before being removed from the U. S. market after contaminated batches caused serious muscle problems. Serotonergic agents in general are thought to reduce carbohydrate craving and promote weight loss. However, experience with the SSRI (selective serotonin reuptake inhibitor) group of antidepressants – Prozac, Zoloft et al – suggests that while they may initially take off a few pounds, the weight creeps back up over a year or two.

5-HTP is an interesting agent, and is used in research settings to “probe” the serotonergic system. However, I think it is far too early to conclude that it is safe and effective for any of the uses you mentioned.

Answer. There are numerous articles and studies on evaluating and treating depression in the medically ill. You may be interested in seeing the entire October, 1994 issue of Psychiatric Annals, which describes how depression may be mimicked by, and coincident with, a wide variety of medical and neurological disorders. More recently, the journal CNS Spectrums (April 1999) devoted its entire issue to “Psychiatric Aspects of Medical Illness.” There is also a fine article by Pierce and Glassman on “Treatment of depression in patients with heart disease”, in the May 1998 issue of the Journal of Practical Psychiatry and Behavioral Health.

Regarding the terminally ill, you may want to see the article by Block, from Dana-Farber Cancer Institute, on assessing and managing depression in the terminally ill patient. This is published in the Feb. 2000 issue of the Annals of Internal Medicine. One of the interesting points made in the Block article is that terminally ill patients usually do not have sustained suicidal ideation; and that when they do, an evaluation for depression should be carried out. Treatment in such cases may improve the quality of life in depressed, terminally ill patients

Answer. I know of at least one study showing no significant interaction between Prozac and alcohol, but everyone is different, and alcohol plus medication can interact in unpredictable ways. That’s why it is usually the doctor’s advice to avoid alcohol, or drink very sparingly, when taking psychotropic medication. It is possible that what you are experiencing are mild withdrawal symptoms as the alcohol is eliminated from your body, but this seems like a stretch to me.

For some people, even small amounts of alcohol can induce either depression or marked anger/aggression – perhaps you are experiencing a muted form of this reaction. (It would have been useful for me to know how you reacted to alcohol before you went on Prozac). Or, could it be that your feelings about drinking are affecting the way you feel the next day? There is some evidence that guilt feelings can worsen hangover from alcohol. I suppose that if you really want to investigate this phenomenon, you could try drinking a non-alcoholic beer (without knowing that it is) and compare it with your reaction to a similarly blinded trial with a regular beer, but beer contains many substances besides alcohol, and you could react even to a non-alcoholic beer. Bottom line: is it really worth pursuing this issue? Maybe the most sensible thing to do is avoid alcohol while you are taking Prozac.