Question. I take Luvox 150 mg per day for chronic depression and obsessive anger problems. My psychiatrist is concerned about my sleep habits, which have basically been the same all my life; I cannot sleep at night, I only sleep soundly in the mid-morning hours. He prescribed Ambien to be taken at bedtime and it put me to sleep right away. I was delighted with that result, however, for two or three days after taking even just one dose, all the obsessive anger and intense depression symptoms would reappear, as if the Ambien negated all the beneficial effects of the Luvox. The psychiatrist prescribed trazodone as a sleeping agent, only to be taken as needed. Well, it works occasionally, but when it does work, I sleep not only through the night but most of the next day as well. But it doesn’t detract from the positive effects of the Luvox. I want to know how drugs such as Ambien and over-the-counter decongestants interfere with SSRIs like Luvox, if such interference is common and if these medications have any property that might cause these problems. Can you offer any insight?

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.

Question. Prime Time Live recently aired a story on treatment of depression, obesity and insomnia with 5-hydroxytryptophan (5-HTP). Is 5-HTP effective and safe?

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.

Question. Do you have a list of drugs for depression, and non-addictive medications for anxiety? Tricyclics of the older vintage would be helpful.

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.

Social phobia has recently been recognized as a chronic and often debilitating disorder. It is estimated to affect up to 10% of the population, with onset occurring early in life.l According to the DSM-IV, in order to be diagnosed with social phobia individuals must meet several criteria. They must have a persistent fear of one or more social or performance situations where they are exposed to unfamiliar people or to possible scrutiny by others. The essential fear of the patient is that he or she may act in a way that will be humiliating or embarrassing. Individuals may be fearful of specific situations such as speaking, eating or writing in front of others, or they may have generalized anxiety involving all social situations. In an attempt to abate their fear, patients will make an effort to avoid social situations. When unavoidable, these social situations provoke anxiety that causes the individual to experience panic-like symptoms (e.g., tachycardia, sweating, trembling, blushing and muscle tension) which continue to escalate throughout the situation. These individuals recognize that their fears are excessive and unreasonable but are unable to prevent their anxieties from interfering with their occupational, academic and social functioning.

While behavior therapy is considered an essential component of treatment, several classes of drugs have been found to be effective. Beta-blockers (atenolol, propranolol) have been used to control bodily symptoms (e.g., tachycardia, trembling and sweating), but their tendency to cause depression is a potential complication. Monoamine oxidase inhibitors (phenelzine, tranylcypromine) also have shown efficacy, but extensive potential for drug-drug and drug-food interactions that may predispose individuals to a hypertensive crisis have decreased their use in many disorders. Benzodiazepines (clonazepam, alprazolam) have also been shown to be effective. Recently, several selective serotonin reuptake inhibitors (SSRIs) have been used successfully to treat patients who suffer from social phobia.

Fluoxetine (Prozac)

A study by Van Ameringen et al. is the most recent open trial evaluating fluoxetine’s efficacy in social phobia. Sixteen patients suffering from social phobia as a primary diagnosis were administered fluoxetine (Prozac) for 12 weeks. Fourteen of the subjects suffered from other psychiatric disorders such as major depression, generalized anxiety, dysthymia and obsessive compulsive disorder. Doses of fluoxetine were initially 20 mg/day and were increased every four weeks according to clinical response and adverse effects. Patients completed various self-reported measures of anxiety, depression and social avoidance at baseline and at weeks 4, 8 and 12. The measures used were the Beck Depression Inventory, Social Avoidance and Distress Scale, Fear of Negative Evaluation Scale, Social Phobia Subscale and Social Anxiety Thoughts Questionnaire. A Clinical Global Improvement Score was also completed by physicians. Thirteen of the 16 patients completed the trial. Those who withdrew did so due to adverse effects. Ten of the 13 patients were considered responders to fluoxetine (Prozac) and three were considered nonresponders. The previously mentioned measures of social anxiety and phobia avoidance showed significant improvement from baseline (p < 0.005). Although the investigators concluded that fluoxetine was successful in treating social phobia, the results were difficult to interpret because 11 of the 13 subjects had comorbid psychiatric disorders known to respond to SSRI therapy. Therefore, the improvement seen may have been due to improvement of symptoms in the concurrent disorders rather than the social phobia.

