Brand Name: Vestra
Active Ingredient: reboxetine mesylate
Indication: Treatment of depression
Company Name: Pharmacia & Upjohn

Vestra: Introduction

As a selective norepinephrine reuptake inhibitor (SNRI), Vestra is the first of a new class of antidepressant drugs. This new mechanism of action appears to produce fewer side effects, such as nausea, headache, and sexual dysfunction, compared with traditional antidepressants. Vestra also possesses a faster onset of action compared to selective serotonin reuptake inhibitors (SSRI), tricyclics, and monoamine oxidase inhibitors, commonly used to treat depression.

Vestra: How It Works

A lack of norepinephrine in the central nervous system (CNS) of depressed individuals is hypothesized to be responsible for several specific symptoms of depression, such as lack of energy, interest, and motivation. Vestra inhibits the reuptake of norepinephrine by the presynaptic nerve terminals. As a result, the neurotransmitter remains in the synapse for a longer period of time.

Vestra: Clinical Study Results

Several clinical studies were conducted to determine the safety, efficacy, and tolerability of Vestra. One study involved 283 patients with recurrent DSM-III-R major depression. These patients were randomized to receive either Vestra or placebo for 46 weeks in a double-blind phase. Vestra was associated with a significantly lower relapse rate than placebo (22% vs. 56%; p < 0.001), as well as a greater cumulative probability of maintained response (p = 0.0001) during long-term treatment. The proportion of relapse- free patients who remained in the study was significantly higher in the Vestra group than in the placebo group at the end of the first six months (61% vs. 40%) and the second six months (88% vs. 59%) of treatment.

A double-blind, randomized, parallel-group, multicenter trial, including 168 patients with acute major depressive episodes, was conducted to compare Vestra to fluoxetine, an SSRI. The patients were administered either Vestra 8-10 mg/day or oral fluoxetine 20-40 mg/day for 8 weeks. Both treatments were found to be similarly effective as assessed by the mean reduction in total Hamilton Depression Rating Score, percentage of responders and patients in remission, Clinical Global Impression severity of illness and global improvement scores, and the Montgomery-Asberg Depression Rating Scale. A sub-analysis of patients with severe depression showed Vestra to have superior efficacy compared to fluoxetine. Both treatments resulted in improvement in Social Adaption Self-evaluation Scale total scores; however, the improvement was more evident in patients who received Vestra and achieved remission.

Vestra: What the Patient Should Know

Although clinical trials have shown a reduced risk for nausea, diarrhea, and somnolence with Vestra compared with fluoxetine, the patient should be aware that an increase in risk for dry mouth, constipation, hypotension, paresthesia, urinary hesitancy, and flushing was observed with Vestra in the trials.

A recent report suggests that the antidepressant drug Prozac (fluoxetine) can be useful in the treatment of bulimia nervosa.

* Researchers at the New York State Psychiatric Institute reviewed findings from 15 controlled studies on the use of anticonvulsants, lithium, fenfluramine and antidepressants in bulimia patients to reach their conclusions; patients in the studies used vomiting to compensate for food intake, were of normal weight, were predominately female, and were young adults.

* Found that only antidepressant therapy – particularly with fluoxetine – was consistently shown to reduce the frequency of binge eating among normal-weight patients with bulimia nervosa.

* Authors suggest that bulimia patients should demonstrate six months of real improvement before any effort is made to discontinue any antidepressant drug therapy.

Question. I used to take 100 mg of imipramine per day for depression. Then I was diagnosed with mixed bipolar and was switched to 750 mg Depakote and 225 mg of Effexor per day. I gained about 50 pounds during the first three months and have not been able to lose any of it. I have a lot of problem with my weight and it has been starting to make me really depressed. Is there a medicine that will not give me this side effect, or should I try a diet or diet pills?

