Panic disorder with or without agoraphobia - Treatment

If panic disorder (with or without agoraphobia) is diagnosed and somatic or neurological pathologies are excluded, then SSRIs are usually the drugs of choice, but exceptions are made in some situations.

In most patients with panic disorder, especially those with comorbid major depression or a history of substance abuse, treatment should begin with an SSRI. Initially, patients with panic disorder are prescribed very low doses: 5-10 mg fluoxetine, 25 mg fluvoxamine, 25 mg sertraline, or 10 mg paroxetine. The patient should be fully informed of the side effects of SSRIs, with particular attention to the possible increase in excitability. Sexual side effects and the risk of developing a manic state should also be mentioned. The physician should pay attention to concomitant therapy. Initially, SSRIs are prescribed in the morning, taking into account the possibility of excitation. However, some patients, on the contrary, experience drowsiness - in this case, it is advisable to move the drug intake to the evening.

The SSRI dose is increased gradually, usually once a week, with careful monitoring to see if the dose increases in anxiety or panic attacks. After a few weeks, the dose can be increased more quickly. If anxiety increases, the dose is reduced or increased more slowly. Monitoring of SSRI blood concentrations is not used in clinical practice, but it may be necessary to monitor the concentration of concomitant medications, such as tricyclic antidepressants.

The anxiolytic effect of SSRIs usually appears no earlier than a week after the start of therapy. The therapeutic effect reaches its maximum after several weeks or months, depending on the tolerability of the drug and, therefore, the rate of dose increase. The same doses are effective for panic disorder as for major depression. The lower limit of effective doses corresponds to 20 mg/day of fluoxetine and paroxetine, 50 mg/day of sertraline, 150 mg/day of fluvoxamine, 40 mg/day of citalopram. The daily dose of most SSRIs can be taken once a day.

Although there is no convincing evidence of the superiority in effectiveness of one drug or another, there are a number of factors that influence the choice of drug for a particular patient. For example, if a patient, along with an SSRI, must take other drugs, the choice of SSRI depends on its effect on cytochrome P450 - it is necessary to avoid prescribing a drug that, by affecting the metabolism of another drug, can cause complications. In addition, it is necessary to take into account differences in pharmacokinetic parameters. Thus, "undisciplined" patients are better off prescribing drugs with a long half-elimination period, for example, fluoxetine. If the patient misses a dose of a drug with a short half-elimination period, then withdrawal syndrome with a rebound increase in anxiety may develop. But when taking a drug with a long half-elimination period, these phenomena are rare. But if the patient needs to prescribe other drugs, then it is better to choose an SSRI with a shorter half-elimination period. Thus, due to the long lifespan of fluoxetine, the blood concentration of fluoxetine remains quite high for several weeks after the drug is discontinued. This makes it difficult to prescribe other drugs, especially MAO inhibitors and tricyclic antidepressants, which are often prescribed in treatment-resistant cases.

High-potency benzodiazepines are indicated for panic disorder mainly in two situations. First, benzodiazepines may be the drug of choice in patients who do not have a psychotropic drug dependence and comorbid major depression, when it is necessary to quickly relieve the patient's paralyzing anxiety (the effect of SSRIs develops too slowly). But even in the absence of anamnestic indications of substance abuse, the patient must be thoroughly informed about the risk of physical dependence. It is because of this risk that benzodiazepines are considered second-line drugs in the treatment of panic disorder. Typically, patients are prescribed SSRIs, and benzodiazepines are used only at the initial stage for rapid symptom relief.

In addition, benzodiazepines are preferred in patients with a history of mania. Unlike other treatments for panic disorder, benzodiazepines do not trigger mania and can be used to treat this condition.

Benzodiazepine treatment, like SSRIs, is started at low doses. Clonazepam is usually preferred, partly because of the higher risk of withdrawal syndrome with alprazolam. However, there are isolated reports that clonazepam more often causes an increase in depression than alprazolam. In many patients, clonazepam is effective at a dose of 0.25-0.5 mg 2-3 times a day (if necessary, an additional dose of the same is allowed). In moderate panic disorder, the effective daily dose is usually no more than 2 mg. However, sometimes the dose has to be increased to 4 mg/day to achieve complete remission. Alprazolam treatment is started at a dose of 0.25-0.5 mg 3 times a day, with a subsequent increase to 2-6 mg/day. However, in some cases the dose has to be increased to 10 mg/day, the maximum recommended dose. Due to the short half-life of alprazolam, it is prescribed 4 times a day, with additional doses allowed if necessary.

