Obsessive Compulsive Disorder: Treatment

Drugs used in obsessive-compulsive disorder

In the past, obsessive-compulsive disorder was considered a condition resistant to treatment. Traditional methods of psychotherapy, based on psychoanalytic principles, rarely brought success. Disappointed and the results of the use of various drugs. 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 in obsessive-compulsive disorder is the method of exposure and prevention reactions. The exposition consists in placing the patient in a situation that provokes discomfort associated with obsessions. At the same time, patients are given instructions on how to resist compulsive rituals - preventing a reaction.

The main tools for treating obsessive-compulsive disorder are currently clomipramine or selective serotonin reuptake inhibitors (SSRIs). Clomipramine, having a tricyclic nature, is an inhibitor of serotonin reuptake.

The modern era in the pharmacotherapy of obsessive-compulsive disorder began in the second half of the 60s with the observation that clomipramine, but not other tricyclic antidepressants (such as imipramine), is effective in obsessive-compulsive disorder. Clomipramine, a 3-chlorine analogue of tricyclic imipramine, inhibits the reuptake of serotonin 100 times more than the original substance. These distinctive clinical and pharmacological features of clomipramine allowed us to formulate a hypothesis about the role of serotonin in the pathogenesis of obsessive-compulsive disorder. The advantage of clomipramine over placebo and non-serotonergic antidepressants is confirmed by numerous studies with double-blind control. The effect of clomipramine in obsessive-compulsive disorder has been studied most thoroughly. Clomipramine was the first drug to be approved by the FDA for use in the United States for obsessive-compulsive disorder. Desmethylclomipramine, the main metabolite of clomipramine, effectively blocks the reuptake of both serotonin and norepinephrine. With prolonged treatment, desmethylclomipramine reaches a higher plasma concentration than the original substance. Most of the side effects of clomipramine can be predicted from its relationship with various receptors. Like other tricyclic antidepressants, clomipramine often causes side effects caused by blockade of acetylcholine receptors (eg, dry mouth or constipation). At the same time, nausea and tremor when taking clomipramine are found as often as with SSRIs. When taking clomipramine, impotence and anorgasmia may also occur. Many patients complain of drowsiness and weight gain. Of particular concern is the possibility of clomipramine to prolong the QT interval and induce epileptic seizures. The risk of epileptic seizures increases significantly with the administration of doses exceeding 250 mg / day. Intended use of a high dose of clomipramine (overdose) can lead to death.

In recent years, with obsessive-compulsive disorder, clinical trials of new generation antidepressants have been conducted, which are both strong and selective inhibitors of serotonin reuptake. This group includes fluvoxamine, paroxetine, sertraline, fluoxetine and citalopram. Unlike clomipramine, none of these drugs lose their selectivity, blocking the re-uptake of serotonin in vivo. In addition, unlike clomipramine and other tricyclic agents, these drugs do not have any significant effect on histamine, acetylcholine receptors and alpha-adrenergic receptors. To date, clinical trials have proven effective in obsessive-compulsive disorder of all existing SSRIs. Like clomipramine, fluvoxamine proved to be more effective against obsessive-compulsive symptoms than desipramine. In the US, the FDA has authorized the use of fluvoxamine, fluoxetine, paroxetine, and sertraline for obsessive-compulsive disorder in adults. The anti-obsessional effect of fluvoxamine is also confirmed in children. SSRIs are generally well tolerated by patients. The most common side effects are nausea, drowsiness, insomnia, tremors and sexual dysfunction, especially anorgasmia. At the same time, there are no serious concerns about the safety of treatment, and the risk of overdose is small.

