Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Fluvoxamine Maleate). A white or almost white, crystalline powder. Sparingly soluble in water freely soluble in alcohol and in methyl alcohol.

The United States Pharmacopeia 31, 2008 (Fluvoxamine Maleate). A white to off-white, crystalline powder. Sparingly soluble in water freely soluble in alcohol and in chloroform practically insoluble in solvent ether. Protect from light.

Adverse Effects, Treatment, and Precautions

As for SSRIs in general (see Fluoxetine). Bradycardia with ECG changes has been noted with fluvoxamine (but see also Effects on the Cardiovascular System in Adverse Effects of Fluoxetine). It is recommended that fluvoxamine should be withdrawn in patients who have increased serum liver enzyme concentrations.

Fluvoxamine may need to be given with caution to patients with hepatic or renal impairment, and to the elderly (see under Uses and Administration, below).

Incidence of adverse effects. The UK CSM has reported that between 25 September 1986 and 23 March 1988 it had received 961 reports of adverse reactions, including 5 deaths, associated with the use of fluvoxamine. The most frequently reported reactions were nausea (183) and vomiting (101). Other reactions included dizziness, somnolence, agitation, headache, tremor, and, during the first few days, worsening of anxiety. There were 13 reports of convulsions. Reports of appetite stimulation and antimuscarinic reactions were unusual. The effects sometimes resolved with time or dose reduction.

The safety profile of fluvoxamine has been reviewed. For a comparison of the adverse reaction profiles of other SSRIs including fluoxetine with that of fluvoxamine, see Incidence of Adverse Effects, under Adverse Effects of Fluoxetine.

Breast feeding. For comments on the use of SSRIs in breast feeding patients, see under Precautions for Fluoxetine.

Children. SSRIs are associated with an increased risk of potentially suicidal behaviour when used for the treatment of depression in children and adolescents under 18 years old for further details, see under Effects on Mental State in Fluoxetine.

Interactions

For interactions associated with SSRIs, see Fluoxetine.

Fluvoxamine can greatly increase plasma concentrations of theophylline, and they should not be given together, or, if this is unavoidable, the dose of theophylline should be halved and plasma-theophylline concentrations monitored more closely.

Pharmacokinetics

Fluvoxamine is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring 3 to 8 hours after a dose. Systemic bioavailability does not appear to be affected by food. It is extensively metabolised in the liver by oxidative demethylation and deamination, to inactive metabolites. Excretion is mainly in the urine about 2% of a dose is excreted as unchanged drug. Fluvoxamine is widely distributed throughout the body and protein binding is reported to be about 80% it has a plasma-elimination half-life of about 15 hours. Fluvoxamine is distributed into breast milk (see Breast Feeding under Precautions in Fluoxetine).

Uses and Administration

Fluvoxamine, an aralkylketone derivative, is an SSRI with actions and uses similar to those of fluoxetine. It is used as the maleate and doses are expressed in terms of this salt.

In the treatment of depression fluvoxamine maleate is given in an initial oral dose of 50 or 100 mg once daily, preferably in the evening in some patients the dose may need to be gradually increased to a maximum of 300 mg daily. It is recommended that daily dosages exceeding 150 mg should be given in 2 or 3 divided doses.

Fluvoxamine maleate is also used in the management of obsessive-compulsive disorder. In the UK, doses are similar to those used in the treatment of depression. The recommended starting dose in the USA is 50 mg once daily this dose may be increased by increments of 50 mg every 4 to 7 days to a maximum of 300 mg daily. Doses above 100 mg daily should be given in 2 divided doses. In both countries the drug may also be used in children aged 8 years and over with obsessive-compulsive disorder. The recommended starting dose is 25 mg once daily, which may be increased in increments of 25 mg every 4 to 7 days to a maximum daily dose of 200 mg (in the USA adolescents over 11 years may be given a maximum dose of 300 mg daily). Daily doses of more than 50 mg should be given as 2 divided doses. It is recommended that if no improvement occurs within 10 weeks, treatment with fluvoxamine should be re-assessed.

In the USA, a modified-release preparation of fluvoxamine maleate is available for the treatment of obsessive-compulsive disorder and social anxiety disorder in adults the initial dose is 100 mg once daily increased, as necessary, to a maximum of 300 mg once daily.

US licensed product information recommends that dosage modification be considered in elderly patients, in whom clearance may be decreased. For dosage in renal and hepatic impairment, see below.

Fluvoxamine should be withdrawn gradually to reduce the risk of withdrawal symptoms.

Administration in hepatic or renal impairment. UK licensed drug information recommends that patients with hepatic or renal impairment should begin therapy with a low dose of fluvoxamine maleate and be carefully monitored US product information only recommends that dosage modification be considered in hepatic impairment, since it considers evidence of accumulation in renal impairment to be lacking.

