Citalopram has been subjected to extensive investigation in depression over the past decade. It has been repeatedly shown to be significantly better than placebo (). Citalopram has also been compared extensively with numerous other antidepressants, including the tricyclic compounds imipramine and clomipramine and the SSRIs fluoxetine, fluvoxamine, and sertraline, and has been found to have comparable efficacy (). Interestingly, one study has suggested a more rapid onset of action for citalopram than for fluoxetine, based on a significantly greater improvement in depression scores after 2 weeks ().
The efficacy of citalopram in obsessive-compulsive disorder has only recently become a subject of interest. Thus, the first large multisite double-blind studies using fixed-dose and flexible-dose strategies have only recently been completed; results of these studies are not available as yet beyond preliminary reports. However, there are several published case reports, open trials, and small double-blind studies available (). The first report of citalopram use in obsessive-compulsive disorder was published by White et al. (1986). They described the case of a 31-year-old man with long-standing obsessive-compulsive disorder who responded within 5 weeks to treatment with 80 mg of citalopram daily. Bejerot and Humble (1991) described a response in two of six severely ill patients with obsessive-compulsive disorder to citalopram 60 mg/day. Koponen et al. (1995) reported that two men in their 20s with lengthy histories of obsessive-compulsive disorder symptoms obtained a good clinical response with citalopram after receiving doses of 30 and 60 mg/day, respectively. The first patient maintained his improvement for 6 months without significant side effects, after which medication was discontinued. The other patient was reported as doing well on medication 9 months later but experienced side effects, including lack of appetite and orgasmic dysfunction, that resolved after the first 2 months of therapy. A recent case report by Bejerot and Bodlund (1998) is particularly interesting. The patient, a 43-year-old woman, had shown no response after 3 months of citalopram, 80 mg/day. However, within days of raising her dose to 220 mg/day, her obsessive-compulsive disorder had markedly improved. This benefit was subsequently maintained on a once-daily dose of 160 mg. The medication was generally well tolerated, aside from palpitations and episodes of tachychardia. It should be noted, however, that this dose far exceeds the recommended range of 20-60 mg.
The first open-label treatment study of citalopram in obsessive-compulsive disorder involved a 12-week trial with doses of up to 60 mg; mean dose at completion was 44.2 mg. Of the 12 patients who completed treatment, 8 were deemed “re-sponders” (). Overall, the mean Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score declined by greater than 40%, from 25.6 to 14.2. Subjects experienced only minimal side effects. Koponen et al. (1997) also reported a 24-week open pilot study of 29 patients meeting DSM-III-R criteria (American Psychiatric Association 1987) for OCD. Individuals with a concurrent diagnosis of major depression or marked depressive symptoms (scoring more than 21 on the Montgomery-Asberg Depression Rating Scale) were excluded, as were those with psychoses, organic brain disease, personality disorders, alcohol or drug abuse, or previous history of resistance to SSRI treatment. The mean score at entry on the Y-BOCS was 20.1; this declined to 5.7 (P = 0.042) at study conclusion. Overall, 76% of the patients (22 of 29) benefited according to a conservative definition of a greater than 50% reduction on Y-BOCS score. Patients also showed significant improvement on scores of depression and quality of life (assessed with the Psychological Well-Being Schedule). Most patients were receiving 40-60 mg/day by the study conclusion; only two had remained on 20 mg. Compliance was monitored by serum drug levels at two time points. All but two patients completed: one refused further treatment and one was discontinued because of noncompliance. The medication was generally well tolerated. Nausea and vomiting were the most commonly reported side effects, and they subsided during the study. Up to 10% of the patients reported sleep disturbance (increased dreaming or decreased sleep), and 5% experienced decreased sexual desire. Eight percent also reported orgasmic dysfunction.
The first published double-blind study involving citalopram compared the efficacy of fluvoxamine, paroxetine, and citalopram during 10 weeks of treatment (). Thirty psychiatric inpatients meeting DSM-III-R criteria on a structured interview (Diagnostic Interview Schedule-Revised [DIS-R]) were randomized to one of the three treatment groups, after which treatment was administered in single-blind fashion (raters were blinded, patients were not). Patients could not meet criteria for any other Axis I condition aside from tic disorders. All patients completed the study. Mean daily dose of medication in the three groups was 290 mg (fluvoxamine), 53.3 mg (paroxetine), and 50.9 mg (citalopram). All drugs achieved a similar magnitude of therapeutic response. When response was defined as improvement of greater than 35% in Y-BOCS score, no significant difference was found between groups, with 60% considered responders to fluvoxamine, 45% to paroxetine, and 40% to citalopram. The Y-BOCS scores of the 11 individuals who received citalopram dropped from a mean of 29.3 at baseline to 19.8 at the endpoint, for a mean reduction of 32% in symptom severity.