Antidepressants that do not have a significant blocking effect on serotonin reuptake (eg, desipramine) are usually ineffective in obsessive-compulsive disorder. In this respect, the obsessive-compulsive disorder contrasts sharply with depression and panic disorder, which, according to most studies, respond equally well to antidepressants - regardless of the degree of selectivity of their effect on re-uptake of catecholamines. This and other differences, revealed in the comparative evaluation of the effectiveness of drugs and electroconvulsive therapy (ECT) in obsessive-compulsive disorder, depression and panic disorder. Nevertheless, the efficacy of SSRIs and clomipramine in obsessive-compulsive disorder is lower than with depression or panic disorder. If, in depression and panic disorder, the response to treatment is often of the "all or nothing" nature, then in obsessive-compulsive disorder it is more likely to be graded and often incomplete. Based on strict efficacy criteria, clinically significant improvement in the treatment of SSRIs or clomipramine can be noted only in 40-60% of patients with obsessive-compulsive disorder.

The blockade of reuptake of serotonin is probably only the first step in the chain of processes, ultimately predetermining the anti-obsessional effect. Based on the data of electrophysiological studies in laboratory animals, the researchers suggested that the mechanism of action of SSRIs in obsessive-compulsive disorder is associated with an increase in serotonergic transmission in the orbitofrontal cortex, which is observed with long-term administration of these drugs.

Since there are currently several effective serotonin reuptake inhibitors, in order to make a choice, it is important to know whether they differ in anti-obsessional activity. A meta-analysis of the results of multicenter studies shows that clomipramine is superior in effectiveness to fluoxetine, sertraline, and fluvoxamine. Nevertheless, the results of meta-analysis should be taken with caution - they may depend on the unequal characteristics of patients included in different studies. Earlier multicenter studies of clomipramine were conducted at a time when there were no other effective agents, whereas in subsequent studies, patients resistant to other drugs (including yyuimipramine) were often included. The best way to compare the effectiveness of drugs is to conduct a direct, comparative, randomized, double-blind study. The results of several such studies comparing the effectiveness of SSRIs and clomipramine have recently been published. In general, these studies did not find the superiority of clomipramine over SSRIs. As for the side effects, here the result was different. With SSRIs, there were fewer serious side effects than with clomipramine, and the tolerability of SSRIs was generally better than that of clomipramine.

[1], [2], [3]

The initial phase of treatment for obsessive-compulsive disorder

Recognition and correct diagnosis of obsessive-compulsive disorder is the first step towards the correct treatment of this condition. For example, patients with obsessive-compulsive disorder often display symptoms of depression and anxiety, and if the doctor pays attention to them, but does not notice the manifestations of obsessive-compulsive disorder, the treatment prescribed by him will be ineffective, since not all antidepressants and only single anxiolytics (and then under big question) have anti-obsessional activity. On the other hand, therapy effective for obsessive-compulsive disorder may be ineffective in the treatment of another disorder, for example, delusional disorders in schizophrenia or obsessive-compulsive personality disorder.

Treatment for obsessive-compulsive disorder should begin with a 10-12-week intake of one of the SSRIs in an adequate dose. Preference is given to SSRIs, because they are better tolerated and safer than clomipramine, but not inferior to it in effectiveness. When choosing a drug from the SSRI group, they are guided by the profile of expected side effects and pharmacokinetic features. It is almost impossible to predict which drug the particular patient will be more effective at. At an early stage of treatment, the main problem is to ensure the patient's compliance by convincing him to take the drug in strict accordance with the prescribed scheme. Particular difficulties arise due to the fact that the symptoms, although they can cause severe discomfort and functional disorders, persist for years, and patients are almost accustomed to them. The dose of SSRIs can be gradually increased every 3-4 days for out-patient treatment (and somewhat faster in inpatient treatment), but with the appearance of side effects (especially nausea), the rate of dose build-up is reduced. Fluoxetine, paroxetine, sertraline and citalopram may be given once a day. The insert-instruction recommends starting treatment with clomipramine and fluvoxamine from a double dose, but in most cases these drugs can be taken once a day, usually at night, as they often cause sedation. In contrast, fluoxetine has an activating action, so it is preferable to take it in the morning so that the drug does not disturb sleep. If the patient received insomnia while taking fluvoxamine, the scheme should be changed so that the main part of the daily dose or the whole daily dose was prescribed in the morning.

