Dopamine depletion hypothesis of cocaine dependence: A test

Measurements of plasma homovanillic acid (HVA), plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), serum prolactin and Hamilton Depression Rating Scale (HDRS) scores were made in 21 cocaine-dependent patients seeking inpatient treatment. These measurements were obtained within 1–3 days of the last dose of cocaine and were repeated after 10–20 days of abstinence from cocaine. Abnormal values on any of the biochemical measurements were unusual and showed no convincing evidence of dopamine or norepinephrine depletion. Ten patients had significant HDRS scores on admission which decreased by 50% or more during hospitalization without specific treatment. The controversy over whether chronic exposure to cocaine depletes dopamine remains unsettled. Howevr, it is more likely that down-regulation of postsynaptic dopamine receptors is the major consequence of such exposure.     

Switch from neuroleptics to clozapine does not influence pituitary–gonadal axis hormone levels in male schizophrenic patients

Hypothalamic dopaminergic and serotonergic inputs participate in the regulation of pituitary hormones, and drugs that block central dopamine and serotonin receptors are expected to influence the hypothalamus–pituitary–gonadal (HPG) and –adrenal (HPA) axes. In schizophrenic patients, the switch from neuroleptics to clozapine influences prolactin and cortisol secretion, but there is no information on possible changes on HPG-axis hormones. We measured the plasma levels of testosterone (TST), LH, FSH, as well as of prolactin (PRL) and cortisol (CORT), in a group of male patients with schizophrenia during treatment with classical neuroleptics with no satisfactory therapeutic response (31 pts, age 30.3±8.5, range 18–50), and 6 weeks later, after switch to treatment with clozapine (CLZ) in doses from 100 to 600 mg daily (mean 328 mg). Psychopathology was assessed using the Brief Psychiatric Rating Scale. The hormone levels were also compared to those of a control group of 38 healthy males. Treatment with CLZ resulted in a reduction in the BPRS score by 30% in the mean. Plasma PRL was reduced from 39.9±26.1 to 8.3±5.0 ng/ml (P<0.001), CORT from 150±42 to 118±39 ng/ml (P<0.003), while LH, FSH, and TST remained unaltered. Compared to healthy controls, patients had higher PRL and CORT levels while on neuroleptics, and no significant differences to any of the estimated hormones, after switch to clozapine. The results show that switching from classical neuroleptics to treatment with clozapine does not have any substantial effect on the HPG-axis hormone plasma levels, although it reduces substantially the levels of prolactin and cortisol.     

经颅磁刺激对精神分裂症患者催乳素水平的影响

目的探讨经颅磁刺激（rTMS）治疗抗精神病药所致高催乳素血症的疗效及安全性。方法将61例利培酮所致高催乳素血症的慢性精神分裂症随机分为两组,研究组（31例）予以低频rTMS刺激,对照组（30例）以假rTMS刺激治疗;并观察血清催乳素、PANSS表、17项汉密尔顿抑郁量表的情况。结果①研究组rTMS刺激后PRL水平[（27.9±7.1）μg/L]较治疗前[（101.5±41.2）μg/L]下降,差异有统计学意义（P〈0.01）;对照组差异无统计学意义（P〉0.05）;研究组治疗1个月后复测PRL[（96.7±38.3）μg/L],已恢复至治疗前水平（P〉0.05）。②治疗前后两组患者PANSS及HAMD17评分变化均无统计学意义（P均〉0.05）。结论低频rTMS治疗可使慢性精神分裂症患者血清高催乳素短期下降。     

Combined treatment with sulpiride and paroxetine for accelerated response in patients with major depressive disorder