Anxiety disorders. Fluvoxamine has been given in a variety of anxiety disorders including obsessive-compulsive disorder, panic disorder, and social anxiety disorder (see under Phobic Disorders).

Hypochondriasis. For reference to the use of SSRIs, including fluvoxamine, in hypochondriasis, see under Fluoxetine.

Preparations

BP 2008: Fluvoxamine Tablets

The United States Pharmacopeia 31, 2008: Fluvoxamine Maleate Tablets.

Proprietary Preparations

Argentina: Luvox

Australia: Faverin Luvox Movox Voxam

Austria: Felixsan Floxyfral

Belgium: Dumirox Floxyfral

Brazil: Luvox

Canada: Luvox

Chile: Luvox

Czech Republic: Fevarin

Denmark: Fevarin

Finland: Fevarin Fluvosol

France: Floxyfral

Germany: Desifluvoxamin Fevarin Fluvohexal Fluvoxadura

Greece: Dumyrox Myroxine

Hong Kong: Faverin

Hungary: Fevarin

India: Fluvoxin Sorest Uvox

Indonesia: Luvox

Ireland: Faverin

Israel: Favoxil

Italy: Dumirox Fevarin Maveral

Japan: Luvox

Malaysia: Luvox

Mexico: Luvox Vumix

The Netherlands: Fevarin

Norway: Fevarin

Philippines: Faverin

Poland: Fevarin

Portugal: Dumyrox

Russia: Fevarin

South Africa: Faverin Luvox

Singapore: Faverin

Spain: Dumirox

Sweden: Fevarin

Switzerland: Floxex Floxyfral

Thailand: Faverin Fluvoxin

Turkey: Faverin

United Kingdom: Faverin

USA: Luvox

Venezuela: Luvox

Fluvoxamine has also been compared with benzodiazepines in several relevant clinical trials. Laws and colleagues (1990) conducted a 6-week, multi-centre double-blind comparison of fluvoxamine (Luvox) and lorazepam in the treatment of mixed anxiety depression in 112 outpatients treated by general practitioners. Dosage could range up to 300 mg/day of fluvoxamine (Luvox) and 6 mg/day of lorazepam. Six patients in the fluvoxamine (Luvox) group and four treated with lorazepam dropped out of the study because of intolerance. The majority of these dropouts occurred during the first week. The average final daily doses indicated that treatment was adequate; 163 mg/day of fluvoxamine (Luvox) and 2.96 mg/day for lorazepam. The investigators found equal and significant reductions in depression and anxiety ratings in both groups.

Chabannes and Douge (1989) reported two comparative trials of fluvoxamine (Luvox) and benzodiazepines. In the first they treated 60 outpatients with “low mood and anxiety” with either fluvoxamine (Luvox) or diazepam for 6 weeks. The average initial HAMD score was 23.4, which is consistent with a moderate or greater severity of depression. Fluvoxamine and diazepam reduced anxiety to an equivalent degree. In a second study they treated 130 outpatients described as having major depression plus anxiety with fluvoxamine (Luvox), prazepam or the combination for 6 weeks. Here there was a trend for a greater decrease in Hamilton Anxiety Scores in patients receiving fluvoxamine (Luvox) alone or fluvoxamine (Luvox) plus prazepam than those treated with prazepam alone.

Citalopram

Shaw and Crimmins (1989) compared citalopram and amitriptyline in a 6-week trial of 59 in- and outpatients suffering from major depression. No differences in antidepressant effectiveness were observed, and the drugs were equally effective in reducing anxiety despite the greater sedative action of amitriptyline. The large clinical trial database shows that the anxiety symptoms seem to respond with the depression but the full analyses have not yet been adequately published.

Summary

A considerable body of evidence has been accumulated supporting the efficacy of the selective serotonin reuptake inhibitors (SSRIs) in treating anxiety symptoms in depression. It is clear that the SSRIs are at least as effective as the TCAs in treating these symptoms and several studies have shown either an overall advantage for the SSRIs compared with tricyclic antidepressants (TCAs) in treating the anxiety symptoms, or else an earlier effect.

Transient increases in anxiety have been reported from time to time during treatment with some SSRIs; however, extensive investigation of large clinical trial databases of the SSRIs as well as specific studies in depressed/anxious patients have shown that SSRIs are effective across the range of depression, including both depressive and anxious symptoms. Significant pretreatment anxiety or agitation does not predict the subsequent development of either of these side effects with an SSRI. All the evidence points to the fact that selective serotonin reuptake inhibitors are particularly effective in the treatment of anxiety symptoms associated with depression. There is some evidence to suggest that anxious-depressed patients may respond better to an SSRI than those with more psychomotor retardation.

