Opposing role of Notch1 and Notch2 in a Kras(G12D)-driven murine non-small cell lung cancer model.

Lung cancer is the leading cause of cancer-related deaths worldwide. Recently, we have shown that Notch1 inhibition resulted in substantial cell death of non-small cell lung cancer (NSCLC) cells in vitro. New compounds targeting Notch signal transduction have been developed and are now being tested in clinical trials. However, the tumorigenic role of individual Notch receptors in vivo remains largely unclear. Using a Kras(G12D)-driven endogenous NSCLC mouse model, we analyzed the effect of conditional Notch1 and Notch2 receptor deletion on NSCLC tumorigenesis. Notch1 deficiency led to a reduced early tumor formation and lower activity of MAPK compared with the controls. Unexpectedly, Notch2 deletion resulted in a dramatically increased carcinogenesis and increased MAPK activity. These mice died significantly earlier due to rapidly growing tumor burden. We found that Notch1 regulates Ras/MAPK pathway via HES1-induced repression of the DUSP1 promoter encoding a phosphatase specifically suppressing pERK1/2. Interestingly, Notch1 but not Notch2 ablation leads to decreased HES1 and DUSP1 expression. However, Notch2-depleted tumors showed an appreciable increase in ß-catenin expression, a known activator of HES1 and important lung cancer oncogene. Characteristically for ß-catenin upregulation, we found that the majority of Notch2-deficient tumors revealed an undifferentiated phenotype as determined by their morphology, E-Cadherin and TTF1 expression levels. In addition, these carcinomas showed aggressive growth patterns with bronchus invasion and obstruction. Together, we show that Notch2 mediates differentiation and has tumor suppressor functions during lung carcinogenesis, whereas Notch1 promotes tumor initiation and progression. These data are further supported by immunohistochemical analysis of human NSCLC samples showing loss or downregulation of Notch2 compared with normal lung tissue. In conclusion, this is the first study characterizing the in vivo functions of Notch1 and Notch2 in Kras(G12D)-driven NSCLC tumorigenesis. These data highlight the clinical importance of a thorough understanding of Notch signaling especially with regard to Notch-targeted therapies.

Isoprene function in two contrasting poplars under salt and sunflecks.

In the present study, biogenic volatile organic compound (BVOC) emissions and photosynthetic gas exchange of salt-sensitive (Populus x canescens (Aiton) Sm.) and salt-tolerant (Populus euphratica Oliv.) isoprene-emitting and non-isoprene-emitting poplars were examined under controlled high-salinity and high-temperature and -light episode ('sunfleck') treatments. Combined treatment with salt and sunflecks led to an increased isoprene emission capacity in both poplar species, although the photosynthetic performance of P. × canescens was reduced. Indeed, different allocations of isoprene precursors between the cytosol and the chloroplast in the two species were uncovered by means of (13)CO2 labeling. Populus × canescens leaves, moreover, increased their use of 'alternative' carbon (C) sources in comparison with recently fixed C for isoprene biosynthesis under salinity. Our studies show, however, that isoprene itself does not have a function in poplar survival under salt stress: the non-isoprene-emitting leaves showed only a slightly decreased photosynthetic performance compared with wild type under salt treatment. Lipid composition analysis revealed differences in the double bond index between the isoprene-emitting and non-isoprene-emitting poplars. Four clear metabolomics patterns were recognized, reflecting systemic changes in flavonoids, sterols and C fixation metabolites due to the lack/presence of isoprene and the absence/presence of salt stress. The studies were complemented by long-term temperature stress experiments, which revealed the thermotolerance role of isoprene as the non-isoprene-emitting leaves collapsed under high temperature, releasing a burst of BVOCs. Engineered plants with a low isoprene emission potential might therefore not be capable of resisting high-temperature episodes.

Poplar volatiles - biosynthesis, regulation and (eco)physiology of isoprene and stress-induced isoprenoids.