Although serotonin reuptake inhibitors are recommended as first-line agents for major depressive disorder, delayed onset of action is problematic, and faster effective treatment is needed. Sulpiride, a dopamine-mediated agent, has been reported to show faster antidepressant efficacy, and we examined the efficacy of adjunctive sulpiride in combination with paroxetine (PAX), compared with PAX alone, to clarify whether the combined treatment exerts faster effect. Forty-one major depressive disorder patients were enrolled in this 12-week open-label trial and were randomly assigned to a PAX (10-40 mg/d) or a PAX (10-40 mg/d) plus sulpiride (100 mg/d) group. Assessments included the Montgomery-Asberg Depression Rating Scale, the 17-item Hamilton Rating Scale for Depression, and the Zung Self-rating Depression Scale on an intent-to-treat basis, and safety was also monitored. Thirty-three patients completed the study. Both PAX + sulpiride and PAX treatments showed a mean reduction in the total Montgomery-Asberg Depression Rating Scale score of 34.4 to 5.6 and 32.2 to 10.4, respectively (P < 0.001). The combined treatment group had a significantly superior outcome in terms of the change in the total Montgomery-Asberg Depression Rating Scale, Hamilton Rating Scale for Depression, and Zung Self-rating Depression Scale scores between week 1 and the study end point (P < 0.05). Median times to response among responders alone for the combined treatment and monotherapy were 2 and 6 weeks, respectively. Both treatments were well tolerated, with no clinically significant differences in safety measures except for an elevation of prolactin in the combined treatment group. The combination treatment may be a safe and effective strategy for accelerating antidepressant response.     

Dopamine receptor responsivity in alcoholic patients before and after detoxification

OBJECTIVE: To assess central dopamine receptor responsivity in alcoholic patients during their usual alcohol consumption and after detoxification. METHOD: Plasma prolactin levels were measured at 0, 30, 60, and 90 min after administration of 5 mg haloperidol i.m. in 21 hospitalized male alcoholic patients during usual alcohol consumption, and 13 days later (mean, range 7-17 days), after detoxification. The test was also performed in seven healthy male volunteers. The patterns of prolactin responses were compared using repeated measures analysis of variance. RESULTS: The prolactin responses to haloperidol increased significantly after detoxification compared to those during usual alcohol consumption (state x time interaction P < 0.01; planned comparisons for times 0 and 90 min between states P = 0.03). Compared to controls, the responses of the patients before detoxification were lower (group-time interaction P = 0.001), and the difference was not significant after detoxification (P = 0.19). The magnitude of plasma prolactin (PRL) responses were not related to duration of alcohol abuse, score in the Brief Michigan Alcoholism Screening Test (BMAST) scale, or family history of alcoholism. CONCLUSIONS: Alcohol detoxification is accompanied by a normalization of the low responsivity of central dopaminergic receptors during alcohol abuse. The data support the hypothesis of a participation of the central dopaminergic system in alcohol dependence.     

Clinical conditions and central dopamine metabolism in alcoholics during acute withdrawal under treatment with different pharmacological agents

A group of 45 male alcoholics were studied during acute withdrawal. Patients were kept in hospital and treated with amobarbital (15 patients), oxazepam (15 patients), and melperone (15 patients) respectively in a double-blind design. Clinical symptoms were rated with a modified version of the Comprehensive Psychopathological Rating Scale after 1, 4 and 7 days. Blood pressure, body temperature and pulse rate were also recorded. Lumbar cerebrospinal fluid was collected after 1 and 7 days. A group of healthy males served as controls. The three treatment groups showed only small differences with regard to the investigated clinical items, except for a higher incidence of epileptic fits being evidenced in the melperone group. Levels of HVA in the cerebrospinal fluid did not differ between the treatment groups and the controls and did not change during treatment. Statistically significant correlations were noted between levels of HVA and auditory and visual hallucinations as well as concentration difficulties. Assuming that HVA levels reflect the activity of the central nervous dopamine system, the findings indicate a connection between central dopamine metabolism, psychotic symptoms and possibly other symptoms during acute alcohol withdrawal in man.     