Fluvoxamine (Luvox)

Fluvoxamine was compared to placebo in a 12-week, double-blind, placebo-controlled trial by Van Vliet et al. Thirty subjects who met the DSM-IV criteria for social phobia were included in the study. Unlike in the previous trial, subjects were excluded from participating if they had concurrent anxiety, depression or personality disorders. Doses of fluvoxamine (Luvox) were gradually increased from 50 mg/day to 150 mg/day over the course of the study. Seven of 15 patients treated with fluvoxamine (Luvox) experienced a statistically significant (p < 0.001) improvement by week 12, as defined by a reduction of 50% or more in the anxiety subscale of the Liebowitz Social Anxiety Scale. When social avoidance tendencies were examined, a nonsignificant improvement was seen in the fluvoxamine (Luvox) group. The investigators concluded that fluvoxamine appears effective in the treatment of social phobia. They suggest that the characteristic of avoidance indicates more resistance to treatment and patients with this characteristic may require longer treatment periods.

Sertraline (Zoloft)

A small, 22-week, double-blind, placebo-controlled crossover study (n = 12) involving sertraline was performed by Katzelnick et al. Subjects had no comorbid mood disorders and were relatively free from depressive symptoms. Sertraline (Zoloft) dosing was initiated at 50 mg/day and was increased by 50 mg every two weeks if there was no treatment response. A statistically significant improvement as measured by the Liebowitz Social Anxiety Scale, the primary outcome measure, was found with sertraline (p = 0.001) but not with placebo. While taking sertraline, 50% of subjects were rated moderately or markedly improved versus 9% of subjects with placebo. The mean daily dose for the sertraline (Zoloft) responders was 100 mg/day. Based on these results, the investigators concluded that sertraline appears to be effective in the treatment of social phobia.

Conclusion

SSRIs have a more favorable side effect profile and lower toxicity risk in overdose situations than other agents used for social phobia (e.g., MAO inhibitors, beta-blockers). In addition, they carry less risk of abuse and dependence than the benzodiazepines. For these reasons, it is hoped that SSRIs will prove effective for this disorder. The above studies show that fluoxetine, fluvoxamine and sertraline appear to be promising treatments. However, the current literature discussing these agents is limited to anecdotal reports, open studies and double-blind trials, each involving a small number of patients. Larger controlled trials comparing the SSRIs to current therapies must be performed before a definitive conclusion can be made on the role of SSRIs in the treatment of social phobia.

Currently, it is recognized that a comprehensive, personalized treatment plan is the best approach in dealing with social phobia. A combination of psychotherapy and pharmacotherapy is ideal. When choosing pharmacotherapy, a valid choice can be made from among selected benzodiazepines, MAO inhibitors or SSRIs. From these options, SSRIs may be a preferred choice when the patient has a comorbid diagnosis such as major depression or obsessive-compulsive disorder. By choosing an SSRI, the clinician is potentially treating several disorders with one agent. However, for a social phobia patient who does not have additional psychiatric disorders, no one agent is considered to be the treatment of choice, due to the lack of comparative trials. Therefore, the choice of an agent should be guided by carefully assessing the individual needs of the patient.

Question. I have a diabetic patient in her early 30s who is also exhibiting signs of anxiety and depression. She’s on 100mg Glucophage as well as 100u Humulin Ultralente and 100-150u Humalog (extreme insulin resistance). I am aware that some of her symptoms of anxiety may be related to the gastric side effects of the Glucophage and that her mood problem may be tied to the diabetes itself, but how would you go about ruling out these symptoms as true mental illness?