The investigation of mixed anxiety depression is to some extent hampered by the imprecise diagnostic criteria currently available. Improvement is needed to facilitate serious study of this category in the future. We have already alluded to the unsatisfactory criteria contained in DSM-IV, which requires the presence of four or more symptoms from a list of 10 as well as the absence of current or previous episodes of major depression, dysthymic disorder, generalized anxiety disorder and/or panic disorder. Yet the symptoms used for diagnosis are nearly the same as those used for the “exclusionary” disorders. If one considers only dysthymic disorder and generalized anxiety disorder, then at least 86% of the possible combinations of four or more symptoms are eliminated.

It might be more useful to conceptualize mixed anxiety depression in a way analogous to that adopted for schizoaffective disorder, which requires that symptoms of schizophrenia and an affective disorder always coexist. If applied to mixed anxiety depression it would require that symptoms of a depressive and anxiety disorder always be present at the same time at either a full or a nearly syndromal level.

In spite of these diagnostic difficulties an increasing number of studies are being carried out on the treatment of mixed anxiety depression. The studies reviewed in this chapter have shown that the SSRIs are at least as effective as TCAs in relieving symptoms of anxiety and depression. They are also better tolerated, as would be expected from their neuropharmacologic profile. It also appears they may be as effective as benzodiazepines in reducing anxiety.

The extensive research and clinical experience with the SSRIs in the treatment of anxious depressed patients supports their efficacy as well as tolerability and safety. It is our opinion that they are now the treatment of choice for this condition, especially when long-term treatment is indicated.

The large epidemiological studies that have been carried out in recent years have drawn attention to the high rates of comorbidity of psychiatric disorders in the general community. Major depression is known to have a high comorbidity with separate anxiety disorders and a problem can arise in attributing certain anxiety symptoms as part of either the depression or the anxiety disorder. The overlap of major depression and an anxiety disorder where both conditions satisfy the full diagnostic criteria is perceived as comorbidity. In this case separate diagnoses may be considered. The overlap of major depression and anxiety disorders, where neither disorder satisfies the full criteria, has come to be known as mixed anxiety depression (MAD). This chapter attempts to address the degree of overlap which is so confusing for the clinician and to assess the data relating the role of selective serotonin reuptake inhibitors (SSRIs) in treatment.

Anxious depression or comorbid anxiety and depression

Mixed anxiety depression is a common but poorly defined condition with multiple possible aetiologies. Both anxiety and depression may occur as a symptom of or reaction to a primary psychiatric or medical disorder. The concept of major depression includes a variety of subgroups, including the more severe (psychotic features, melancholia) and chronic subtypes. Anxiety disorders are classified according to whether and how the anxiety is limited to particular situations (phobias, compulsions), thoughts (obsessions) or times (panic attacks). Generalized anxiety disorder (GAD) may be thought of as chronic anxiety which is not limited to any of these dimensions. Some basic researchers believe that anxiety and depression exist on a continuum and that depression may represent under-activity of serotonergic pathways while anxiety results from over-activity in serotonergic neurones.

There are two general meanings for mixed anxiety depression. One is the depressed patient who has signs or symptoms of an anxiety disorder which does not meet the threshold for a separate diagnosis, such as the patient with panic attacks which do not occur often enough or with the requisite number of symptoms to be diagnosed as panic disorder. The other is the patient with generalized anxiety disorder who intermittently fulfils criteria for major depression. Mixed anxiety depression also appears as an experimental diagnosis in DSM-IV (Table: Research criteria for mixed anxiety depressive disorder (DSM-IV)). Its anxiety symptom criteria are very similar, and in some cases identical, to those for GAD. However, DSM-IV requires that the disorder does not meet, and never has met, criteria for generalized anxiety disorder, major depression, dysthymic disorder and/or panic disorder. This is a problem, especially because the symptom threshold for dysthymic disorder is so low (requiring only two symptoms) that chronically depressed and anxious patients will almost never meet criteria for mixed anxiety depression. One might summarize this by saying that mixed anxiety depression (MAD), as it is currently regarded, is an admixture of a subsyndromal depressive disorder with a subsyndromal anxiety disorder. In a sense it is a testament to the importance of MAD that it has received as much research attention as it has despite this lack of satisfactory diagnostic criteria.

Table: Research criteria for mixed anxiety depressive disorder (DSM-IV)

Anxiety symptoms in depression

The scales employed for rating the severity of depression reflect the nature of these anxiety symptoms as integral to the depression. The scores on these anxiety items are seen to reduce as the depression improves and the items have good face validity in depression. For example, the Hamilton Scale for Depression (Hamilton, 1960) includes items to measure agitation, somatic anxiety and psychic anxiety. Three items that measure sleep disturbance and an item to assess the phenomenon of depersonalization feelings also form part of the scale. Moreover, it can be argued that the items for assessing obsessional symptoms and hypochondriasis also register anxiety symptoms. Most studies of the efficacy of various treatments for depression have shown that the symptoms measured by these anxiety items in the scales improve at the same rate as other symptoms of depression.