Serum dopamine-beta-hydroxylase activity and alcohol withdrawal symptoms

Fifty male alcoholics had serum dopamine-beta-hydroxylase (DBH) activity, and serum prolactin (PRL) levels measured on the day of withdrawal, and 22 of them also on days 7 and 28 after it. The obtained values were related to the development of withdrawal symptoms. Treatment was begun with meprobamate on the first day of withdrawal, and from day 7 it was completed with disulfiram (250 and 500 mg/day, respectively). Serum DBH activity decreased significantly by day 7, however a further fall of it occurred by day 28 only in patients receiving high doses (500 mg) of disulfiram. PRL levels rose over the period of withdrawal which reached significance level on day 28. No correlation was found between serum DBH activity and the severity of withdrawal symptoms. Serum DBH activity did not differ from that of the healthy controls at either point of time, while serum PRL level was significantly elevated throughout the period of the study.     

Detection of dopaminergic modulators in a tier I screening battery for identifying endocrine-active compounds (EACs)

Apomorphine (APO; D(2) receptor agonist), haloperidol (HAL; D(2) receptor antagonist), and reserpine (RES; a dopamine depletor that acts to lower brain dopamine levels by depleting central nervous system monoamines via disrupting storage vesicle function) have been examined in a Tier I screening battery, which has been designed to detect endocrine-active compounds (EACs). The Tier I battery incorporates two short-term in vivo tests (a 5-day ovariectomized female battery and a 15-day intact male battery using Sprague-Dawley rats) and an in vitro yeast transactivation system (YTS). In addition, two blood collection procedures were evaluated for their utility in detecting HAL-induced increases in serum prolactin (PRL) levels (i.e., the stress associated with each procedure). In the in vivo female battery, both HAL and RES increased serum PRL concentrations as expected, although the increase caused by RES was marginal. Increases in serum PRL levels are enhanced when daily dosages are administered via multiple-daily dosing of the test compound, which results in higher sustained blood levels of the test compounds. APO failed to decrease serum PRL concentrations in the female battery. In the in vivo male battery, HAL increased serum PRL concentrations as expected. However, APO and RES failed to affect serum PRL concentrations. The blood collection comparison experiment demonstrated that possible confounding of the data can occur with serum PRL concentrations when animals are exposed to stress. Basal levels of PRL were approximately fourfold higher in animals that were bled via the tail vein procedure when compared to PRL levels from animals that were bled under CO(2) anesthesia at euthanization. As a result of the higher basal PRL levels, the HAL-induced increase in serum PRL concentrations was completely attenuated in the tail-vein bled animals (1.3-fold). In contrast, HAL produced a fivefold increase in serum PRL in animals where blood was collected under CO(2) anesthesia at euthanization. Hence, collection of blood from animals under CO(2) anesthesia at euthanization is an acceptable approach for detection of compounds that increase PRL. In summary, HAL-like compounds would be identified in the Tier I male and female battery primarily via increased serum PRL concentrations. RES-like compounds would be identified in the Tier I male battery via decreased gonadotropins and steroids and possibly in the Tier I female battery by a minimal increase in serum PRL concentrations. Compounds that produce a marginal increase in serum PRL when administered using single daily dosing can also be confirmed in an in vivo female battery with multiple dosing because this regimen increases the magnitude of the PRL increase. APO, a D(2) receptor agonist, was not detected in the in vivo male or female batteries, but in both instances the top dosage produced minimal decreases in body weight (99 to 96% of control). Hence, the proposed Tier I battery needs to be further evaluated with higher dosages of APO and other D(2) receptor agonists to determine whether it is capable of detecting such agents.     

The convergent validity of the Drug Impairment Rating Scale for Cocaine.

The Halikas-Crosby Drug Impairment Rating Scale for Cocaine (HAL DIRS-C) is designed to measure improvement in drug treatment through interval assessment of impact of cocaine use on daily functioning, relationships with other people, other alcohol and drug use, cocaine withdrawal symptoms, adverse effects associated with cocaine use, and personal outlook over the previous week. The scale is a 25-item clinical rating scale administered in the context of a semistructured interview (modeled after and similar to the Hamilton Rating Scale for Depression). The HAL DIRS-C was administered weekly to 147 subjects participating in a 12-week, double-blind medication trial with a psychosocial treatment component. Without breaking the pharmacologic blind, the HAL DIRS-C score was found to be significantly related to study retention, ongoing psychosocial treatment participation, urinalysis results, and other measures of outcome. The results support the validity of the HAL DIRS-C as a standardized measure of improvement or outcome in clinical research involving the treatment of cocaine abuse.     