Answer. That’s a tough question. The bottom line is: if she looks depressed and anxious; sounds depressed and anxious; and acts depressed and anxious, it’s probably best to treat her as if she IS depressed and anxious. But let me back up and give you some background material, drawn from a chapter [in press] written by my colleague, Dr. David Harnett, and edited by Dr. Mantosh Dewan and myself. Depression in patients with diabetes mellitus is common; diagnostically vexing; often malevolent in its course; and frequently associated with poor blood glucose (glycemic) control and diabetic complications. The prevalence of major depression in diabetes-considering both Type I insulin-dependent diabetes mellitus [IDDM] and Type II non-insulin dependent diabetes mellitus [NIDDM] – is about 15 to 20% (Lustman et al, 1997b; Gavard et al, 1993). As with depression in the medically well, depression in diabetic cohorts is characterized by a positive family history of depression and typical depressive symptomatology (Lustman et al, 1992). Some, but not all, studies have found a female predominance of depression in diabetic populations (Lustman et al, 199; Popkin et al, 1988). As in other medical illnesses, diabetics may report apparent “depressive” symptoms such as weight loss, fatigue and hypersomnia that are actually a direct manifestation of diabetes. Indeed, disordered sleep may be characteristic of non-depressed diabetics. (Leedom et al, 1991) One clue to depression in diabetics is the patient’s amplification of somatic symptoms of physical illness, and his difficulty habituating to these aversive symptoms (Katon, 1996). For example, depressed diabetics may report polydypsia that is not correlated with elevated glycosated hemoglobin (gHb or Hb-A1C) values (Lustman et al, 1988b). (gHb reflects glucose control over the previous three months). The clinician’s misinterpretation of such “somatic” complaints may lead to underdiagnosis of depression in these diabetic patients. Mild hyperglycemia with associated polyuria, polyphagia, polydipsia, fatigue, blurred vision, or paresthesia may further confound diagnosis by mimicking hypochondriasis. (Kornstein and Gardner, 1993) Cognition may also be impaired by hyperglycemia, (Reed and Mooradion, 1998) especially in elderly diabetics, (Tun et al, 1990) but can be partially improved by better glycemic control (Meneilly et al, 1993, Testa and Simonson, 1998). Hypoglycemia may present with adrenergic symptoms such as anxiety, diaphoresis, tremor, irritability and palpitations. In the elderly, neuroglycopenic symptoms of hypoglycemia may be more likely, including dizziness, headache, weakness, tiredness, blurred vision, and confusion (Reed and Mooradion, 1998). Another potential variable contributing to depression in such patients is diabetes-related atherosclerotic brain disease causing “vascular depression.” (Alexopoulos et al, 1997). Accumulating research suggests that history of depression, and especially current depression, is associated with poor glycemic control as reflected in elevated gHb (Lustman et al, 1997b, Cohen et al, 1997.) It has even been suggested that major depression increases the risk for NIDDM. (Eaton et al, 1996) Poor glycemic control is clearly associated with diabetic complications. Yet the relationship between depression and diabetic complications is complex. While neuropathy (Leedom et al, 1991) and retinopathy (Cohen et al, 1997) for example, may act as psychosocial precipitants of depression, depression may well contribute to diabetic complications via impaired glycemic control. (Cohen et al, 1997) Depression may impair glycemic control because of lack of adherence to dietary and exercise programs. Obese NIDDM patients were less likely to complete a weight-control program if they had a history of major depression. (Marcus et al, 1992) Alternatively, depression may worsen glycemic control via neuroendocrine mechanisms. Possibilities include hyperglycemia secondary to depression-related hypercortisolemia and complex effects of depression on growth hormone. (Holsboer, 1995). In short: the differential diagnosis is a bear!
What about the treatment of depressed diabetics? SSRIs are certainly worth considering. An open, 10-week study (Goodnick et al, 1997) of depressed NIDDM patients given sertraline 50mg revealed significant improvement on two depression rating scales and dietary compliance. Modest improvement of gHb levels were seen. While SSRIs have advantages over TCAs in depressed diabetics, potential SSRI-related gastrointestinal distress and sexual dysfunction may be hard to discern in a multi-problem medical patient taking many medications. In addition, SSRI-related diarrhea may lead to hypoglycemia in IDDM patients ( Tanya Korkosz, MD, Personal communication 1998). Furthermore, diabetics receiving multiple medications must be monitored for the potential enzyme-inhibiting effects of the SSRIs. For example, the sulfonylurea agent tolbutamide, though now used less frequently, is a substrate for the hepatic cytochrome P450-2C9 isoenzyme, which is inhibited by fluoxetine (Prozac) and fluvoxamine(Luvox).(Harvey and Preskorn, 1996). Sertraline (Zoloft) or citalopram (Celexa) are much less likely to inhibit the cytochromes.
There are few relevant studies of other antidepressants in depressed diabetics. Warnock and Biggs (1997) described a 54-year-old depressed woman with IDDM treated with nefazodone (200-400 mg/day) who showed both a reduced need for insulin and a good antidepressant response. However, nefazodone, a potent P450-3A4 inhibitor, must not be prescribed in diabetics receiving cisapride – a pro-kinetic agent and P450-3A4 substrate sometimes used to alleviate diabetic gastroparesis as well as gastroesophageal reflux – because of potential Q-T prolongation and arrhythmia risk. (Janssen, 1998).
The evidence suggests that depression should be vigorously treated in diabetics. Hopefully, future research will verify that antidepressant treatment will improve not only immediate quality of life, but also the long-term course of diabetes mellitus. The clinician should probably be more willing to consider long-term maintenance treatment. While enthusiasm is warranted for the potential benefits of SSRIs over TCAs in depressed diabetes, such enthusiasm must already be tempered by the increasing realization that SSRIs may cause weight gain, (Sussman and Ginsberg, 1998a, 1998b, Richelson, 1998) especially when taken for many months. Perhaps the proposed benefits of SSRIs on glycemic control are also, to some extent, short-lived. This possibility was anticipated in the study, (O’Kane et al, 1994) mentioned previously, in which fluoxetine lessened weight and gHb of non-depressed obese NIDDM patients at 3 and 6 months, but not 9 and 12 months. Bupropion (Wellbutrin), nefazodone (Serzone) and venlafaxine (Effexor) may be less likely to cause weight gain (Sussman and Ginsberg, 1999).
Finally, I have found the Beck Depression Inventory to be a good guide to the presence of “true” depression, even in medically complicated patients. If your patient has a very high score on the Beck, I’d take that seriously, especially if guilt or self-deprecation are prominent. As for the anxiety component, venlafaxine is now FDA-labelled for generalized anxiety, but has significant GI side effects. If you use it, “start low (18.75 mg/day) and go slow.” Buspirone could also be considered. And, of course, getting a face-to-face consultation evaluation never hurts. Hope this lengthy response helps some!