If the effect is positive, the drug intake should be extended for at least 6 months. Withdrawal symptoms may occur when benzodiazepines are discontinued. In these cases, a slower reduction in doses over 1-2 months is recommended. Withdrawal of benzodiazepines can also be facilitated by auxiliary cognitive-behavioral psychotherapy. If the patient does not tolerate even a slow reduction in dose, it is recommended to replace the drug with a benzodiazepine with a longer half-elimination period or add an SSRI and only then try to discontinue the benzodiazepine. If the effect is good, it is advisable to continue treatment for a long time. However, many patients nevertheless prefer to discontinue the drugs as quickly as possible.

If SSRIs are ineffective, a benzodiazepine, tricyclic antidepressant, or new mixed serotonin-norepinephrine reuptake inhibitor (eg, venlafaxine) may be prescribed. Before prescribing a tricyclic antidepressant, ECG is required in patients with somatic diseases, children, and the elderly to exclude cardiac conduction disturbances. Patients should be warned about the possibility of anticholinergic side effects and orthostatic hypotension. Treatment with venlafaxine, as with SSRIs, should be started at a low dose, since it can cause a transient increase in anxiety.

In anxiety disorders, tricyclic antidepressants are effective in the same doses as in major depression. Treatment of panic disorder with imipramine begins with a dose of 10 mg 1-2 times a day, then it is increased to 200 mg/day (1.5-3 mg/kg/day). The optimal dose is considered to be 2.25 mg/kg/day. As with SSRIs, the dose of the tricyclic antidepressant at the beginning of treatment is increased gradually, usually by 10 mg 1-2 times a week. The optimal level of imipramine and N-desmethylimipramine is considered to be within 110-140 ng/ml.

There are insufficient data on the optimal doses and blood concentrations of other tricyclic antidepressants in the treatment of panic disorder, and when conducting therapy, one should focus on the doses and concentrations used in the treatment of major depression. The therapeutic blood concentration for desipramine is 125 ng/ml, for nortriptyline - 50-150 ng/ml (this is the only tricyclic antidepressant for which the therapeutic range for major depression is limited from above). The starting dose of desipramine is usually 25 mg/day, then it is increased to 150-200 mg/day, in some cases - up to 300 mg/day. Treatment with nortriptyline is usually started with a dose of 10-25 mg/day, and then it is increased to 100-150 mg/day. In most somatically healthy adults, there is no need to monitor the ECG, but in children and the elderly, an ECG should be recorded before each dose change, given the possibility of side effects associated with cardiac conduction disturbances.

If treatment with first- and second-line drugs is ineffective, MAO inhibitors may be prescribed. MAO inhibitors are highly effective in panic disorder, but their use is limited by the possibility of serious side effects. One of the main inconveniences in the treatment of MAOIs is the need for a break in drug intake (a "washout" period) between the withdrawal of SSRIs and the appointment of an MAO inhibitor. When their effects overlap, serotonin syndrome is possible. After treatment with a short-acting SSRI, the break in drug therapy should be at least two weeks; after taking a drug with a long half-life (for example, fluoxetine), the break in drug therapy should last up to two months. Treatment with MAOIs is usually started with a low dose (15 mg phenelzine or 10 mg tranylcypromine), then it is increased once or twice a week.

The advisability of monitoring MAO activity in platelets in major depression is debated, since the therapeutic effect is achieved only with significant suppression of enzyme activity. In the treatment of anxiety, the need for this method arises extremely rarely. In panic disorder, MAOIs are usually prescribed 2-3 times a day, with the effective dose of phenelzine being 60-75 mg/day (approximately 1 mg/kg), and tranylcypromine - 20-30 mg/day.

If the use of MAOIs is undesirable, then in resistant cases two antipanic drugs are combined, which can enhance each other's effect. For example, to enhance the effect, a benzodiazepine is added to an SSRI or vice versa. The combination of tricyclic antidepressants with benzodiazepines is also used quite widely. The disadvantage of this approach is that the side effects of each drug can also potentiate each other. In addition, there is no convincing data that would confirm the effectiveness of this approach. For most combinations (including the combination of one of the drugs with psychotherapy), randomized clinical trials have not been conducted that would confirm their advantage over monotherapy. When combining drugs, caution should be exercised, avoiding drugs whose interaction can lead to dangerous consequences (for example, SSRIs and MAOIs). In combination therapy, third-line drugs can also be used, including anticonvulsants (if there are signs of bipolar disorder) or calcium antagonists.

Although most patients are successful with one of the above regimens, panic disorder is often chronic or recurrent, so treatment should be long-term. After the effect is achieved, the patient should continue taking the medication at a stable dose for at least 6 months. If the patient has responded quickly to treatment, then an attempt to discontinue the drug within a year is justified. If the patient's condition is difficult to stabilize, then longer therapy is necessary. For almost all drugs, a slow reduction in dosage is recommended to avoid withdrawal syndrome. According to preliminary data, adjuvant psychotherapy can facilitate the procedure of reducing the dosage in patients who have been taking a particular drug for a long time.

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