Some of the items in the Hamilton Rating Scale are more sensitive to treatment change than others and Hamilton himself recognized that the depersonalization and obsessional items, which are less sensitive, should be used more appropriately for diagnostic purposes only.

SSRI in the Treatment of Anxiety Symptoms Within Depression

Some treatments are acknowledged to be more effective than others in treating particular anxiety symptoms that occur with depression. The items that measure disturbed sleep improve more rapidly in response to sedative antidepressants with marked histaminergic receptor properties such as the sedative tricyclic antidepressants or mianserin. This has been shown in a number of comparisons with non-sedative antidepressants such as the selective serotonin reuptake inhibitors. However, the advantage seen with the sedative antidepressants, which is more evident at the start of treatment, tends to diminish as the sleep improves as part of the general improvement of the depression in response to SSRIs. By the end of the acute treatment period, the advantage of the sedative antidepressants on sleep is no longer evident. On the other hand, the negative effects on psychomotor function of the histaminergic activity become apparent with daytime drowsiness and the need to desist from driving cars or operating heavy machinery.

The early effect of anxiolytic drugs on disturbed sleep and certain other anxiety, symptoms in depression has been reported but an antidepressant effect cannot be attributed to these drugs merely on these grounds. The studies of benzodiazepines in the treatment of depression show their effects on improving the sleep items and anxiety but also show that they are less effective, or not effective at all, in improving other features of depression, and it is for this reason that, independently of the associated long-term problems of tolerance and dependence, benzodiazepines are not licensed or recommended for the treatment of major depression. Some studies have reported an increase in paradoxical aggression with benzodiazepines, possibly mediated by a mechanism involving disinhibition, and this characteristic makes these drugs unsuitable for depression, where there is an elevated risk of suicide attempts.

The selective advantages of selective serotonin reuptake inhibitors (SSRIs) in treating the anxiety symptoms of depression compared with sedative tricyclic antidepressants came as a surprise. Zimelidime, an early non-sedative SSRI that was withdrawn from the market, was found to be more effective than amitriptyline in treating the anxiety symptoms of depression in a 6-week treatment study. This finding raised the possibility that serotonin reuptake might have a special beneficial effect on the symptoms of anxiety within depression. Subsequent analysis for paroxetine (Paxil) and fluvoxamine (Luvox) have confirmed this hypothesis, with a differential advantage in treating anxiety symptoms in depression reported for the SSRIs compared with reference tricyclic antidepressants. These observations led to the hypothesis that SSRIs might have particular advantages in treating separate anxiety disorders, such as panic disorder and social phobia.

The first generation of antidepressant medication included tricyclics (TCAs) and monoamine oxidase inhibitors. A number of investigators have shown these drugs to be helpful in the treatment of anxious depression. Several trials have also shown TCAs to be equivalent or even superior to benzodiazepines in the treatment of this syndrome. SSRIs improved over tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) in two main areas: tolerability and safety. However, anxiety and agitation have been reported as occasional side effects with all selective serotonin reuptake inhibitors, which might lead to reluctance to use these agents in anxious depression. A review of the available data concerning the use of SSRIs in anxious depression, especially relating to whether baseline anxiety is a poor prognostic sign, is therefore timely.

The first line of evidence is indirect. It stems from the observation that patients with anxiety disorders often have concomitant depressive symptoms. There is considerable direct evidence of the efficacy of the SSRIs in anxiety disorders. All four SSRIs approved for marketing in the USA have shown sufficient efficacy to garner an official indication for at least one anxiety disorder, obsessive-compulsive disorder (OCD). Paroxetine (Paxil) and sertraline (Zoloft) are also indicated for the treatment of panic disorder (PD). While patients with bona-fide major depression are usually excluded from trials of an antidepressant in an anxiety disorder, it is likely that a substantial number of the subjects in OCD and PD trials had clinically significant depressive symptoms.

Filteau and colleagues analysed data from 10 studies of SSRIs (sertraline (Zoloft); zimelidine; fluvoxamine (Luvox); fluoxetine (Prozac)); selective noradrenergic uptake inhibitors — desipramine, maprotiline, oxaprotiline; mixed uptake inhibitors — amitriptyline, imipramine (Tofranil); and partial 5-HT2 antagonists — ritanserin, trazodone (Desyrel), nefazodone. The data showed no differences between the efficacy of these classes in agitated or retarded depression. In a subsequent analysis the same investigators found that SSRI responders tended to be initially more anxious and agitated than non-responders.

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. 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. 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.

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.

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!

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.

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.