Answer. First of all, I can appreciate your frustration. Weight gain, unfortunately, is a common side effect of many mood medications, including Depakote and Lithium. Effexor, on the other hand, is not commonly associated with weight gain. I do not recommend diet pills, since the long-term consequences of their use are not well-known. Nutritional counseling and a moderate exercise program are very important parts of weight management, though I do not want to mislead you. Even pushed to the maximum, these are unlikely to shed 50 pounds. Still, you may be able to take off 8-15 pounds with major dietary changes and regular, vigorous exercise, as medically prescribed.

Changing from Depakote to carbamazepine (Tegretol) might lead to less weight gain, though Tegretol can have its own side effects and risks. This would require a thorough discussion with your doctor. It is also important to make sure that your thyroid function is adequate. Women with bipolar disorder have a rather high rate of hypothyroidism, which can lead to weight gain. Thyroid hormone combined with a mood stabilizer can sometimes reduce mood swings. In my experience, it can prevent further weight gain for some patients. However, thyroid medication should not be used as a diet pill, and also has its own risks. While lithium can also promote significant weight gain, it is possible that for you, the weight gain might be less than with the Depakote. There is no way to predict this. Lithium, however, is not as effective as Depakote for mixed bipolar disorder.

I wish I could give you a quick and easy solution to your problem, but there is really none that I know of. And, it is very important that you continue with your medications until and unless a change is made. Finally, it is also important to discuss your feelings of depression with your therapist, and to consider a support group or other means of addressing these feelings. I wish you well.

Question. I am a mental health professional. However, I also find myself searching for information to console me personally. I have been diagnosed with major depression. I go regularly to a psychiatrist and I am currently taking Wellbutrin SR. What is the potential for recurrence of depressive symptoms while taking a prescribed medication that has worked well for over three years? Can you give me some information about the number of mental health professionals who have major depression? I still worry about the stigma even though I work daily in the field.

Answer. I can understand how the stigma of your depression might be a source of distress to you, even though we now have a number of excellent role models of successful mental health professionals who suffer from mood disorders. An excellent example is Dr. Kay Redfield Jamison, author of An Unquiet Mind; Jamison herself suffers from bipolar disorder, and has confronted this publicly and in her writing.

Regarding rates of relapse or recurrence of major depression: the bad news is, major depression tends to be a recurrent illness. As a group, about 55% of individuals with a single episode of major depression will go on to have a second episode. Individuals who have had two episodes have a 70% chance of having a third. The good news is that with appropriate medication and psychotherapy, the outlook is quite favorable. Frank et al (Arch Gen Psychiatry, Dec. 1990) found that when patients with recurrent depression were treated with imipramine 200 mg per day in combination with interpersonal therapy, nearly 80% went for three years without a recurrence of major depression. This has generally been my clinical experience with patients who initially do well on various antidepressants (including Wellbutrin) and are maintained in appropriate psychotherapy.

I am not aware of any studies that have actually determined rates of major depression among mental health professionals. However, there are several studies of professional “burnout” that you may be interested in. Clark et al (Hospital & Community Psychiatry, August 1987) looked at burnout among psychiatrists in community mental health centers and found that 46 of 96 expressed dissatisfaction with their work. Another study of burnout found that among the psychiatric staff of a large HMO, “high emotional exhaustion and depersonalization” were found, based on the Maslach Burnout Inventory (Snibbe et al, Psychol Rep, 1989; 65:775-80). You may also be interested in the article by Cushway & Tyler on “stress in clinical psychologists” (Int J Soc Psychiatry, Summer 1996).

Regarding signs to watch for, this could become a problem if it begins to preoccupy you. Hypervigilance usually creates its own problems, in my experience. Symptoms I am sure you are familiar with-sleep disturbance, loss of appetite, reduced energy, etc. – would be of concern, of course. If it is of any consolation, I have personally known or treated a number of mental health professionals with major depression, and you are far from alone in this respect. Your professional practice organization might have more information and/or referrals for support. Good luck!