Although there is agreement among experts that an adequate duration of trial antidepressant treatment should be 10-12 weeks, their views on the level of the adequate dose are less clear. Some (but not all) studies of SSRIs and clomipramine, in which doses of drugs have been fixed, show that higher doses for obsessive-compulsive disorder are more effective than lower doses. In the case of paroxetine, a dose of 20 mg did not exceed the placebo efficacy, and the minimum effective dose was 40 mg / day.

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

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

A multicenter study of fluvoxamine in adolescents and children 8 years of age and older with obsessive-compulsive disorder showed that at this age, treatment with a dose of 25 mg per night should be started. Then every 3-4 days the dose should be increased by 25 mg, maximum - up to 200 mg / day. Starting at a dose of 75 mg / day, fluvoxamine should be taken 2 times a day, with most of the dose prescribed at night. In elderly people and patients with hepatic insufficiency, lower doses are usually used.

Long-term therapy of obsessive-compulsive disorder

Until now, it remains unclear how long patients with obsessive-compulsive disorder should take the drug after they have responded to the trial therapy. In practice, most patients continue taking the drug for at least 1 year, in some cases, permanent treatment is required. The likelihood of recurrence in the event of a sudden discontinuation of antidepressant use in obsessive-compulsive disorder is very high - in some studies it reaches 90%. In this regard, a special controlled study is needed to determine whether the gradual withdrawal of the drug for a long time (for example, for 6 months or more), as is usually the case in clinical practice, leads to a lower level of relapse. An alternative to a gradual but steady discontinuation 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 for obsessive-compulsive disorder may be lower than that required to achieve an initial therapeutic effect.

With the sudden withdrawal of clomipramine, paroxetine, fluvoxamine and sertraline, side effects are possible. The withdrawal syndrome with a sudden discontinuation of fluoxetine was reported relatively rarely, which is due to a longer half-life of the primary drug and its metabolite, norfluoxetine. The complex of symptoms when SSRIs are abolished is variable, but especially includes influenza-like symptoms, dizziness, lightheadedness, insomnia, bright dreams, irritability and headache that last for several days, sometimes more than 1 week. Although serious side effects are not recorded, these symptoms cause severe discomfort to patients. To reduce the risk of withdrawal syndrome, it is recommended to gradually reduce the dose of clomipramine and all SSRIs, with the exception of fluoxetine.

Correction of side effects

Due to the chronic nature of the disease, even mild side effects of medications can have a significant effect on the compliance and quality of life of patients. Clinical experience shows that with prolonged therapy with clomipramine, patients are more often concerned with weight gain, drowsiness, sexual dysfunction (impotence or anorgasmia), dry mouth, urinary retention, constipation, tremor. When taking clomipramine, it is possible to increase the level of hepatic transaminases in the blood, therefore, liver tests should be performed at least once a year. These same recommendations are relevant for suspected drug hepatitis. When adding a drug that increases the concentration in the plasma of tricyclic antidepressants, it may be necessary to reduce the dose of clomipramine. With prolonged SSRIs, patients may be disturbed by daytime sleepiness, sleep disturbance, anorgasmia, weight gain (not as frequent as with clomipramine), tremor. Drowsiness is most pronounced in the morning and is especially evident with monotonous activity, for example, when driving a car. Because side effects are often dose-dependent, when they occur, you should first lower the dose of the drug. In some cases, an additional remedy is used to correct insomnia or sexual dysfunction.

