Reducing Lexapro may cause nausea
The pure escitalopram
PHARMACYDrug profileby Thilo Bertsche and Martin Schulz, Berlin
Escitalopram is the effective S-enantiomer of the racemic citalopram, for which patent and licensing monopolies have expired. In the first studies, the therapeutic effectiveness of the enantiomer started earlier than that of the racemic mixture.
Selective serotonin reuptake inhibitors (SSRIs), such as citalopram (Cipramil® and others), fluoxetine (Fluctin® and others) or paroxetine (Seroxat® and others), not only have well-documented efficacy in most forms of anxiety disorders and depressive disorders . They are also better tolerated compared to other antidepressants and have a lower incidence of serious side effects. For these reasons, SSRIs play a central role in the therapy of numerous mental illnesses, but they can differ in terms of duration of action and possible interactions (1, 2).
Escitalopram is the antidepressant S-enantiomer of the racemate citalopram. The pharmacological activity of the individual enantiomers in racemic mixtures can sometimes differ considerably, individual enantiomers can even be completely ineffective, but they can be associated with side effects. That is why the use of pure enantiomers makes sense in principle. But do the theoretical advantages of the pure enantiomers also have a clinical effect compared to the racemate and improve the effectiveness and side effects?
For depression or panic disorder
Escitalopram is approved for the treatment of major depressive episodes and panic disorders with or without agoraphobia (claustrophobia in which people avoid walking around large streets and squares, using public transport or leaving a protective room such as their home).
Escitalopram is taken once a day with or without food. The usual dose in the treatment of major depressive episodes is 10 mg. Depending on the individual response of the patient, the dose can be increased to a maximum of 20 mg daily. Those treated usually respond after two to four weeks. Once the symptoms have receded, the patient must continue to take the antidepressant for six months to ensure that the therapy is successful.
Some patients with panic disorder may experience increased anxiety symptoms at the beginning of antidepressant therapy, but these usually go away after two weeks of further treatment. To reduce the risk of these paradoxical symptoms of anxiety, a low starting dose is recommended. For example, a patient with panic disorders with and without agoraphobia receives 5 mg daily for the first week of treatment, only then is it increased to 10 mg. Depending on the response, the attending physician may increase the dose up to a maximum of 20 mg daily. The full effectiveness is achieved after about three months, the treatment lasts several months.
The available preclinical and clinical data have not provided any indications that SSRIs lead to addiction. On discontinuation, the dose should be reduced gradually over one to two weeks in order to avoid possible withdrawal syndromes (3).
Pay attention to the dose
Because escitalopram is eliminated more slowly in older patients than in younger patients, systemic availability in the elderly is increased by 50 percent. The responsible doctor should therefore consider starting treatment with half the usual dose and a reduced maximum dose in patients over 65 years of age.
Use in children and adolescents under 18 years of age is not recommended as safety and efficacy have not been studied in this age group.
No dose adjustment is required in patients with mild to moderate renal impairment. However, caution is advised in patients with severely impaired renal function and a clearance of less than 30 ml / min. In the case of hepatic insufficiency, a dose of 5 mg daily is recommended for the first two weeks of treatment. Depending on the individual response of the patient, the dose can be increased to 10 mg.
Researchers observed that people with impaired CYP-2C19 function, so-called poor metabolisers, have twice as high a plasma concentration of escitalopram as people with a high metabolic rate (extensive metabolisers). If a reduced metabolism via CYP-2C19 is known, those affected should be treated with a dose of 5 mg daily for the first two weeks, which can be increased to 10 mg depending on the response (3).
High affinity for the transporter
Escitalopram (S - (+) - citalopram) selectively inhibits the reuptake of serotonin (5-hydroxytryptamine, 5-HT), which results in the antidepressant effect. The IC50 for the blockade of 5-HT uptake in rat brain synaptosomes in vitro is 2.1 nM compared to 3.9 nM for citalopram and 280 nM for the R enantiomer. The binding affinity for the human 5-HT transporter is 1.1 nM.
A deficiency of the neurotransmitter serotonin or norepinephrine seems to be an important factor in the pathogenesis of depression. While the reuptake inhibition occurs immediately, the changed neurotransmitter concentrations in the synaptic gap only cause a downregulation of receptors with a certain latency, which can explain the actual antidepressant effectiveness. Like citalopram, escitalopram has little or no affinity for other receptors (3 - 5).