Question. I have read reports that antidepressants prescribed for patients in the depressed phase of cyclothymic or bipolar II illness can (a) shorten the cycles of the illness (b) possibly lead to refractory depression in the long run and (c) precipitate hypomanic episodes. Are you aware of any data on these issues? Do you know of any information on alteration of other aspects of the course of mild bipolar illness? Finally, is there any consensus in the field regarding the appropriate treatment of depressed phases of mild bipolar illness?

Answer. I suggest you read (if you haven’t already) Akiskal’s article in the April 1994 Journal of Clinical Psychiatry (suppl), on dysthymic and cyclothymic depression, as well as the study by Altshuler et al in the August 1995 American Journal of Psychiatry.

There is still a fair amount of controversy as to whether antidepressants can affect cycle length or “switching” in bipolar illness; and if so, how much and in which subtypes of bipolar disorder. The consensus seems to be – and I concur with this–that at least some bipolar patients are sensitive to antidepressants, particularly tricyclics, and that their course can worsen substantially with use of these agents.

As early as 1977, Akiskal and colleagues found that Tricyclic Antidepressants (TCAs) given over 6 weeks doubled the rate of hypomania in predominantly depressed cyclothymic patients. Akiskal’s group supports the notion that patients with “soft” indicators of bipolar illness may be particularly susceptible to the mood destabilizing effects of TCAs. (They think trazodone and trimipramine may be less noxious, perhaps because these agents are less disruptive of sleep.) On the other hand, Himmelhoch has data showing that the Monoamine Oxidase Inhibitor (MAOI) tranylcypromine (in comparison with imipramine) may be useful in “anergic” bipolar depression, with only brief, mild hypomania associated with use.

Similarly, some data suggest that bupropion has less likelihood of promoting cycling in “soft bipolar depressives,” usually when used in concert with a mood stabilizer. Akiskal believes that in bipolar II patients, it is best to use “conservative” doses of MAOIs, bupropion, or Selective Serotonin Reuptake Inhibitors (SSRIs), and to stay away from TCAs. This is close to my own view, though I have seen and treated some bipolar patients who did fine for many years on tricyclics (in combination with mood stabilizers) and could not maintain mood stability without the TCA – but some of these cases were treated before the availability of newer agents. Altshuler et al also found that antidepressant-induced cycle acceleration (but not induced mania) is associated with female gender and type II bipolarity.

With respect to any consensus on the treatment of mild bipolar illness, I would offer my own summary: avoid antidepressants of any kind if possible; use lithium (actually a pretty good antidepressant) as the mainstay of treatment unless there are “mixed” or dysphoric features (in which case, I’d use valproate); and when forced to treat depression, start with low doses (37.5 mg/day) of bupropion. It’s also important to rule out borderline hypothyroidism in rapid cyclers. Thyroxine may, in my experience, be useful not only as a mood stabilizer, but as a mild antidepressant in some bipolar depressed patients.

Question. My patient is in the second trimester of her pregnancy. She has panic disorder and depression. In the past, she responded well to Zoloft and Klonopin. What are the safest medications for the next few months?

Answer. The short, no-frills answer to your question is that any of the major antidepressants or anxiolytics are probably safe, now that the most vulnerable period of organ-formation (the first trimester) has passed. I see no reason why Zoloft and/or Klonopin could not be restarted, if the clinical situation is severe enough to warrant the modest risks. An OB/GYN consult is always a reasonable precaution, but I would not necessarily be governed by it, if you believe your patient must be on a medication. If you care to read on, here is the more complicated story:

With respect to antidepressants (ADs) in pregnancy, most data come from studies of tricyclics and fluoxetine(Prozac); we have only a modicum of information about newer agents such as sertraline (Zoloft), paroxetine (Paxil), venlafaxine (Effexor) and nefazodone (Serzone). The tricyclics (e.g., desipramine (Norpramin), imipramine (Tofranil), nortriptyline (Pamelor)) appear to have little potential for teratogenicity. Similarly, a recent study by Pastuszak and colleagues (1993) found no evidence of teratogenicity in 128 women taking fluoxetine during the first trimester, when compared to matched controls. While there was a trend toward higher miscarriage rates in the fluoxetine group compared to controls taking known non-teratogens, the risk was small (relative risk, 1.9) and comparable to that of tricyclics. (Interestingly, depression itself may also raise the risk of miscarriage). A recent study by Chambers et al. (New England Journal of Medicine 1996, vol. 335, pp. 1010-1015) found no significant differences between fluoxetine-treated pregnant women and controls in spontaneous pregnancy loss or major structural anomalies; however, the incidence of three or more minor anomalies was significantly higher in the fluoxetine cohort.

