Obsessive-compulsive disorder - Treatment

Medicines Used for Obsessive Compulsive Disorder

In the past, obsessive-compulsive disorder was considered a treatment-resistant condition. Traditional psychotherapy methods based on psychoanalytic principles were rarely successful. The results of using various medications were also disappointing. However, in the 1980s, the situation changed due to the emergence of new methods of behavioral therapy and pharmacotherapy, the effectiveness of which was confirmed in large-scale studies. The most effective form of behavioral therapy for obsessive-compulsive disorder is the method of exposure and response prevention. Exposure involves placing the patient in a situation that provokes the discomfort associated with obsessions. At the same time, patients are given instructions on how to resist performing compulsive rituals - response prevention.

The main treatments for obsessive-compulsive disorder are currently clomipramine or selective serotonin reuptake inhibitors (SSRIs). Clomipramine, being a tricyclic, is a serotonin reuptake inhibitor.

The modern era of pharmacotherapy of obsessive-compulsive disorder began in the second half of the 1960s with the observation that clomipramine, but not other tricyclic antidepressants (such as imipramine), was effective in obsessive-compulsive disorder. Clomipramine, a 3-chlorine analogue of the tricyclic imipramine, is 100 times more potent in inhibiting serotonin reuptake than the parent substance. These distinctive clinical and pharmacological properties of clomipramine led to the hypothesis that serotonin plays a role in the pathogenesis of obsessive-compulsive disorder. The superiority of clomipramine over placebo and nonserotonergic antidepressants has been confirmed by numerous double-blind studies. The effect of clomipramine in obsessive-compulsive disorder has been studied most thoroughly. Clomipramine was the first drug to receive FDA approval for use in the United States for obsessive-compulsive disorder. Desmethylclomipramine, the major metabolite of clomipramine, effectively blocks the reuptake of both serotonin and norepinephrine. With long-term treatment, desmethylclomipramine reaches higher plasma concentrations than the parent drug. Most of the side effects of clomipramine can be predicted based on its interactions with various receptors. Like other tricyclic antidepressants, clomipramine often causes side effects due to acetylcholine receptor blockade (eg, dry mouth or constipation). However, nausea and tremor are as common with clomipramine as with SSRIs. Impotence and anorgasmia may also occur with clomipramine. Many patients complain of drowsiness and weight gain. Of particular concern is the potential for clomipramine to prolong the QT interval and cause seizures. The risk of seizures increases significantly with doses exceeding 250 mg/day. Intentional administration of a high dose of clomipramine (overdose) may be fatal.

In recent years, clinical trials of new-generation antidepressants that are both potent and selective serotonin reuptake inhibitors have been conducted in obsessive-compulsive disorder. This group includes fluvoxamine, paroxetine, sertraline, fluoxetine, and citalopram. Unlike clomipramine, none of these drugs loses its selectivity by blocking serotonin reuptake in vivo. In addition, unlike clomipramine and other tricyclics, these drugs do not have any significant effect on histamine, acetylcholine, and alpha-adrenergic receptors. To date, clinical trials have proven the effectiveness of all existing SSRIs in obsessive-compulsive disorder. As with clomipramine, fluvoxamine has proven to be more effective in reducing obsessive-compulsive symptoms than desipramine. In the US, the FDA has approved fluvoxamine, fluoxetine, paroxetine, and sertraline for use in adults with obsessive-compulsive disorder. The anti-obsessive effect of fluvoxamine has also been confirmed in children. SSRIs are generally well tolerated by patients. The most common side effects are nausea, drowsiness, insomnia, tremor, and sexual dysfunction, especially anorgasmia. At the same time, there are no serious concerns regarding the safety of treatment, and the risk of drug overdose is low.

Antidepressants that do not significantly block serotonin reuptake (e.g., desipramine) are generally ineffective in obsessive-compulsive disorder. In this respect, obsessive-compulsive disorder stands in stark contrast to depression and panic disorder, which most studies show respond equally well to antidepressants, regardless of their degree of selectivity for catecholamine reuptake. These and other differences emerge when comparing the efficacy of drugs and electroconvulsive therapy (ECT) in obsessive-compulsive disorder, depression, and panic disorder. However, the efficacy rates of SSRIs and clomipramine in obsessive-compulsive disorder are lower than in depression or panic disorder. While the response to treatment in depression and panic disorder is often all-or-nothing, in obsessive-compulsive disorder it is more graded and often incomplete. Based on strict criteria of effectiveness, clinically significant improvement with SSRI or clomipramine treatment can be seen in only 40-60% of patients with obsessive-compulsive disorder.