Plants interact with their environment through a wide variety of biogenic volatile organic compounds (BVOCs), with isoprenoids ( identical with terpenes), i.e. isoprene, mono- and sesquiterpenes, playing an important role. Isoprene, a hemiterpene, is the simplest isoprenoid compound mainly emitted by tree species like poplars, oaks and willows. Woody plants alone comprise 75% of the global isoprene emitted to the atmosphere. Due to its significant influence on atmospheric chemistry, research has been focused on this C5 compound, with poplar being the most prominent model system. Recent studies indicate that isoprene can enhance thermotolerance or quench oxidative stress, while also interfering with the attraction of herbivores and parasitoids to plants. In this paper, we report on biosynthesis, regulation and function of isoprene and other stress-induced volatile isoprenoids in poplar, and discuss the future scientific challenges in this genus with respect to the importance of plant volatiles in high-density poplar biomass plantations.

Effect of crude glycerol on pellet mill production and nursery pig growth performance.

The objective of this study was to determine the effects of diets containing crude glycerol on pellet mill production efficiency and nursery pig growth performance. In a pilot study, increasing crude glycerol (0, 3, 6, 9, 12, and 15%) in a corn-soybean meal diet was evaluated for pellet mill production efficiency. All diets were steam conditioned to 65.5 degrees C and pelleted through a pellet mill equipped with a die that had an effective thickness of 31.8 mm and holes 3.96 mm in diameter. Each diet was replicated by manufacturing a new batch of feed 3 times. Increasing crude glycerol increased both the standard (linear and quadratic, P < 0.01) and modified (linear, P < 0.01; quadratic, P

Growth response of broilers to spray-dried plasma in pelleted or expanded feed processed at high temperature.

A series of 4 experiments evaluated effects of mash conditioning temperature from a pellet mill or expander on performance of broilers fed pelleted diets containing spray-dried plasma (SDP). All experiments utilized Ross x Ross 308 male broilers randomly assigned to their respective treatments (6 or 10 broilers/pen and 8 or 10 pens/treatment). Treatments in Exp. 1 consisted of a control (0% SDP), SDP coated postpelleting, or SDP blended into the meal prepelleting. Experiment 2 and 3 included the same 3 treatments as in Exp. 1 but with additional treatments of SDP blended into the meal and conditioned at 90 or 95 degrees C before pelleting. In Exp. 4, treatments consisted of a control (0% SDP) or SDP blended into the meal and pelleted (85 degrees C conditioning temperature) or expanded (149 degrees C final effective temperature) and then pelleted. Corn-soybean meal-based diets were formulated to be equal in lysine and ME in all experiments. Pelleted diets were conditioned for 15 s at 85 degrees C, and expanded diets were conditioned at 95 degrees C, 29.7 MJ/t, 13.95 kg/cm2 cone pressure, exit temperature of 149 degrees C, and then pelleted through a 4 x 32-mm die. In Exp. 1, ADG and feed intake were improved (P < 0.05) for broilers fed SDP from d 1 to 28 of age, with greater BW at d 42. In Exp. 2, both in early (d 1 to 28 of age) phases, and overall (d 1 to 42 of age), broilers fed SDP had improved (P < 0.05) gain and efficiency. In Exp. 3, ADG, feed intake, efficiency of gain, and BW were improved (P < 0.01) for broilers fed SDP from d 1 to 21 of age, regardless of conditioning temperature. In Exp. 4, broilers fed SDP had improved (P < 0.05) gain, BW, and feed intake regardless of processing method. Overall, the results of all of the experiments demonstrated that pellet conditioning temperature from 85 to 95 degrees C and expander temperatures to 149 degrees C did not impair the positive growth effects of SDP in pelleted or expanded broiler feed.

Randomized, double-blind comparison of venlafaxine and sertraline in outpatients with major depressive disorder. Venlafaxine 631 Study Group.