This study has been widely criticized, however, on a number of methodologic grounds. The more anticholinergic tricyclics (e.g., amitriptyline, doxepin) can occasionally induce fetal tachyarrythmias, urinary retention or intestinal obstruction. Clomipramine (Anafranil), a tricyclic used mainly in the treatment of obsessive-compulsive disorder, also has substantial anticholinergic effects, and would be expected to produce similar effects in the neonate. Wisner et al (1993) found that the doses of tricyclic antidepressant required to achieve remission actually increased during the second half of pregnancy, reaching 1.6 times the mean dose required when the patients were not pregnant. This was attributed, in part, to enhanced hepatic metabolism of antidepressants during pregnancy and to increased volume of distribution. Neonatal irritability, tachypnea, tremor and hypotonia may result from either tricyclic toxicity or withdrawal. It is therefore prudent to monitor maternal blood levels of tricyclics throughout pregnancy and gradually to reduce the dosage during the week before delivery.

Little is known about the excretion of antidepressants into breast milk or the effects of this on the nursing infant. Some studies indicate that several antidepressants or their metabolites can accumulate in breast milk, possibly peaking at about 4-6 hours after an oral dose. (See the review by Wisner et al. in the September 1996 issue of the American Journal of Psychiatry). It is not clear to what extent antidepressants accumulate in the blood of the nursing infant or whether significant adverse effects result from such accumulation. Wisner et al. (1996) conclude that sertraline is a good choice, with respect to breast-feeding. However, many clinicians feel that breast-feeding is best avoided when the mother is taking antidepressants postpartum.

Miller (1994) concluded that the tricyclics of choice during pregnancy are desipramine and nortriptyline, due to the comparative wealth of data about them, the ability to monitor serum levels and a favorable side effect profile. Alternatively, fluoxetine (Prozac) may be a reasonable choice for the pregnant patient with major depression, in light of the data from Pastuszak et al. Finally, the clinician should keep in mind that ECT appears to be a safe and effective alternative for the pregnant patient with severe depression.

With respect to benzodiazepines (BZDs): In the 70s and 80s, diazepam (Valium) was found to be associated with cleft lip and palate in the fetus and other benzodiazepines were suspected of this association. More recently, one Swedish group has linked maternal use of benzodiazepines during pregnancy with both impaired intrauterine growth and various dysmorphic birth defects. A recent review concluded that the available data indicate a positive association between first-trimester in utero exposure to benzodiazepines and a specific anomaly oral cleft.

Diazepam may double the risk of oral cleft, while alprazolam may increase the risk by more than 11-fold. However, most available data suggest that BZDs do not markedly increase the absolute risk of cleft palate or other congenital abnormalities in exposed fetuses. Thus, the baseline risk of cleft palate is about 6 in 10,000. With alprazolam exposure during the first trimester, the risk may rise to 7 in 1000, still less than 1%. The teratogenicity of lorazepam (Ativan) is less clear. Clonazepam (Klonopin) has not been evaluated for teratogenesis in controlled studies of human subjects; however, based on animal data, clonazepam seems to have low teratogenic potential (Altshuler et al, 1996) . The presence of alcohol and other substance abuse in pregnant women using benzodiazepines complicates interpretation of the data. Infants exposed to BZDs either in the last trimester or at the time of parturition may show muscular hypotonicity, failure to feed, impaired temperature regulation, apnea and low Apgar scores). The data on behavioral teratogenicity and developmental delay are inconclusive.