Serotonin reuptake blockade is likely to be only the first step in a chain of processes that ultimately determine the anti-obsessional effect. Based on electrophysiological studies in laboratory animals, researchers have suggested that the mechanism of action of SSRIs in obsessive-compulsive disorder is associated with increased serotonergic transmission in the orbitofrontal cortex, which is observed with long-term use of these drugs.

Since there are currently several effective serotonin reuptake inhibitors, it is important to know whether they differ in their anti-obsessional activity in order to make a choice. A meta-analysis of the results of the multicenter trials shows that clomipramine is superior to fluoxetine, sertraline, and fluvoxamine. However, the results of the meta-analysis should be taken with caution, as they may be influenced by differences in the characteristics of the patients included in the different trials. The earlier multicenter trials of clomipramine were conducted at a time when no other effective drugs were available, while the later trials often included patients who were resistant to other drugs (including clomipramine). The best way to compare the effectiveness of drugs is to conduct a head-to-head randomized, double-blind trial. The results of several such trials comparing the effectiveness of SSRIs and clomipramine have been published recently. In general, these trials did not find an advantage of clomipramine over SSRIs. With regard to side effects, the results were different. SSRIs produced fewer serious side effects than clomipramine, and SSRIs were generally better tolerated than clomipramine.

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Initial phase of treatment for obsessive-compulsive disorder

Recognizing and correctly diagnosing obsessive-compulsive disorder is the first step toward correct treatment of this condition. For example, patients with obsessive-compulsive disorder often have symptoms of depression and anxiety, and if a doctor pays attention to them but does not notice the manifestations of obsessive-compulsive disorder, then the treatment prescribed by him will be ineffective, since not all antidepressants and only a few anxiolytics (and even then it is highly questionable) have anti-obsessive activity. On the other hand, therapy that is effective in obsessive-compulsive disorder may be ineffective in treating another disorder, such as delusional disorders in schizophrenia or obsessive-compulsive personality disorder.

Treatment of obsessive-compulsive disorder should begin with 10-12 weeks of taking one of the SSRIs in an adequate dose. SSRIs are preferred because they are better tolerated and safer than clomipramine, but are not inferior to it in effectiveness. When choosing a drug from the SSRI group, one should focus on the profile of expected side effects and pharmacokinetic characteristics. It is almost impossible to predict which drug will be more effective for a particular patient. At the early stage of treatment, the main problem is to ensure patient compliance, convincing him or her to take the drug in strict accordance with the prescribed regimen. Particular difficulties arise due to the fact that the symptoms, although they can cause severe discomfort and functional impairment, persist for years, and patients almost get used to them. The dose of SSRIs can be gradually increased every 3-4 days during outpatient treatment (and somewhat faster during inpatient treatment), but if side effects appear (especially nausea), the rate of dose increase is reduced. Fluoxetine, paroxetine, sertraline, and citalopram can be given once daily. The package insert recommends starting clomipramine and fluvoxamine with twice-daily dosing, but in most cases these drugs can also be given once daily, usually at night, because they often cause sedation. In contrast, fluoxetine has an activating effect, so it is preferable to take it in the morning so that the drug does not interfere with sleep. If insomnia occurs while taking fluvoxamine, the regimen should be modified so that most or all of the daily dose is given in the morning.

Although there is agreement among experts that an adequate duration of antidepressant treatment is 10–12 weeks, there is less agreement on the appropriate dose level. Some (but not all) fixed-dose studies of SSRIs and clomipramine show that higher doses are more effective than lower doses in obsessive-compulsive disorder. In the case of paroxetine, 20 mg was not superior to placebo, and the lowest effective dose was 40 mg/day.