BACKGROUND: This 8-week, double-blind, randomized trial compared the efficacy and tolerability of venlafaxine and sertraline in patients with major depression. METHOD: Outpatients (N = 147) with DSM-IV major depressive disorder and a baseline 21-item Hamilton Rating Scale for Depression (HAM-D) score of at least 18 were randomly assigned to venlafaxine, 37.5 mg b.i.d., or sertraline, 50 mg once daily. From day 15, the doses could be increased to venlafaxine, 75 mg b.i.d., or sertraline, 50 mg b.i.d. Efficacy was assessed with the 21-item HAM-D, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions scale (CGI) using a modified intent-to-treat analysis. RESULTS: No significant differences were noted between treatments for mean HAM-D, MADRS, or CGI scores. At week 8, the HAM-D response rate was 83% with venlafaxine (N = 75) and 68% with sertraline (N = 72) (p = .05). A HAM-D score less than 10 was recorded in 68% of venlafaxine-treated and 45% of sertraline-treated patients at week 8 (p = .008). Among patients who increased their dose, the remission rate (HAM-D score < 10) was 67% with venlafaxine and 36% with sertraline at week 8 (p < .05). The overall discontinuation rate was 21% with venlafaxine and 17% with sertraline. The most common adverse events with venlafaxine were nausea, headache, and sweating and with sertraline were nausea, headache, and diarrhea. CONCLUSION: Among patients who increased their dose, approximately twice as many experienced a remission with venlafaxine, which is a more clinically relevant endpoint than response and represents the proportion of patients who have recovered or are well.

Efficacy and tolerability of mirtazapine versus citalopram: a double-blind, randomized study in patients with major depressive disorder. Nordic Antidepressant Study Group.

We aimed to compare the antidepressant and anxiolytic effects, tolerability and effects on quality of life of mirtazapine and citalopram in a randomized, double-blind, multicentre, 8-week study. Patients with a Major Depressive Episode (DSM-IV) and a baseline score of > or = 22 on the Montgomery-Asberg Depression Rating Scale (MADRS) were randomized to 8 weeks treatment with either mirtazapine (n = 137, 15-60 mg/day) or citalopram (n = 133, 20-60 mg/day). Efficacy was evaluated by the MADRS, Hamilton Anxiety Scale (HAM-A), Clinical Global Impression scales (CGI), the Leeds Sleep Evaluation Questionnaire (LSEQ) and Quality of Life Enjoyment and Satisfaction Questionnaire (QLESQ). The efficacy analyses were performed on the Intent-To-Treat Group using the Last Observation Carried Forward method. Vital signs and laboratory variables are measured and adverse events recorded at each weekly visit. The magnitude of reduction from baseline in group mean MADRS scores was large in both groups, reaching after 8 weeks of treatment mean scores of 9.1 in the mirtazapine group and 8.9 in the citalopram group. Both treatments also resulted in a substantial improvement in anxiety symptoms, sleep disturbances and quality of life, and high percentage of responders. However, at day 14, statistically significantly larger magnitudes of change favouring mirtazapine were present in the group mean MADRS, HAM-A and CGI-Severity of illness and Quality of life scores. A difference of 2.3 points on MADRS favouring mirtazapine is considered indicative for a clinically relevant superiority between two proven antidepressants. Mirtazapine treatment was also related to faster improvement of sleep, quality of sleep and improved alertness following awakening, as shown by statistically significant differences on the self-rating LSEQ at various time points. There were no differences between two treatment groups on self-rating QLSEQ. Both drugs were well tolerated, with a low number of patients in either group prematurely terminating the study due to adverse events (mirtazapine: 3.6%, citalopram, 3.0%). Sweating and nausea were statistically significantly more frequent in the citalopram group and increased appetite and complaints of weight increase in the mirtazapine group. There were no clinically relevant changes in laboratory parameters and vital sign variables with either treatment, except for clinically relevant increase in body weight, occurring more frequently in mirtazapine patients. In this study, mirtazapine and citalopram were equally effective in reducing symptoms of depression and anxiety, and well tolerated. However, mirtazapine was significantly more effective than citalopram after 2 weeks of treatment on the MADRS, HAM-A and CGI Severity of illness and Quality of life scales. This finding, consistently present at all major efficacy variables, suggests potentially faster onset of efficacy of mirtazapine over citalopram.

Effect of ingredients and processing parameters on pellet quality.

