Fighting the darkness of depression

Since its approval in the eighties, millions of people around the world have been successfully treated with fluvoxamine. The drug is indicated for the treatment of obsessive compulsive (OCD), major depressive (MDD) and social anxiety disorders (SAD).

In the previous issue of The Specialist Forum we focused on the efficacy of fluvoxamine in the treatment of OCD. In this article, the focus is on the treatment of MDD and SAD.

Selective serotonin reuptake inhibitors

Fluvoxamine’s – the first of the selective serotonin reuptake inhibitors (SSRIs) – efficacy and safety in the treatment of adults and children have been shown in several major trials.

According to psychiatrist, Dr Ilse du Plessis,  SSRIs has been first-line treatment for depressive disorders since the eighties and it kept its place in the arsenal of options to treat MDD, which accounts for  4.4% of the total overall global disease burden.

Since then more molecules became available with similar actions, and in spite of different drugs with different mechanisms of actions being available, SSRIs has kept its place as first step in the uphill climb to try and conquer the darkness of depression.

Antidepressant are said to be all the same as clinical trials have shown little difference in efficacy or tolerability among the different SSRIs, and even between SSRIs and other classes. However, some differences should be noted.

Rarely has a class of drug changed prescribing habits so drastically in psychiatry, than the introduction of SSRIs, because of its side effect profile, said Dr du Plessis. Side effects are usually mild and transient, yet the biggest advantage, is the relative safety in overdose in a population at risk.

Side effects

SSRIs can cause nausea and gastrointestinal upset, especially at the onset of treatment, due to the high concentration of 5-hydroxytryptophane (5-HT) receptors in the gut. This with headache, insomnia and initial agitation, is usually transient. Other possible problems include hiponatraemia, bleeding, sweating and a tremor.

Paroxetine has been associated with more anticholinergic side effects and weight gain than other SSRIs, and sertraline with more diarrhoea. The most troublesome side effect for patients – usually when they have recovered from symptoms and have to stay on the medication for the full treatment period after remission (six to nine months for a first episode, 18-24 months for a second episode, or lifelong if more severe recurrent episodes with a positive family history) – is sexual dysfunction that can be experienced as a decreased libido or a delayed orgasm.

The management can be to wait for receptor adaptation, and keeping in mind the changes in libido may be associated with the depression itself. Dose reduction, ‘drug holidays’ or switching to a different drug in the same class may work, but care should be taken to monitor a relapse of the depression. A Cochrane review found that addition of sildenafil, tadalafil or bupropion may improve sexual function.

Serotonin syndrome

A serious side effect is serotonin syndrome and is often missed, but may need emergency treatment even in an intensive care unit in severe cases. Symptoms include restlessness, diaphoresis, tremor, shivering, myoclonus, confusion, convulsions, and may ultimately result in death. It is a higher risk when more than one serotonergic drug are combined, or with drug interactions at cytochrome level.

Factors influencing choice of specific SSRI

Even though SSRIs are recommended as first-line agents in the treatment of depressive disorders, the choice of specific medication should preferably be made in conjunction with the patient, taking into account the presence of comorbid medical conditions and concomitant medication, age, gender, pregnancy and breastfeeding, a history of a previous good response to a specific molecule, patient preference, specific symptoms experienced, cost and medication side effect profile.

As SSRIs are not only registered for the use in depressive disorders, the presence of comorbid conditions can guide one in the choice of the appropriate drug registered to treat both conditions.

Discontinuation symptoms

Discontinuation symptoms are experienced due to receptor adaptation or receptor rebound after stopping of antidepressants. It can be avoided or reduced by slowly tapering the drug over at least four weeks. The symptoms can be experienced also after missed doses of SSRIs with a short half-life, stressed Dr du Plessis.

Discontinuation symptoms are experienced by at least a third of patients, within five days of stopping treatment. Symptoms include flu-like symptoms, ‘shock-like’ sensations, dizziness exacerbated by movement, insomnia, vivid dreaming and irritability, even problems with concentration and memory or movement disorders. The reintroduction of the SSRI and slower tapering of the molecule manage it.

Efficacy in the treatment of MDD

The first trial to access the role of fluvoxamine in the treatment of depression dates back to 1976. Since then several studies have investigated the efficacy of fluvoxamine.

A study by Sonawalla et al, assessed changes in depressive symptoms and anxiety levels in outpatients with MDD and comorbid anxiety disorder.

Participants were treated with fluvoxamine for 12 weeks. The researchers found that 53% of the patients showed a 50% reduction in depressive symptoms. They concluded that fluvoxamine is effective in treating outpatients with MDD and major comorbid anxiety disorders. The drug had ‘a significant effect on both depression and anxiety symptoms’, noted the authors.

Del Porto et al also studied the efficacy and tolerability of fluvoxamine in the treatment of MDD. This was a six-week open trail. A secondary objective was the evaluation of the effects of fluvoxamine on the sleep of the patients.

Some 69% of the patients obtained a favourable response (defined, as 50% improvement in the Hamilton Depression Rating Scale (HAM-D 17) and the remission rate (HAM-D 17 <7 was 52%.

The specific analysis of the sleep items of the HAM-D 17 showed significant improvement from the second week and the improvement was sustained until the end of the study.

The adverse events were those expected for the SSRI, predominantly gastrointestinal complaints, transitory and of low intensity in most of the cases.