Studies of fluoxetine in obsessive-compulsive disorder have shown that 60 mg/day is more effective than 20 mg/day, but both 20 and 40 mg/day were more effective than placebo. However, at 60 mg/day, fluoxetine was more likely to cause side effects than at lower doses. In practice, it is recommended to prescribe fluoxetine at 40 mg/day for about 8 weeks - and only then make a decision

On further dose escalation. In order to correctly assess the efficacy of a particular drug, the criteria for the adequacy of the trial treatment should be defined. Trial therapy with clomipramine, fluvoxamine, fluoxetine, sertraline, paroxetine, and citalopram should last 10-12 weeks, with the minimum daily dose of the drug being 150, 150, 40, 150, 40, and 40 mg, respectively. Although trial treatment with fluoxetine at a dose of 40 mg/day for 8-12 weeks seems adequate, a conclusion about fluoxetine resistance should be made only after its dose has been increased to 80 mg/day (provided that the drug is well tolerated).

A multicenter study of fluvoxamine in adolescents and children aged 8 years and older with obsessive-compulsive disorder showed that treatment should be started at this age with a dose of 25 mg at night. The dose should then be increased by 25 mg every 3-4 days, up to a maximum of 200 mg/day. Starting with a dose of 75 mg/day, fluvoxamine should be taken twice daily, with most of the dose administered at night. Lower doses are generally used in elderly individuals and patients with liver failure.

Long-term therapy for obsessive-compulsive disorder

It is still unclear how long patients with obsessive-compulsive disorder should take the drug after they have responded to a trial of therapy. In practice, most patients continue taking the drug for at least 1 year, and in some cases, continuous treatment is required. The relapse rate in case of abrupt discontinuation of an antidepressant for obsessive-compulsive disorder is very high - in some studies it reaches 90%. Therefore, a special controlled study is needed to determine whether gradual withdrawal of the drug over a long period (e.g., 6 months or more), as is usually the case in clinical practice, leads to a lower relapse rate. An alternative to gradual but steady withdrawal of the drug may be to reduce the dose to a new stable level. As clinical experience and a recent study show, the maintenance dose in obsessive-compulsive disorder may be lower than those required to achieve the initial therapeutic effect.

Adverse effects may occur with abrupt discontinuation of clomipramine, paroxetine, fluvoxamine, and sertraline. Withdrawal syndrome has been reported relatively rarely with abrupt discontinuation of fluoxetine, which is explained by the longer half-life of the parent drug and its metabolite norfluoxetine. The symptom complex during SSRI withdrawal is variable, but most often includes flu-like symptoms, dizziness, lightheadedness, insomnia, vivid dreams, irritability, and headache, which last for several days, sometimes more than 1 week. Although serious side effects are not reported, these symptoms cause significant discomfort to patients. To reduce the risk of withdrawal syndrome, it is recommended to gradually reduce the dose of clomipramine and all SSRIs except fluoxetine.

Correction of side effects

Due to the chronic nature of the disease, even mild side effects of drugs can have a significant impact on compliance and quality of life of patients. As clinical experience shows, with long-term therapy with clomipramine, patients most often complain of weight gain, drowsiness, sexual dysfunction (impotence or anorgasmia), dry mouth, urinary retention, constipation, tremor. When taking clomipramine, the level of liver transaminases in the blood may increase, so liver tests should be performed at least once a year. The same recommendations are relevant if drug-induced hepatitis is suspected. When adding a drug that increases the concentration of tricyclic antidepressants in the plasma, it may be necessary to reduce the dose of clomipramine. With long-term use of SSRIs, patients may complain of daytime sleepiness, sleep disturbances, anorgasmia, weight gain (not as frequent as with clomipramine), tremor. Drowsiness is most pronounced in the morning and is especially common during monotonous activities, such as driving. Since side effects are often dose-dependent, the first step in treating them is to reduce the dose. In some cases, an additional medication is prescribed to correct insomnia or sexual dysfunction.