Tolerance in the comparison of citalopram
Side effects are most common during the first or second week of treatment and usually decrease in intensity and frequency with continued treatment. When stopped suddenly, some patients experience dizziness, headache, and nausea. Reversible hyponatremia is rare during therapy with SSRIs, but has been described more frequently in high-risk patients (3). A comparison of the side effects of escitalopram and citalopram is particularly interesting, although it does not reveal any significant differences (table) (5).
side effectPlacebo (percent)
n = 592Citalopram (percent)
n = 408 Escitalopram (percent)
n = 715 Treatment-related side effects 64.0 76.5 72.7 Headache 16.4 19.9 15.8 Nausea 7.4 17.2 15.0 Ejaculation disorders 0 8.8 9.3 Insomnia 3.9 8.6 9.2 Diarrhea 5.2 10.8 8.0 Drowsiness 2.2 4.7 6.9 Dry mouth 4.6 8.1 6.2 Dizziness 3.5 5.6 6.0 Flu-like symptoms 4.1 6.1 5.0 Cold 5.1 5.6 4.9 Sinusitis 2.2 5.1 4.3
Seizures and risk of suicide
SSRIs can lower the seizure threshold. If these occur, the attending physician should stop the treatment. SSRIs should not be used in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. They should stop taking antidepressants as soon as the frequency of seizures increases. SSRIs should also be discontinued if patients enter a manic phase during therapy. The active ingredients are known to increase the risk of suicide in the first few weeks of treatment (3).
Diabetics and pregnant women
In diabetics, treatment with SSRIs can change the diabetic parameters so that the insulin dose or the oral antidiabetic drugs have to be adjusted. Due to limited clinical experience, caution is also advised in patients with coronary artery disease. For escitalopram there is no clinical information on its use during pregnancy. In reproductive toxicity studies with escitalopram in rats, embryofetotoxic effects but no increased incidence of malformations were observed. It can be assumed that escitalopram is excreted in breast milk (3).
Serotonin Syndrome with MAOIs
Side effects between MAOIs and SSRIs can be serious. Serotonin syndrome, which may be life-threatening, is particularly feared. It is characterized by central restlessness, rigidity (muscle stiffness as a result of increased muscle tone), hyperreflexia and fever. Serotonin syndrome can also occur through serotonergic drugs such as tramadol or triptans as migraine drugs. The therapeutic approach differs depending on the type of MAO inhibitor.
- Tranylcypromine (unselective, irreversible):
Escitalopram must not be used in combination with MAO inhibitors such as tranylcypromine. Treatment with escitalopram must not be started until 14 days after the end of therapy with tranylcypromine at the earliest. Tranylcypromine should not be used until 7 days after stopping escitalopram.
- Moclobemide (selective MAO-A, reversible):
If possible, escitalopram should not be used together with MAO inhibitors such as moclobemide or, if possible, in the lowest dose and with special therapy monitoring. Treatment with escitalopram should not be started until one day after the end of therapy with moclobemide at the earliest.
- Selegiline (selective MAO-B, irreversible):
In combination with selegiline (irreversible MAO-B inhibitor), caution should be exercised because of the possible development of serotonin syndrome. Selegiline in doses of up to 10 mg / day could be used safely together with racemic citalopram (3).
Think about interactions
It has been reported that concomitant therapy with lithium or tryptophan increases the effects of SSRIs, so they should only be used with caution. The combination of escitalopram and oral anticoagulants can affect blood clotting. Particularly in self-medication, it should be noted that simultaneous treatment with St. John's wort preparations in effective doses can increase the risk of side effects (3).
Which Antidepressant Is The Best? Antidepressants can be classified into different groups, which, due to their different characteristics, enable individually tailored therapy. Depending on the extent of their drive-enhancing or inhibiting or sedating effect, a distinction is also made between antidepressants for inhibited-depressive and agitated / anxious-depressive syndromes. The most important group because of their high effectiveness are the non-selective monoamine reuptake inhibitors (NSMRI), mostly tricyclic or tetracyclic antidepressants. There is broad experience for these and they have also been well studied in severe depression and patient groups who are mostly excluded from clinical trials of newer drugs. The anticholinergic side effects, for example on the heart and the lowering of the seizure threshold, limit the therapeutic use.