Relationship between central serotonergic neurotransmission and reduction in alcohol intake by citalopram.

The relationship between the effect of citalopram on alcohol intake and central serotonergic neurotransmission, as assessed by prolactin (PRL) response to fenfluramine, was investigated in 17 male heavy drinkers. A positive correlation was obtained, suggesting that the status of central serotonergic neurotransmission in individuals is associated with the treatment response to citalopram. When the group of subjects were divided into those with high and low PRL response (above and below median, respectively) to fenfluramine, those with high PRL response had a significant reduction in alcohol intake during citalopram treatment, whereas those with low PRL response had no such effect. Thus, in subjects with evidence of unimpaired or only slightly impaired central serotonergic neurotransmission (high PRL response) citalopram may have beneficial effect on alcohol consumption, whereas in those with more evidently impaired serotonergic neurotransmission (low PRL response) citalopram treatment may have no effect on or may even increase the alcohol consumption.     

Effects of fenoldopam on alpha-methyl-p-tyrosine-stimulated prolactin secretion in conscious rats

Pituitary dopamine D-2 receptors participate in the regulation of prolactin (PRL) release. No dopamine D-1 receptors have so far been identified in the pituitary gland. The present study was designed to assess the effects of fenoldopam, a selective dopamine D-1 receptor agonist, on alpha-methyl-p-tyrosine-stimulated PRL release. Fenoldopam dose dependently reduced the alpha-methyl-p-tyrosine-stimulated PRL secretion. This inhibitory effect of fenoldopam was abolished after pretreatment with SCH 23390, a specific dopamine D-1 receptor antagonist, suggesting the involvement of a dopamine D-1 receptor in PRL secretion.     

Sertraline treatment of co-occurring alcohol dependence and major depression

BACKGROUND: Major depressive disorder occurs commonly in association with alcohol dependence, both in clinical samples and in the community. Efforts to treat major depressive disorder in alcoholics with antidepressants have yielded mixed results. This multicenter, double-blind, placebo-controlled trial of sertraline was designed to address many of the potential methodological shortcomings of studies of co-occurring disorders. METHOD: Following a 1-week, single-blind, placebo lead-in period, 328 patients with co-occurring major depressive disorder and alcohol dependence were randomly assigned to receive 10 weeks of treatment with sertraline (at a maximum dose of 200 mg/d) or matching placebo. Randomization was stratified, based on whether initially elevated scores on the 17-item Hamilton Depression Rating Scale declined with cessation of heavy drinking, resulting in a sample of 189 patients with Hamilton Depression Rating Scale scores > or =17 (group A) and 139 patients with Hamilton Depression Rating Scale scores < or =16 (group B). RESULTS: Both depressive symptoms and alcohol consumption decreased substantially over time in both groups. There were no reliable medication group differences on depressive symptoms or drinking behavior in either group A or B patients. CONCLUSION: Despite careful attention to methodological considerations, this study does not provide consistent support for the use of sertraline to treat co-occurring major depressive disorder and alcohol dependence. The high rate of response among placebo-treated patients may help to explain these findings. Further research is needed to identify efficacious treatments for patients with these commonly co-occurring disorders.     