There is also some evidence that benzodiazepines may increase duration of labor and lead to prolonged withdrawal symptoms in the neonate, when mothers have been maintained on these agents throughout pregnancy. Withdrawal effects may be more likely when high doses of short-acting benzodiazepines have been used. Benzodiazepines should not be stopped suddenly during pregnancy, rather, tapered slowly as delivery approaches. The non-benzodiazepine anxiolytic buspirone (BuSpar) has been shown to increase the number of stillbirths in rats, when given in high doses; however, there are insufficient data in humans to determine the risks of buspirone during pregnancy.

While there is evidence that several benzodiazepines (e.g., diazepam, lorazepam, oxazepam) are excreted into breast milk, the actual levels of BZDs detected in breast milk seem to be fairly low and the consequent risk to the infant, quite small. Lorazepam seems to have minimal accumulation in the fetus and the percentage of the maternal dose of lorazepam to which a nursing infant is exposed is roughly 2.2%. Thus, use of low dose lorazepam in the nursing mother – particularly on a prn, or short-term basis – is probably safe for the infant. The excretion of buspirone into human breast milk has not been adequately studied.

Given the above risks, are benzodiazepines contraindicated during pregnancy? There is no absolute contraindication. Rather, the modest risks of BZD exposure must be weighed against the severity of the patient’s condition; the risks of no medication; and the risks of alternative medications. For example, inadequately treated panic attacks may themselves pose a risk to the fetus. Tricyclic antidepressants, fluoxetine and perhaps other SSRIs, may be reasonable alternatives to benzodiazepines for the treatment of panic disorder during pregnancy . Cognitive-behavioral therapy (CBT) may also be helpful in a variety of anxiety disorders and may reduce the need for psychotropics during pregnancy.

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.

Question. I am a 40-year-old mother of two. A year ago I began taking Zoloft 150 mg per day. This medication has been a miracle for me. I am considering having another child and wonder if any studies have been done on the effects of Zoloft on the fetus/mother/pregnancy.

Answer. There is unfortunately very little known about the effects of sertraline [Zoloft] in human pregnancy. The standard medical advice is to avoid any medication, if possible, during the first three months of pregnancy, since this is the period of greatest organ development in the developing fetus. After the first trimester, most antidepressants would pose very little risk to the fetus or mother, and what little risk there is must be carefully weighed against the risk of recurrent major depression.

The makers of Zoloft cite studies on animals in their product information, but, frankly, I doubt this is of great use to potential human mothers. It may be more useful to look at a study of a closely related (though not identical) antidepressant, Prozac [fluoxetine], which has been studied in pregnant women taking this agent during the first trimester. The study (by Pastuszak et al, JAMA, 1993) found no evidence of teratogenicity (birth defects) in the pregnant women taking Prozac, compared to a control group. There was a trend toward a higher miscarriage rate among those taking Prozac, but the risk was relatively small. Depression itself can also increase the risk of miscarriage. If these results are comparable to those with Zoloft, the risk of using either medication during pregnancy would be very small – but as yet, we don’t know. I would discuss the risks and benefits very carefully with your psychiatrist and obstetrician, and go from there.

Question. After five months of severe depression that was unresponsive to medication, I had ECT and came out of the depression. I was immediately started on Wellbutrin and Zoloft and have been on them for over a year now. The only atypical side effects I experienced were spontaneous myoclonic jerks and those are infrequent now. For the past two weeks, I awake early in the morning due to severe fine tremors of my hands and abdominal muscles. Any ideas about the cause? I am concerned because Wellbutrin isn’t approved for more than a year’s use.

Also, do you agree with my psychiatrist’s view that because of my depression’s severity and having a brother who committed suicide after life-long depression, I am going to be on some type of antidepressants for the remainder of my life?