The researchers concluded that their study confirmed the efficacy and tolerability of fluvoxamine in the treatment of MDD, and also its efficacy in the treatment of sleep disturbs among depressed patients. Again, the profile of adverse events was those expected of a SSRI. It should be emphasised that few patients reported sexual dysfunction (2.5% of the patients), noted the researchers.

Efficacy in the treatment of SAD

SAD, characterised by a fear of embarrassment in public, is the most common anxiety disorders with a lifetime prevalence of at least 10%. SAD presents in either a generalised form, associated with a fear of many situations or the nongeneralised form, where the fear presents in just one or two situations.

Symptoms are severe, particularly in the generalised form, and lead to significant impairment in education, work, social, and family situations. Onset is usually before or during adolescence.

Fluvoxamine was the first SSRI to be evaluated in a randomised, controlled trial for the treatment of SAD. The findings showed a significantly greater improvement with fluvoxamine than with placebo on the Liebowitz Social Anxiety Scale (LSAS), Hamilton Anxiety Scale, and the 90-item Symptom Checklist.

In a larger study, fluvoxamine was shown to be significantly superior to placebo on the LSAS, Brief Social Phobia Scale, Social Phobia Inventory, and the Clinical Global Impression (CGI) response rate.

Two later studies involving moor than 500 patients diagnosed with generalised SAD, confirmed that the controlled release formulation of fluvoxamine (100mg/day-300mg/day) was significantly more effective than placebo on the LSAS, CGI severity scale, and the Sheehan Disability Scale (SDS).  The author of the review noted that fluvoxamine has also shown some efficacy in patients with taijin kyofusho, a disorder thought to be a form of SAD unique to Eastern cultures. The term taijin kyofusho translates into the disorder (sho) of fear (kyofu) of interpersonal relations (taijin).

Maintenance treatment

SAD is a chronic disorder and therefore requires maintenance treatment. A 24-week, double-blind extension study, involving 109 patients who showed at least minimal improvement after 12 initial weeks of treatment with fluvoxamine CR (100mg/day-300mg/day) or placebo, showed that patients treated with fluvoxamine continued to show greater improvement than those in the placebo arm. The researchers noted that the magnitude of change was smaller in the extension than in the acute phase.

Fluvoxamine is effective in children and adolescents diagnosed with SAD as well as other anxiety disorders. Fluvoxamine was the first SSRI approved by the US Food and Drug Administration for use in children.

A randomized, double-blind study in 128 children and adolescents aged 6–17 years (>70% aged ≤ 12 years) with SAD, separation anxiety disorder, or generalised anxiety disorder, fluvoxamine (up to 300mg/day) was shown to be significantly more effective than placebo from week three weeks onwards on the Pediatric Anxiety Rating Scale.

According to the authors the mean score was <10 in the fluvoxamine group, indicating no more than mild anxiety, whilst it remained high in the placebo group.

The response rate (CGI improvement score of <4) was 76% with fluvoxamine and 29% with placebo.  Participants were treated for eight weeks.

An open-label extension study (six months) showed that anxiety symptoms remained low in 94% of patients who initially responded to fluvoxamine.

Some 48 participants in the placebo arm were classified as nonresponders, yet 56% showed a clinically significant improvement in anxiety when switched to fluvoxamine. In addition, 71% of the 14 initial fluvoxamine nonresponders also showed a significant improvement when switched to fluoxetine.

How does it work?

Fluvoxamine inhibits the reuptake of serotonin, but has little effect on dopamine and norepinephrine uptake systems. In addition, apart from binding to σ1 receptors, it has a low affinity for neurotransmitter receptors. The affinity of fluvoxamine for σ1receptors, which may be involved in psychosis and aggression, is greater than that seen with the other SSRIs.

The drug is efficiently absorbed after oral administration and its bioavailability is not affected by food. Thereafter it undergoes widespread distribution, although it has lower plasma protein binding than all other SSRIs with the exception of citalopram.

Extensive metabolism occurs in the liver, with less than 4% of the dose being excreted unchanged. None of the resulting metabolites have psychotropic activity, which increases by 30%–50% after multiple dosing, thus making it suitable for once-daily dosing. Excretion is via the urine. There is minimal excretion of fluvoxamine in breast milk.

The pharmacokinetic profile of fluvoxamine is unchanged in patients with renal impairment but slower elimination in patients with hepatic impairment may necessitate an initial dose reduction.

Age has little impact, although slow titration is advised in elderly patients and the recommended maximum dose for children is 200mg/day.

In contrast to a number of other SSRIs, fluvoxamine is only a weak inhibitor of cytochrome P450 (CYP) 2D6 and is therefore unlikely to result in interactions when used in combination with drugs that are metabolised by this isoenzyme, e.g. many antipsychotics.

Fluvoxamine is, however, a potent inhibitor of CYP1A2 and a moderate inhibitor or CYP3A4 and CYP2C19, and may prolong the elimination of agents metabolised by these isoenzymes, e.g. warfarin, theophylline, and some benzodiazepines. There are no interactions between fluvoxamine and alcohol, lithium or digoxin.

 

References:

Irons J. Fluvoxamine in the treatment of anxiety disorders. Neuropsychiatr Dis Treat, 2005.

Sonawalla SB, Spillmann MK, Kolsky AR. Efficacy of fluvoxamine in the treatment of major depression with comorbid anxiety disorders. J Clin Psychiatry, 1999.

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