If a patient taking an SSRI experiences insomnia, it is important to exclude the possibility that this is a consequence of inadequate treatment of comorbid depression or persistent obsessive thoughts. If these causes are excluded, it is advisable to prescribe a drug to correct this side effect. The most commonly used antidepressant in this situation is trazodone, a triazolopyridine derivative (50-100 mg at night), since it has a sedative effect without causing addiction. An alternative to trazodone may be a benzodiazepine with a hypnotic effect. It should be taken into account that fluvoxamine can increase the plasma concentration of triazolobenzodiazepines (eg, alprazolam) by inhibiting its metabolism in the liver, but does not affect the metabolism of lorazepam. Zolpidem is structurally different from benzodiazepines, although it is a benzodiazepine receptor agonist. It has an advantage over benzodiazepines because, according to some data, it causes less dependence and amnestic effect. The development of sexual dysfunction in patients taking psychotropic drugs always requires a comprehensive examination to identify its cause. In cases where it can be associated with drug intake, several options are offered. It has been reported that cyproheptadine, an antihistamine that also blocks 5-HT2 receptors, promotes the reversal of anorgasmia and delayed ejaculation caused by serotonergic drugs, in particular fluoxetine. However, drowsiness is often observed when taking cyproheptadine, which may be dose-dependent. According to a small open study, the a2-adrenergic receptor antagonist yohimbine can counteract the adverse effects of clomipramine and fluoxetine on the sexual sphere. A case of regression of fluoxetine-induced sexual dysfunction in a 50-year-old patient with the addition of bupropion has also been described. The mechanism of the beneficial effect of bupropion on sexual function remains unclear. A beneficial effect of drug holidays has also been reported, which was established in an open study in 30 patients with SSRI-induced sexual dysfunction. Patients taking paroxetine and sertraline, but not fluoxetine, reported significant improvement in sexual function after a two-day drug holiday.

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Approaches to the treatment of resistant cases of obsessive-compulsive disorder

Despite advances in pharmacotherapy for obsessive-compulsive disorder, approximately 50% of patients fail to achieve the desired effect with a single drug. Moreover, even in cases where a positive effect is observed, only a small proportion of the symptoms can be completely eliminated. In this regard, new, more advanced approaches to the treatment of obsessive-compulsive disorder resistant to drug therapy are needed.

Increasing the dose and changing the antidepressant. If the SSRI or clomipramine is not effective enough, the dose can be increased to the maximum recommended level if the drug is well tolerated. Fortunately, SSRIs are generally safe even at high doses. In contrast, clomipramine should generally not be prescribed at a dose exceeding 250 mg/day without careful medical monitoring (e.g. regular ECG recording) and strict indications.

Although the literature discusses the advisability of prescribing SSRIs when clomipramine is ineffective, there are numerous examples of SSRIs being able to improve a patient's condition when another drug, including clomipramine, has proven ineffective. The authors of such reports recommend prescribing a new SSRI if adequate trial treatment with another representative of this class has proven unsuccessful. If the effect is partial, it is usually recommended to switch to combination therapy. If the patient does not tolerate one of the SSRIs, it is recommended to try another drug, choosing it taking into account possible side effects.

If SSRIs or clomipramine are ineffective, other classes of antidepressants may be considered. Preliminary data suggest that venlafaxine is effective in some patients with obsessive-compulsive disorder. The monoamine oxidase inhibitor phenelzine may also be useful in obsessive-compulsive disorder, but it is impossible to predict in advance in which patients it will be effective based on clinical data.

Combination therapy: adding another drug to an SSRI or clomipramine.

If monotherapy with an SSRI or clomipramine has resulted in only partial improvement, or if two courses of trial therapy with different SSRIs have been unsuccessful, then combination therapy is indicated. Today, most combination therapy strategies involve adding a second drug capable of modulating serotonergic transmission to the previously prescribed SSRI or clomipramine, such as tryptophan, fenfluramine, lithium, buspirone, pindolol, or another SSRI. Addition of a neuroleptic is also possible.

Only a few cases have been described in which the addition of tryptophan, an amino acid precursor to serotonin, was effective. Oral tryptophan preparations are not currently used in the United States because of the risk of developing eosinophilic myalgic syndrome, a very serious disease of the blood and connective tissue with a potentially fatal outcome.

In small open studies, the addition of d,1-fenfluramine (Pondimen) or dexfenfluramine (Reduca), which enhance serotonin release and block its reuptake, to SSRIs resulted in a reduction in OCD symptoms. However, no controlled studies have been conducted with these drugs. In September 1997, the manufacturer (Wyeth-Ayerst) withdrew the drugs from the market after reports of serious cardiac complications. In addition, serious complications such as primary pulmonary hypertension, neurotoxic effects, and serotonin syndrome (when combined with SSRIs) are possible with these agents.