Answer. Your symptoms are, indeed, puzzling! It is hard to posit some new drug or drug interaction as a cause of the muscle tremors, since you have been on the same medications at the same dose for a year. As you may know, serotonergic antidepressants (SSRIs) like sertraline [Zoloft] can occasionally cause tremors or other extrapyramidal reactions, perhaps as a result of decreased dopamine in certain brain regions. But the fact that you awaken with these symptoms, and are apparently relieved after taking your medication, suggests a more complicated mechanism.

In theory, it is possible that, overnight, your plasma levels of sertraline drop significantly, such that you actually get some mild withdrawal effects by morning; muscle twitching could be due to this, though it would be very atypical. It is theoretically possible that you are developing some kind of dyskinesia, related to the sertraline, and that you are actually masking it by taking your morning medications. The theory is that chronic dopaminergic blockade, due to the sertraline, leads to compensatory dopamine receptor hypersensitivity, with resultant muscle twitching or dyskinesia. Taking the medication in the morning might temporarily relieve this by reestablishing dopamine receptor blockade. All this, I want to emphasize, is very speculative on my part.

For the vast majority of patients taking SSRIs, no problems of the sort you describe ever develop, and even in animal models, the effects I’ve described (e.g., on dopamine) are still open to debate. I haven’t said anything about the bupropion [Wellbutrin], since the mechanism of action of Wellbutrin is not well understood; however, it probably has effects on both norepinephrine and dopamine, in high enough doses. There may well be pharmacokinetic interactions between sertraline and bupropion.

Could there be some third factor – say, a change in your caffeine intake, or some over-the-counter medication, or a recent infection – that could account for the change in the past two weeks? At this point, it might be instructive (if your doctor concurs) to try changing the timing of one or both of your medications, sequentially. For example, if you are taking the Zoloft in the a.m., try taking it at bed time, or vice versa. If you are taking the Wellbutrin in the a.m. and afternoon, try shifting it to afternoon and late evening, etc. But frankly, since this is so recent a phenomenon, the most prudent course may be simply to wait another two weeks and see if it persists.

You might also want to have the plasma level of your bupropion checked, along with its metabolite, hydroxy-bupropion. High levels of the metabolite have been associated with various neurologic side effects – though it’s hard to account for why this would now be a problem. Dosage reduction of one or both medications could also be a reasonable maneuver that might shed light on the problem. This would need to be weighed against the risk of recurrent depression, of course, and all these issues should be discussed with your psychiatrist.

Finally, as to your being on an antidepressant for the remainder of your life – that is a difficult question, and the answer may depend on how risk-averse you are. The average patient with non-bipolar major depressive disorder will have five to six depressive episodes over a period of 20 years. If a patient has already had two major depressive episodes, the odds are about 70% that he or she will have at least one further episode. For these reasons, most psychiatrists would agree that the average patient with two or more serious episodes of depression should remain on antidepressant medication indefinitely. Perhaps your case is somewhat harder to categorize; on the one hand, your first episode was much milder, but on the other hand, your family history is very strong for major depression.

In general terms, I concur with your psychiatrist’s view, but who knows what the future will bring? We are already investigating the use of magnetic fields to treat depression. Cognitive behavioral therapy is proving to be a robust treatment for depression. Rather than thinking in terms of the remainder of your life, it might be more helpful to reassess the situation every two to three years – but in the mean time, the medication makes a good deal of sense. Good luck with the side effect issue – it is a puzzler!

Question. I am on Prozac and suffer severe lower back pain and general aches and pains throughout the body especially the joints. Is there any link?

Answer. I can’t tell you with any degree of confidence whether, in your case, there is a “link” between your taking Prozac and the pain you describe. (Did the aches and pains begin soon after you started the Prozac? This would be an important question to answer). There are many causes of lower back pain and aches and pains – Prozac would be a relatively rare cause, but a few cases have been reported. In one case, however, the joint pain was accompanied by fever, skin rash, and swollen lymph glands – which is not what you are describing. There is also a case report of Prozac actually improving arthritis.

I suggest you discuss this question with the physician who is prescribing the Prozac, and consider consulting a rheumatologist if you have not already done so. If the Prozac is implicated, changing to a different antidepressant may be warranted.