The attending physician must gradually increase the dosage of tricyclic antidepressants, the target dosage must be individually tailored, but sufficiently high. Newer, non-selective drugs such as mianserin (Tolvin® and others), trazodone (Thombran® and others) or viloxazine (Vivalan®) have a more favorable spectrum of side effects for many patients, but they have less experience in therapy. Damage to the blood count such as leukopenia or agranulocytosis are more common with mianserin than with other NSMRIs.
The selective serotonin reuptake inhibitors such as escitalopram (Cipralex®), citalopram (Cipramil® and others), fluoxetine (Fluctin® and others), fluvoxamine (Fevarin® and others), paroxetine (Seroxat® and others) or sertraline (Gladem® and others) ) are usually well tolerated. However, particular attention should be paid to interactions via cytochrome P450 isoenzymes. Under no circumstances should MAO inhibitors be given at the same time as SSRIs. Agitation, sleep disorders, nausea, and sexual dysfunction are typical side effects of SSRIs. Venlafaxine (Trevilor® and others) selectively inhibits both serotonin and norepinephrine reuptake. Venlafaxine thus corresponds to an NSMRI without its vegetative, undesirable effects. Reboxetine (Edronax®) is a specific norepinephrine reuptake inhibitor (NRI). Tranylcypromine (Jatrosom® N) and moclobemide (Aurorix®) are used therapeutically as MAO inhibitors. Benzodiazepines can be used as adjuvants, especially as sedatives and anxiolytics and low-potency neuroleptics for neurotic components (1, 2).
Escitalopram as a cytochrome inhibitor
The metabolism of escitalopram is mainly controlled by CYP 2C19. CYP 3A4 and CYP 2D6 probably also contribute to the metabolism, albeit to a lesser extent. Since escitalopram inhibits the enzyme CYP 2D6, caution should be exercised in combination with medicinal products that are mainly metabolised via this enzyme and that have a narrow therapeutic index: for example flecainide, propafenone and metoprolol or antidepressants such as desipramine, clomipramine, nortriptyline or neuroleptics such as Risperidone, thioridazine and haloperidol. Patients should therefore receive these drugs at a lower dose. Simultaneous treatment with desipramine or metoprolol, for example, doubled the plasma concentrations of these two CYP-2D6 substrates (3).
Escitalopram is absorbed regardless of food intake and its pharmacokinetics are linear. The plasma levels are in equilibrium within about a week. At a daily dose of 10 mg, steady-state concentrations averaging 50 nmol / l (range 20 to 125 nmol / l) are achieved. After multiple dosing, the mean tmax is four hours. As with citalopram, the absolute bioavailability is around 80 percent and the apparent volume of distribution after oral administration is 12 to 26 l / kg. Both escitalopram and its major metabolites bind between 50 and 80 percent to plasma proteins.
Escitalopram is demethylated in the liver to form pharmacologically active metabolites, some of which, like the parent substance, are excreted as glucuronides. The elimination half-life after multiple dosing is around 30 hours and the oral plasma clearance is around 0.6 l / min, with the main metabolites having a significantly longer half-life. Escitalopram and its major metabolites are believed to be both metabolised by the liver and eliminated by the kidneys, with most of the dose being excreted as metabolites in the urine. No significant change in plasma concentration was found in people with impaired CYP-2D6 function (3, 5).
Placebo comparison without surprise
Not surprisingly, escitalopram, as an effective enantiomer of the well-known citalopram, has been shown to be effective in placebo-controlled studies (6). For example, in an eight-week double-blind study, 191 patients with major depression received escitalopram 10 mg daily and 189 placebo. This intervention phase was preceded by a one-week placebo phase in both groups. After eight weeks, the condition of the verum group improved significantly compared to placebo according to a depression rating scale. After just one to three weeks, depending on the score used, the escitalopram administration was able to achieve the first significant improvements in comparison with placebo. The dropout rate was at the placebo level, but nausea occurred more frequently in the verum group than in the placebo group.