Question. Can you please give me your opinion on the P450 inhibitory effects of SSRIs, namely, fluoxetine, paroxetine, citalopram, sertraline and fluvoxamine? Which appears to have the least clinically significant effects on this and other liver enzymes? How do these effects demonstrate themselves to patients? How clinically significant are the effects?

Answer. I’ll give you the bottom line first, then fill in some of the details: if you are only worried about inhibitory effects of SSRIs on the cytochromes, it’s best to avoid using fluoxetine [Prozac], fluvoxamine [Luvox], and paroxetine [Paxil]. Instead, go to either sertraline [Zoloft] or citalopram [Celexa]. Neither of these latter two SSRIs have substantial inhibitory effects on the cytochromes, though that doesn’t mean they are fail-safe medications.

Furthermore, for many patients, Prozac, Luvox, or Paxil may simply work better for depression. To cite some data from Dr. Sheldon Preskorn [see Harvey & Preskorn, Journal of Clinical Psychopharmacology, 1996; 16:273-85], “both fluoxetine and paroxetine have substantial inhibitory effects on the cytochrome P450 2D6 (CYP 2D6) system. Fluoxetine also has substantial inhibitory effects on CYP 2C9 and moderate inhibitory effects on CYP 2C19. Fluvoxamine has substantial inhibitory effects on CYP 1A2 and 2C19, and moderate effects on CYP 3A3/4.”

In and of themselves, these inhibitory effects rarely are felt by patients, unless they are taking some other medication whose blood levels rise in the presence of one of these strongly-inhibiting SSRIs. For example, someone taking the antipsychotic clozapine [Clozaril] may experience marked side effects (sedation, dizziness) if fluvoxamine [Luvox] is added. This is because clozapine is metabolized (in part) through CYP 1A2, which fluvoxamine strongly inhibits. In other cases, the psychiatrist may actually take advantage of these inhibiting effects, by using the SSRI as a kind of magnifying glass, that is, using it to boost blood levels of some other therapeutic agent, which is prescribed in a very small dose.

In other cases, the rise in blood levels effected by one of these SSRIs is clinically insignificant, from the patient’s standpoint. It is always a matter of the particular drugs involved, and the particular patient. For example, some patients may lack the CYP enzymes required to break down a particular drug, or have an unusually active form of the enzyme. You might want to get hold of some of Dr. Preskorn’s recent articles on this subject for further details.

Question. I have an 80-year-old relative with Parkinson’s disease and depression who was started on Prozac with good initial effects on mood and energy levels. Unfortunately, he complained of worsening tremor. A pharmaceutical representative for Zoloft has suggested that this antidepressant would be a better choice for use in patients with parkinsonian symptoms because it has some dopaminergic effects. Have there been any studies of patients with Parkinson’s disease suggesting which antidepressants, and presumably which neurotransmitter modulation, are most efficacious in treatment?

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 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 obsessive compulsive disorder and panic disorder. I was recently prescribed Luvox. I have had no adverse reactions, and my doctor insists that I up the dosage. On the Internet, I discovered that Luvox reacts with nicotine. I am a smoker and I wonder how they interact. I have noticed some benefit to taking Luvox and would like to increase the dose, but not at the risk of the unknown. Do you have any further information?