If there is insomnia in the patient taking an SSRI, it is important to rule out the possibility that this is a consequence of inadequate therapy of comorbid depression or persistent obsessive thoughts. If these reasons are excluded, it is advisable to prescribe a drug to correct this side effect. Most often in this situation, use antidepressant trazodone, which is a derivative of triazolopyridine (50-100 mg at night), because it has a sedative effect without inducing dependence. An alternative to trazodone may be benzodiazepine with a hypnotic effect. It should be borne in mind that fluvoxamine can increase the concentration in the plasma 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 an agonist of benzodiazepine receptors. It has an advantage over benzodiazepines, because, according to some reports, it causes less dependence and an amnestic effect. The development of sexual dysfunction in patients taking psychotropic drugs, always requires a comprehensive survey to determine its cause. In cases where it can be associated with taking the drug, offer several options for action. It has been reported that cyproheptadine, an antihistamine drug that also blocks 5-HT2 receptors, promotes the reverse development of anorgasmia and delayed ejaculation caused by serotonergic agents, in particular fluoxetine. However, when taking cyproheptadine, drowsiness is often observed, which may be dose-dependent. According to a small open study, the antagonist of a2-adrenoreceptors yohimbine can counteract the adverse effects on the sexual sphere of clomipramine and fluoxetine. A case of regression of sexual dysfunction in a 50-year-old patient caused by fluoxetine, with the addition of bupropion, is also described. The mechanism of the positive effect of bupropion on sexual function remains unclear. It was also reported that the positive effect of the medical holidays, which was established in an open study in 30 patients with sexual dysfunction caused by SSRIs. Patients taking paroxetine and sertraline, but not fluoxetine, reported a significant improvement in sexual function after a two-day medical vacation.

[4], [5], [6], [7], [8]

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

Despite the advances in the pharmacotherapy of obsessive-compulsive disorder, approximately 50% of patients do not achieve the desired effect with a single drug. Moreover, even in those cases when there is a positive effect, symptoms can be completely eliminated in only a small part of them. In this regard, new, more advanced approaches to the treatment of obsessive-compulsive disorder, resistant to drug therapy, are needed.

Increase the dose and replace antidepressant. If the intake of SSRIs or clomipramine is not effective enough, then if the drug is well tolerated, its dose can be raised to the maximum recommended level. Fortunately, SSRIs are usually safe even in high doses. In contrast, clomipramine should not normally be administered at a dose exceeding 250 mg / day without careful medical supervision (eg regular ECG registration) and strict indications.

Although the literature discusses the appropriateness of prescribing SSRIs for clomipramine inefficiency, there are numerous examples of SSRIs being able to improve a patient's condition if another drug, including clomipramine, has been ineffective. The authors of such reports recommend the appointment of a new SSRI, if an adequate trial treatment by another representative of this class was unsuccessful. With partial effect, as a rule, it is recommended to switch to combination therapy. If the patient does not tolerate one of the SSRIs, then it is recommended to try another drug, selecting it taking into account possible side effects.

If SSRIs or clomipramine are not effective, other classes of antidepressants may be prescribed. Preliminary data indicate that venlafaxine is effective in some patients with obsessive-compulsive disorder. Fenelzin monoamine oxidase inhibitor may also be useful in obsessive-compulsive disorder, but it is impossible to predict in advance which of the patients it will be effective in, according to clinical data.

Combination therapy: the addition to SSRIs or clomipramine of another drug.

If the monotherapy of SSRIs or clomipramine only led to a partial improvement, or if two courses of trial therapy with different SSRIs were unsuccessful, then combined therapy is indicated. To date, most combination therapy strategies include the addition of a second drug to the previously prescribed SSRI or clomipramine, capable of modulating serotonergic transmission, for example, tryptophan, fenfluramine, lithium, buspirone, pindolol or other SSRIs. Possible and the addition of an antipsychotic.

Only isolated cases have been described, in which the addition of tryptophan, the amino acid precursor of serotonin, was effective. Currently, oral tryptophan drugs are not used in the US because of the risk of developing eosinophilic myalgic syndrome - a very serious disease of the blood and connective tissue with possible fatal outcome.

In small open trials, the addition of d, 1-fenfluramine (pondimene) or dexfenfluramine (redox) to SSRIs, which enhance the release of serotonin and block its re-uptake, has reduced the symptoms of obsessive-compulsive disorder. However, no controlled studies of these drugs have been conducted. In September 1997, the manufacturer (Wyeth-Ayerst) withdrew the drugs from the market after reporting serious cardiac complications. In addition, when using these substances, such serious complications as primary pulmonary hypertension, neurotoxic effects and serotonin syndrome (when combined with SSRIs) are possible.