Patients respond earlier
In therapeutic practice, a comparison with citalopram is of particular interest. Gorman et al. examined placebo-controlled studies on the treatment of major depression with escitalopram and citalopram in a pooled analysis. Data from three similarly designed studies with escitalopram (10 to 20 mg / day) and citalopram (20 to 40 mg / day) were included in the meta-analysis (7). Efficacy was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression of Improvement (CGI-I scale). The development of the associated anxiety disorders was also determined.
The evaluation showed that both escitalopram and citalopram significantly improved depression and anxiety symptoms compared with placebo. According to the MADR scale, the number of responders was also greater among the antidepressants than with the placebo. With escitalopram, the symptoms improved significantly after one week of treatment compared to placebo, while with citalopram it was not until the end of the fourth or sixth week of treatment. The results also coincide with preclinical studies which, in animal models, showed an earlier response to escitalopram (5 mg / kg body weight) compared to citalopram (10 mg / kg body weight) (8).
A current double-blind study compared escitalopram in moderately to severely depressed patients in outpatient treatment with placebo and citalopram (9). Patients were randomized to receive escitalopram 10 to 20 mg (n = 155), citalopram 20 to 40 mg (n = 160), or placebo (n = 154) per day for eight weeks. The effectiveness was determined using various rating scales in comparison to the initial value. Using the MADR scale, for example, the value improved to 15 points in the escitalopram, 13.6 points in the citalopram and 12.1 points in the placebo group.
While the antidepressants performed significantly better than placebo on all scales, escitalopram only tended to be better than citalopram. Up to the eighth week, a total of more patients responded to escitalopram than to citalopram: 63.7 percent had a lower MADRS value by more than half, with placebo it was 48.2 (p = 0.009) and with citalopram 52.6 Percent (p = 0.021). Escitalopram showed a side effect profile comparable to that of citalopram.
Conclusion: The clinical relevance of the earlier response remains open After patent and licensing market monopolies for Citalopram expired, the effective enantiomer has now been brought onto the market as a “new monosubstance”.Since the pharmacological activity of enantiomers often differs, the sole therapeutic use of the active enantiomer is in principle desirable. But whether this significantly improves the effectiveness in the clinic or reduces side effects is also an open question for escitalopram.
Like the racemate citalopram, escitalopram is also an effective antidepressant from the SSRI group. The side effects are comparable to those of citalopram in terms of their clinically relevant frequency and severity. There are no differences in the potential for interaction with citalopram. In initial comparative studies, the therapeutic effectiveness of the pure enantiomer began earlier than that of the racemic mixture. Should the differences in the effect actually prove to be clinically relevant in the first few weeks, an effect starting a week earlier could above all improve the patient's compliance.
- Drugs Commission of the German Medical Association, Recommendations for the Therapy of Depression, Drug Ordinance in Practice, Special Issue 8, 1st Edition 1997.
- German Society for Psychiatry, Psychotherapy and Neurology (DGPPN), practice guidelines in psychiatry and psychotherapy, treatment guidelines for affective diseases. Short version at www.dgppn.de/leitlinien.htm, as of December 2003.
- Specialist information Cipralex 10 and 20 mg, Lundbeck company, as of June 2003.
- Mutschler, E., et al., Drug effects - textbook of pharmacology and toxicology, Wissenschaftliche Verlagsgesellschaft Stuttgart, 8th edition 2001.
- Cipralex basic brochure, Lundbeck (Switzerland), at www.cipralex.ch/pdf/product/basis_d.pdf (as of December 23, 2003).
- Wade, A., Escitalopram 10 mg / day is effective and well tolerated in a placebo-controlled study in depression in primary care. Int. Clin. Psychopharmacol. 17 (2002) 95-102.
- Gorman, J. M., et al., Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder, pooled analysis of placebo-controlled trails. CNS Spectrums 7, Suppl. 1 (2002) 40-44.
- Montgomery, S. A., Escitalopram (S-enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model. Pharmacol. Toxicol. 88 (2001) 282-286.
- Lepola, U. M., et al., Escitalopram (10-20 mg / day) is effective and well tolerated in a placebo-controlled study in depression in primary care. Int. Clin. Psychopharmacol. 18 (2003) 211-217.
Dr. Thilo Bertsche and Dr. Martin Schulz
Center for Drug Information and Pharmaceutical Practice (ZAPP) of the ABDA
© 2004 GOVI-Verlag
Email: [email protected]
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