Lithium supplementation has been shown to enhance the effects of antidepressants in depression. It is suggested that lithium potentiates the effects of antidepressants by enhancing serotonergic transmission by increasing presynaptic serotonin release in some brain regions. Despite some early encouraging reports, the efficacy of lithium supplementation in obsessive-compulsive disorder has not been confirmed in controlled studies. Although lithium is of limited benefit in obsessive-compulsive disorder, it may be useful in selected patients, particularly those with significant depressive symptoms.

In two open-label studies, adding the 5-HT1 receptor partial agonist buspirone to previously prescribed fluoxetine resulted in improvement in patients with obsessive-compulsive disorder. However, these encouraging findings were not confirmed in three subsequent double-blind studies. Adding buspirone may be beneficial in patients with obsessive-compulsive disorder with concomitant generalized anxiety disorder.

Pindolol is a non-selective beta-adrenergic receptor antagonist that also has high affinity for 5-HT1A receptors and blocks the presynaptic action of 5-HT1A receptor agonists. Some studies have shown that pindolol can weaken or enhance the effect of antidepressants in depression. Similar studies in obsessive-compulsive disorder have not yet allowed a definitive conclusion to be made, but additional studies are currently underway.

In some patients with obsessive-compulsive disorder resistant to SSRI monotherapy, physicians prescribe two SSRIs simultaneously. However, this strategy has little empirical or theoretical support. The benefits of prescribing two SSRIs over a high dose of one drug are difficult to explain based on current understanding of the pharmacodynamics of these agents. Double-blind, controlled trials comparing the efficacy of two drugs with high-dose SSRI monotherapy are needed.

Although antipsychotics alone are ineffective in OCD, there is accumulating evidence that a combination of an SSRI and an antipsychotic may be useful in some patients with tic-related obsessive-compulsive disorder. Double-blind, placebo-controlled studies have shown that adding haloperidol to fluvoxamine in antidepressant-resistant patients may result in improvement. One study randomized patients who were resistant to fluvoxamine monotherapy to receive either haloperidol or placebo in addition to a fixed dose of fluvoxamine for 4 weeks. The combination of haloperidol and fluvoxamine resulted in a greater reduction in OCD symptoms in patients with comorbid tics. According to preliminary data, the atypical neuroleptic risperidone (risperidone), which blocks both dopamine and serotonin 5-HT2 receptors, is able to reduce obsessive-compulsive disorder when added to SSRIs.

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New and experimental treatments for obsessive-compulsive disorder

There are a number of other treatments used in OCD. The most important is intravenous clomipramine, the only treatment with more or less convincing empirical evidence. A recent study has been launched to evaluate the efficacy of the "second messenger" precursor inositol in OCD. Clinical trials of immunomodulatory agents (e.g., prednisolone, plasmapheresis, intravenous immunoglobulin) or antibacterial agents (e.g., penicillin) are currently underway in patients with PANDAS.

Non-pharmacological treatments for obsessive-compulsive disorder include electroconvulsive therapy (ECT) and neurosurgical interventions. ECT, considered the "gold standard" treatment for depression, is considered to be of limited value in obsessive-compulsive disorder, despite anecdotal reports of its effectiveness in drug-resistant cases. In some cases, the benefits of ECT were short-lived.

Modern stereotactic neurosurgical techniques should not be equated with the previously used rather crude neurosurgical interventions. Recent studies show that stereotactic destruction of the cingulum fascicle (cingulotomy) or the anterior limb of the internal capsule (capsulotomy) can lead to significant clinical improvement in some patients with obsessive-compulsive disorder, without serious side effects. However, a number of questions related to neurosurgical treatment of obsessive-compulsive disorder remain unanswered:

1. What is the true effectiveness of surgical treatment (compared to placebo)?
2. Which technique (cingolotomy, capsulotomy, limbic leucotomy) is more effective and safe?
3. What targets are most appropriate to target?
4. Is it possible to predict the effectiveness of stereotactic surgeries based on clinical data?

At present, stereotactic psychosurgery should be considered as a last resort for patients with severe obsessive-compulsive disorder who have not responded to 5 years of documented, consistent, adequate treatment with multiple SSRIs or clomipramine, behavioral therapy, at least two combination treatment regimens (including a combination of SSRIs and behavioral therapy), a trial of an MAOI and a new antidepressant (eg, venlafaxine), or ECT (if depression is present).