Dopamine D2 receptors involved in Peony-Glycyrrhiza Decoction,an herbal preparation against antipsychotic-associated hyperprolactinemia

Clinical studies have demonstrated the effectiveness of an herbal preparation called Peony-Glycyrrhiza Decoction(PGD) in alleviating antipsychotic-induced hyperprolactinemia(hyperPRL).In the present study,we further examined the pharmacological action of PGD on hyperPRL in in vitro and in vivo models,and associations with dopamine D2 receptors.Treatment with PGD at 1-5 g·L-1 significantly suppressed prolactin(PRL) secretion and synthesis in MMQ cells,a model of hyperPRL derived from pituitary adenoma cells.The suppressive effects were completely abolished by pretreatment with 10 μmol·L-1 haloperidol,a dopamine D2 receptor antagonist.Consistent with a D2-action,PGD did not affect PRL in rat pituitary somatolactotropic tumor-derived GH3 cells that lack the D2 receptor expression.In a rat model of hyper PRL,produced by repeated injection of metoclopramide(MCP),another dopamine D2 receptor antagonist,chronic PGD(2.5-10 g·kg-1 daily) significantly reduced elevated serum PRL.The reduction in magnitude was similar to that elicited by bromocriptine(BMT),a potent dopamine D2 receptor agonist currently used for treatment of hyperPRL.Neither PGD nor BMT altered serum estradiol,but PGD reversed decreased serum progesterone to control level,whereas BMT did not.These results indicate that the anti-hyperPRL effects of PGD are associated with the modulation of D2 receptors.The present study provides experimental evidence in support of clinical use of PGD as an effective treatment of antipsychotic-induced hyperPRL.     

Neuroendocrine effects of apomorphine in chronic schizophrenic patients under long-term neuroleptic therapy and after drug withdrawal: Relations to psychopathology and tardive dyskinesia

The sensitivity of the dopaminergic hypothalamic pituitary system, as indicated by growth hormone (GH) release after apomorphine (0.5 mg SC), was studied in 11 chronic schizophrenic in-patients under long-term neuroleptic (NL) therapy and after 12 and 30 days' drug withdrawal. GH peak levels after a 12-day drug-free period were significantly elevated (13.1±12 ng/ml) as compared to NL therapy (4.6±6.1 ng/ml). Controls showed a significant higher mean peak GH response (13.6±10 ng/ml) compared to chronic schizophrenic patients under long-term NL therapy. The GH response of patients with symptoms of tardive dyskinesia (TD) did not differ significantly from that of patients without signs of TD.The prolactin (PRL) serum levels under long-term NL treatment were within the normal range in male schizophrenics but decreased significantly after 12 days' drug withdrawal. The data presented indicate a reduced sensitivity of the hypothalamic-pituitary dopamine receptors under long-term NL therapy. The significant increase in GH response on day 12 probably corresponds to a readjustment from a mostly blunted GH response under NL therapy back to stimulated levels of normal controls. No supersensitivity of the pituitary dopamine recpetors could be detected.     

Anxiogenic effects of Sumatriptan in panic disorder: a double-blind, placebo-controlled study.

BACKGROUND: Several lines of evidence point to serotonergic abnormalities in patients with panic disorder (PD). Our goal was to further examine central serotonergic function in panic patients using autonomic and subjective responses to the postsynaptic serotonin 5-HT1D receptor agonist Sumatriptan. METHOD: Using a double-blind, randomized, placebo-controlled design, we assessed autonomic and subjective responses to oral Sumatriptan (100 mg) and placebo in 15 patients with PD, free of medication. Subjective responses were measured using the Hamilton Anxiety Rating Scale (HAM-A), National Institute of Mental Health Anxiety Scale (NIMHA), a modified version of the Panic Symptom Inventory (PI), Hamilton Depression Rating Scale (HAM-D), and Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: PD patients exhibited significantly enhanced autonomic and subjective responses following challenge with Sumatriptan. We observed an increased pulse rate and augmentation of various parameters measured on different anxiety scales. A constant inclination of aggravation of the measured parameters was detected during the hour post challenge. CONCLUSION: Oral administration of Sumatriptan, a 5-HT1D agonist, has been associated with an anxiogenic effect in PD patients.     