Pidrman and Tuma conducted a double-blind clomipramine-controlled study of citalopram in obsessive-compulsive disorder for which preliminary results for the first 14 individuals were published in 1997. They have subsequently reported on a total of 34 patients (). Patients met International Classification of Diseases (ICD)-IO diagnostic criteria for obsessive-compulsive disorder (OCD); individuals with significant depression on the Hamilton Depression Rating Scale (Ham-D), substance abuse, seizures or other organic brain disorder were excluded. Treatment was initiated at 20 mg citalopram or 75 mg clomipramine, which could be titrated up to double that amount after the third week. Unfortunately, the trial was only 6 weeks long, limiting the possible degree of response to the medication. Nonetheless, significant improvement (defined as a greater than 20% reduction in Y-BOCS score) was observed in 14 of the 15 citalopram subjects and 13 of the 16 clomipramine subjects. No significant difference in efficacy was found between the two groups, although side effects were more marked in the clomipramine group. The authors reported low levels of side effects, including tremor, akathisia, dry mouth, nausea, dizziness, and tachycardia; all of these diminished by the fourth week of treatment.
The results of a more definitive double-blind placebo-controlled mul-ticenter trial have not been fully analyzed as yet; however, preliminary results in a sample of 401 patients were similar to those for other SSRIs (). Subjects were randomized to receive 12 weeks of citalopram at 20, 40, or 60 mg/day after a 1-week single-blind placebo run-in. The individuals receiving citalopram obtained a statistically significant greater improvement on their Y-BOCS score than did the placebo group, with observed decreases of 9.4, 9.5, and 11.4 points for the three medication dose levels and 6.7 points in the placebo group. Thus, as with fluoxet-ine and paroxetine, trends indicate that higher doses of citalopram may be more effective than lower ones. Similar results were seen on secondary outcome measures, including the Montgomery-Asberg Depression Rating Scale, National Institute of Mental Health Obsessive Compulsive scale (), and the Sheehan Disability Scale (). As in previous studies, the medication was described as well tolerated at all dose levels; nausea, headache, and insomnia were the most commonly reported side effects.
Citalopram: Case Example
Mr. K. was a 42-year-old single man with an approximately 15-year history of obsessive-compulsive disorder with comorbid chronic depression and panic disorder. He had previously received trials of all available serotonin reuptake inhibitors (clomipramine, fluoxetine, fluvoxamine, sertraline, and paroxetine) but had either not responded or had been unable to tolerate therapeutic trials of all these agents. A large number of other psychotropic medications had also been tried without success over the years, including several benzodi-azepines, neuroleptics, TCAs, and phenelzine. At presentation, he was being maintained on high-dose clonazepam with partial alleviation of panic attacks.
Mr. K’s principal obsessive-compulsive disorder symptoms consisted of almost constant intrusive, vague thoughts that he would be responsible for something terrible happening. This resulted in ongoing repetition rituals of virtually all actions to avoid harm. Additionally, he described avoidance of certain bad numbers and subsequently would feel unable to do anything at all for extended periods until the clock would show it was a “safe” time. For example, getting out of bed could take an hour or more because he would repeatedly swing his legs off and back onto the bed, initially waiting for it to “feel right” and then until it was a “safe” time. He would try to avoid moving or doing anything for hours at a time to avoid rituals, sitting in front of the television regardless of what was shown. As a result, he was severely disabled, with rituals occupying or immobilizing him for most of his waking time. He would leave his apartment as little as possible, going out only twice per week for groceries and doctor appointments. He was extremely dysphoric, anhedonic, and quite hopeless, and he had longstanding complaints of poor concentration and lack of energy. He also reported constant passive suicidal ideation.
After being seen at the Anxiety Disorders Clinic, Mr. K. was initially treated with venlafaxine but had severe dose-limiting insomnia and no clinical benefit on a low dose of 37.5 mg twice daily. Attempts to treat the insomnia with imovane, chloral hydrate, and several benzodiazepines (in addition to his usual dose of clonazepam) were ineffective. He was switched to nortryptiline, which after 6 weeks at 150 mg/day resulted in remission of depression and further reduction in frequency and severity of panic symptoms. Obsessions and compulsions were unsurprisingly unchanged. The decision was made to add citalopram to the tricyclic agent. After 2 weeks of citalopram, 20 mg/day he reported some reduction in the intensity of obsessional fears and was able to occasionally limit rituals after only a few repetitions. He experienced insomnia, which responded to an increase in his late-evening dose of clonazepam. However, complaints of frequent headaches led to a decrease to 10 mg with loss of benefit. His nortryptiline was subsequently decreased to 50 mg and the citalopram increased back to 20 mg. He reported some nausea, diminishing with time. After 10 weeks on this combination, he had achieved an approximately 30% reduction in his obsessive-compulsive disorder symptoms. Clinically, this translated to a marked reduction in periods of total immobilization from several times per day to only a few times per week. Although he still reported occasional lengthy rituals, he would generally only repeat actions for 5-30 minutes at a time. He had also begun to leave his apartment on a more regular basis.
At 1-year follow-up, Mr. K. continued to benefit from this combination of medications. Several attempts had been made to further increase the citalopram or decrease the nortryptiline dose, but these attempts resulted in complaints of severe headaches and recurrence of depression, respectively. obsessive-compulsive disorder symptoms continued to occupy at least half of his waking time, but were, in his own estimation, “manageable.” He had become involved in a committed, caring relationship for the first time in more than 15 years and was living with his partner. After some discussion, the decision was made to continue on this medication regimen indefinitely, in view of his lengthy history of treatment resistance.
Selections from the book: Current treatments of obsessive-compulsive disorder (2001)