It has been proven that the addition of a lithium drug enhances the action of antidepressants in depression. It is suggested that lithium potentiates the action of antidepressants, enhancing serotonergic transmission by increasing the presynaptic release of serotonin in certain parts of the brain. Despite several early encouraging reports, the effectiveness of adding lithium in obsessive-compulsive disorder has not been confirmed in controlled studies. Although in general, the effectiveness of lithium in obsessive-compulsive disorder is small, it can be useful in some patients, especially if there is a pronounced depressive symptomatology.

In two open studies, the addition of a partial agonist of 5-HT1 receptor buspirone to previously prescribed fluoxetine has led to an improvement in patients with obsessive-compulsive disorder. However, these encouraging data were not confirmed in three subsequent studies with double-blind control. The addition of buspirone may be useful in patients with obsessive-compulsive disorder in the presence of a concomitant generalized anxiety disorder.

Pindolol is a non-selective beta-adrenoreceptor antagonist, which also has a high affinity for 5-HT1A receptors and blocking the presynaptic action of 5-HT1A receptor agonists. Some studies have shown that pindolol can reduce or enhance the effect of antidepressants in depression. Similar studies in obsessive-compulsive disorder have not yet made a definitive conclusion, but additional studies are under way.

Some patients with obsessive-compulsive disorder, resistant to SSRI monotherapy, the doctors prescribe simultaneously two SSRIs. However, this strategy is little substantiated both empirically and theoretically. The advantages of prescribing two preparations of SSRIs before a high dose of a single drug is difficult to explain, based on modern ideas about the pharmacodynamics of these drugs. Double-blind, controlled studies are needed comparing the effectiveness of taking two drugs with SSRI monotherapy in a high dose.

Although the neuroleptics themselves are ineffective in OCD, data are accumulating that a combination of SSRIs and neuroleptics may be useful in some patients with obsessive-compulsive disorder associated with tics. As double-blind, placebo-controlled studies show, the addition of haloperidol to fluvoxamine in patients resistant to an antidepressant may lead to improvement. In one study, randomisation of patients who were resistant to fluvoxamine monotherapy was randomized. Over the next 4 weeks, patients in addition to a fixed dose of fluvoxamine were assigned haloperidol or placebo. It turned out that the combination of haloperidol and fluvoxamine led to a more significant decrease in the symptoms of obsessive-compulsive disorder in patients with comorbid tics. According to preliminary data, the atypical neuroleptic rice peridone (rispolept), which blocks both dopamine and serotonin 5-HT2 receptors, is able to reduce obsessive-compulsive disorder when added to SSRIs.

[9], [10], [11], [12], [13], [14], [15]

New and experimental methods for treating obsessive-compulsive disorder

When obsessive-compulsive disorder is used and a number of other methods of treatment. First of all, intravenous administration of clomipramine should be mentioned - the only method whose effectiveness is confirmed by more or less convincing empirical data. Recently, with obsessive-compulsive disorder, a study was begun on the effectiveness of the predecessor of the "second mediator" inositol. Currently, clinical trials of immunomodulating agents (eg, prednisolone, plasmapheresis, IV immunoglobulin) or antibacterial agents (eg, penicillin) in patients with PANDAS have been carried out.

Non-pharmacological methods for treating obsessive-compulsive disorder include electroconvulsive therapy (ECT) and neurosurgical interventions. ECT, considered the "gold standard" for treatment of depression, is considered to have limited value in obsessive-compulsive disorder, despite some reports of its effectiveness in cases resistant to drug therapy. In some cases, the positive effect of ECT was short-lived.

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

1. What is the true efficacy of surgical treatment (compared to placebo)?
2. what method (tsingolotomiya, capsulotomy, limbic leukotomy) is more effective and safe?
3. what are the most appropriate targets to be affected?
4. is it possible to predict the effectiveness of stereotactic operations based on clinical data?

Currently, stereotactic psychosurgery should be considered as the last opportunity to help patients with severe obsessive-compulsive disorder who did not respond to consistently conducted for 5 years documented adequate treatment courses with several SSRIs or clomipramine, courses of behavioral therapy in at least two combination treatment regimens (including a combination of SSRIs and behavioral therapy), trial treatment of MAOI and a new antidepressant (eg, venlafaxine), ST (with depression).