Serum creatine kinase activity differentiates alcohol syndromes of dependence,withdrawal and delirium tremens

Previous reports described significant differences in serum creatine kinase (CK) activity in bipolar disorder and various forms of depression. The comorbidity of depression and alcohol syndromes was also widely described. We aim to examine potential differences in serum CK level in different alcohol-related syndromes. We assessed morning serum CK activity in 114 inpatients, diagnosed by the Structured Clinical Interview for DSM-IV: Fifty-five subjects with alcohol dependence, 28 with alcohol withdrawal and 31 with delirium tremens (DT's). We found low normal CK activity for the alcohol dependence, higher for alcohol withdrawal and the highest for DT's. Peripheral CK activity of four patients that were admitted during each of the three phases showed similar pattern. These findings may be related to enhanced dopamine activity in alcohol dependence and conversely, to a significant decrease in dopamine activity during withdrawal syndromes. We suggest a supplementary simple laboratory tool for the detection of alcohol-related states.     

A clinical and pharmacodynamic evaluation of sulpiride

In a double-blind study the therapeutic efficacy of sulpiride was compared to that of haloperidol — an established neuroleptic agent. A total of 30 female patients with a diagnosis of chronic schizophrenia were initially stabilised on the dosage of haloperidol which produced optimum therapeutic response when given once or twice daily. The patients were then randomly allocated to receive either sulpiride or haloperidol over a period of 12 weeks. Plasma drug concentrations and prolactin levels were determined. Clinical effects were evaluated by Brief Psychiatric Rating Scale (BPRS), Wing Rating Scale, and Extrapyramidal Symptoms Rating Scale (EPS). A standardised side-effects checklist was used.Treatment with sulpiride was associated with a significant rise in plasma prolactin level, but paradoxically these patients had significantly reduced extrapyramidal symptoms.No significant correlation was found between plasma sulpiride concentration and prolactin level or any of the clinical variables. The study confirms the antipsychotic activity of sulpiride.     

Neuroendocrine serotonergic and dopaminergic responsivity in male schizophrenic patients during treatment with neuroleptics and after switch to risperidone

RATIONALE: The pharmacological profile of risperidone is that of an atypical neuroleptic regarding its serotonin 5-HT2A and dopamine D2 receptor blocking properties. Treatment with risperidone, though, results in considerably elevated plasma prolactin (PRL) levels which are not observed with other atypical neuroleptics, such as clozapine, indicating a differentiated action on receptors that are involved in PRL release, mainly dopaminergic and serotonergic. OBJECTIVE: To assess the responsivity of serotonergic and dopaminergic receptors during treatment with neuroleptics and after switch to risperidone, using neuroendocrine paradigms. METHODS: Two neuroendocrine challenge tests, measuring the PRL increases induced by acute administration of serotonergic (clomipramine, 25 mg i.v.) and dopaminergic (haloperidol, 5 mg i.m.) drugs were performed in 13 male schizophrenic patients during treatment with typical neuroleptics and, later, after 6 weeks of treatment with risperidone. The tests were also performed in a group of nine healthy male volunteers. PRL was estimated in blood samples taken every 15 min for 1 h for clomipramine and every 30 min for 2 h for haloperidol. Psychopathology was assessed using the Brief Psychiatric Rating Scale (BPRS). RESULTS: During treatment with neuroleptics (mean dose 1354 mg chlorpromazine equivalents, range 300-2400 mg), i.m. haloperidol caused significant elevations in plasma PRL, which were totally abolished after 6 weeks treatment with risperidone (mean dose 12.1 mg/day, range 8-16 mg/day), indicating complete D2 receptor blockade. In contrast, the PRL increases obtained after clomipramine administration during neuroleptic treatment were preserved after treatment with risperidone. Both PRL response patterns to clomipramine were similar to that of healthy controls. BPRS score was 50.2+/-9.3 points during neuroleptic treatment and was reduced after risperidone to 30.1+/-6.6 points, i.e., 40% in the mean. CONCLUSIONS: During treatment with typical neuroleptics, the PRL responses to clomipramine are normal, and they are preserved after switch to risperidone in doses that cause complete dopamine receptor blockade. Risperidone, a dopamine and 5-HT receptor blocker, does not affect 5-HT receptors that are involved in the PRL release by the 5-HT uptake blocker clomipramine, indicating a different behavior than other atypical neuroleptics such as clozapine or olanzapine, for which a reduction of the PRL release induced by serotonergic agents like fenfluramine or mCPP has been reported. A conclusive identification of the 5-HT receptor subtypes that are involved in this different action cannot be identified at present, but it should be taken into account that risperidone differs from clozapine, showing higher affinity for 5-HT2A than 5-HT2C receptors and lacking the marked affinity of clozapine to 5-HT1A receptors.     