Answer. I am not sure quite what you discovered on-line, but my own literature search and a call to the makers of the Nicotrol patch turned up no reports of any adverse reactions with the combination of Nicotrol patch and Luvox-type medications (termed SSRIs, and including Luvox, Prozac, Zoloft, and Paxil). This, of course, does not prove that adverse reactions can’t occur

Since Luvox is a relatively new agent, it is certainly possible that you have uncovered a problem not reported in the literature yet (or reported to the makers of Nicotrol). There are some issues surrounding nicotine, antidepressants and depression that you may be picking up on-line. First of all, there have been some reports of depressive bouts occurring in patients who have a history of depression and who have suddenly quit smoking “cold turkey.” I have not seen this reported with OCD or panic disorder, but I wouldn’t discount the possibility.

It is also true that nicotine in various forms can induce or activate the enzyme system in the liver that breaks down some antidepressant drugs, including some tricyclics like imipramine. Since the metabolic route for fluvoxamine (Luvox) is not well-described, it is theoretically possible that nicotine (either smoked or via patch) might affect the metabolism of Luvox. Indeed, I know of one report showing that smokers have a 23% reduction in fluvoxamine levels compared to nonsmokers (van Harten et al, Clinical Pharmacology & Therapeutics, 1992;52:427-35).

Conversely, it is known that Luvox inhibits an enzyme system in the liver called 1A2. This is the same system induced by nicotine. It is theoretically possible that Luvox might raise nicotine levels by inhibiting the 1A2 system, but it is not known (at least by me, or the makers of Nicotrol) which enzyme system breaks down nicotine. In short, I have no information suggesting that you would be at any significant risk by using Luvox with nicotine, but I cannot absolutely rule out the possibility. I can tell you that 25 mg of Luvox is unlikely to be very helpful for OCD, as I’m sure your doctor would agree. Most likely, a slow, careful increase in the dose would be safe, with or without nicotine. A slow increase is usually better tolerated in patients who have panic disorder, in any case.

By the way, I strongly recommend you get some behavioral therapy to help you quit smoking gradually, and not rely on the patch. The manufacturer agrees with this comprehensive approach.

Question. I am taking 20mg of Paxil and am seeing a behavior therapist for obsessive-compulsive disorder. My obsessions have been greatly subdued and I feel I have a life again. The other day my doctor told me he wanted to switch to Luvox. I was wondering if you could tell me more about the switch and what this will most likely mean for my OCD? I would also like to know about Luvox and possible interactions with other drugs, particularly antihistamines and melatonin? Also, I find it hard to sleep on Paxil. Would melatonin help?

Answer. Frankly, I would think twice before switching from Paxil if you have done very well on it, except for some insomnia. Of course, Luvox is a perfectly fine medication for obsessive-compulsive disorder (OCD), and is even FDA-labeled for that specific use (as is Paxil). Both are probably roughly equal in effectiveness for OCD. Luvox is actually a bit more likely to produce insomnia than is Paxil (11% vs. 7%, placebo-adjusted rates). There are some drug-drug interactions to avoid with Luvox, including use of two antihistamines: terfenadine and astemizole (Seldane and Hismanal). This is less likely to be a problem with Paxil. Luvox should never be used together with an MAOI-type antidepressant.

In theory, Luvox might elevate blood levels of other drugs, including tricyclic antidepressants, Xanax, Halcion, Tegretol, Clozapine, Inderal, theophylline, erythromycin, and warfarin (a blood thinner), and this list is not exhaustive. However, not all these interactions are necessarily clinically significant; the ones to stay away from with Luvox are MAOI, terfenadine, and astemizole. As far as something to help with sleep while taking Paxil: a very small dose of a sedating tricyclic, such as doxepin 10 mg to 25 mg, could help (elevations of doxepin blood levels would probably not be a major concern at that dose, but levels should be monitored).

Trazodone (Desyrel) 25 mg to 50 mg at bed could also help, though there is a very small chance that this might worsen OCD symptoms. A small amount of lorazepam (Ativan) 0.5 mg to 1.0 mg could also be of help. I am not aware of adverse interactions between melatonin and either Paxil or Luvox; however, two caveats: 1) There is very little published research in this area, since melatonin is available over-the counter; and 2) there have been reports of melatonin aggravating depressive symptoms. Whether it would aggravate OCD is not clear, but I’m not sure I’d take the chance. I would encourage you to discuss all these issues carefully with your doctor.