Clinical effect of nemifitide, a novel pentapeptide antidepressant, in the treatment of severely depressed refractory patients

Clinical data were evaluated from an open-label, single-center, pilot study in patients with chronic refractory depression. The primary efficacy criterion was the change from baseline using the Montgomery-Asberg Depression Rating Scale. The secondary efficacy criteria were the 17-item Hamilton Depression Rating Scale and the Clinical Global Impression-Improvement scale. Response to treatment (40-240 mg once per day by subcutaneous injection for 10-20 doses) was defined as more than 50% improvement in the Montgomery-Asberg Depression Rating Scale from baseline or Clinical Global Impression-Improvement < or =2 and lasting for at least two sequential weeks. Patients with a sustained response at the end point in the acute main treatment phase were enrolled for up to 2 years in a maintenance phase of the study to determine duration of response and to initiate retreatments upon relapse. Of the 25 patients with chronic refractory depression, 11 patients showed a response for Montgomery-Asberg Depression Rating Scale and one responded according to the secondary criterion Hamilton Depression Rating Scale. In seven of the 11 responders to Montgomery-Asberg Depression Rating Scale the effects were sustained for the remainder of the acute phase. Two additional sustained responders identified according to secondary criteria (Hamilton Depression Rating Scale or Clinical Global Impression-Improvement) were also enrolled in the maintenance phase. All nine sustained responders were retreated, as needed, in the maintenance phase of the study, ranging from 71 to 660 days. Mean duration of response following initial treatment and between retreatments was around 2 months. Pharmacokinetic data indicated dose-proportional systemic exposure to the drug.     

Short-term intravenous citalopram augmentation in partial/nonresponders with major depression: a randomized placebo-controlled study

Approximately 30-45% of patients with major depressive episode (MDE) do not fully respond to standard recommended treatments and further strategies of intervention, including pharmacological augmentation, have been proposed for these patients. This study was aimed to evaluate the efficacy of short-term, low-dose (10 mg/day) intravenous (i.v.) citalopram augmentation versus placebo in a sample of patients with MDE and partial or no response to selective serotonin reuptake inhibitors (SSRIs). Thirty-six patients with a Diagnostic and Statistical Manual for Mental Disorders, 4th edition, text revision criteria MDE and partial or no response to oral SSRIs were selected and randomly assigned to citalopram (n=18) or to placebo (n=18) i.v. augmentation. The augmentation regimen lasted 5 consecutive days during which the patients were maintained on their current treatment with oral SSRIs. Analyses of variance with repeated measures on Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale total scores, administered daily with blind-raters conditions, were done. With regard to the Hamilton Depression Rating Scale total scores, a significant time effect (F=42.02, P<0.0001) and timextreatment effect (F=21.17, P<0.0001) were found in favor of citalopram. Similar results were obtained from the analysis on Montgomery-Asberg Depression Rating Scale total scores: time effect (F=50.07, P<0.0001), timextreatment effect (F=19.91, P<0.0001), and treatment effect (F=4.07, P=0.05). Even though referred to a small sample, the present findings seem to suggest that short-term, low-dose, i.v. citalopram augmentation may be effective in depressed patients with partial or no response to oral SSRIs. Further controlled studies performed with double-blind conditions are warranted to confirm the present results.