Rations containing varying ratios of corn, high-oil corn, soybean meal, and mechanically expelled soybean meal were pelleted. The effects of ingredients, conditioning steam pressure, and mixing paddle configuration inside the conditioner on pellet quality were investigated. Ration ingredients strongly affected pellet quality. Increasing the protein content increased the pellet durability, whereas increasing the oil content above 7.5% greatly decreased pellet durability. High-oil corn and mechanically expelled soybean meal produced acceptable pellets when combined with soybean meal and regular corn, respectively. However, poor pellet quality resulted when rations containing high-oil corn and mechanically expelled soybean meal were processed. Increasing the residence time in the conditioner by changing mixing paddle pitch resulted in an average 4.5-point increase in pellet durability indices among 65:35 (wt) corn:soybean meal and 65:35 high-oil corn:soybean meal rations.

Effects of omitting vitamin and trace mineral premixes and(or) reducing inorganic phosphorus additions on growth performance, carcass characteristics, and muscle quality in finishing pigs.

Three experiments were conducted to determine the effects of omitting vitamin and trace mineral premixes and(or) reducing inorganic phosphorus additions to finishing diets on growth performance, carcass characteristics, and muscle quality in pigs. In Exp. 1, a corn-soybean meal-based diet (.70% lysine, .65% Ca, and .55% P) was used as the control. Pigs (n = 128; average initial BW of 85.7 kg) were fed the control diet or the control diet without 1) the vitamin premix, 2) the trace mineral premix, or 3) both premixes. Omitting the premixes had no effect on ADG (P>.39); gain/feed (P>.17); carcass backfat thickness (P>.42); and marbling, color, and firmness of the longissimus muscle (P>.11). In Exp. 2, pigs (n = 128; average initial BW of 86.2 kg) were fed the control diet (.65% Ca and .53% P) used in Exp. 1 and the control diet without 1/3 (.56% Ca and .46% P), 2/3 (.51% Ca and .40% P), or all (.47% Ca and .31% P) of the added monocalcium phosphate (MCP). Omitting up to 2/3 of the MCP increased ADG (quadratic effect, P<.02) and had no effect on meat quality (P>.12), but backfat thickness increased slightly (quadratic effect, P<.02). In Exp. 3, pigs (n = 160; average initial BW of 86.6 kg) were fed the control diet used in Exp. 1 or the control without 1) the vitamin and trace mineral premixes, 2) 2/3 of the MCP, or 3) the premixes and 2/3 of the MCP. Treatment had no effects on ADG (P>.23), gain/feed (P>.94), stomach lesions (P>.37), or serum gamma globulins (P>.08). In conclusion, vitamin and trace mineral premixes and up to 2/3 of the supplemental MCP can be omitted during late finishing (i.e., approximately the final 30 d) to reduce nutrient excesses that increase cost of feeding and nutrients excreted in waste material.

Moclobemide and fluoxetine for panic disorder. International Panic Disorder Study Group.

An international, multicentre, double blind parallel group study compared the tolerability and efficacy of moclobemide with the selective serotonin reuptake inhibitor (SSRI) fluoxetine for panic disorder. SSRIs have been shown effective for panic. The target dose of moclobemide was 450 mg and of fluoxetine was 20 mg. There were two consecutive studies. An eight week study of acute adverse events, tolerability and efficacy was followed by a long-term extension study to 1 year. The efficacy data showed no significant difference between moclobemide and fluoxetine. Both had acute efficacy, with 63% moclobemide and 70% fluoxetine patients (ns) panic free at 8 weeks. Both agents were well tolerated to 8 weeks, but moclobemide had fewer severe adverse events (5) than fluoxetine (9). There were no severe adverse events in the extension phase with either drug, and almost all patients completing 1 year extension treatment (moclobemide 61 patients, fluoxetine 65) were much or very much improved. These data suggest moclobemide and fluoxetine are tolerated and effective for both acute panic treatment and maintenance therapy.

A 12-week study comparing moclobemide and sertraline in the treatment of outpatients with atypical depression.

One hundred and ninety-seven outpatients with atypical depression [Atypical Depression Diagnostic Scale (ADDS) score=4] were randomized to 12 weeks of double-blind treatment with sertraline or moclobemide in a multicentre, parallel-group clinical trial. Patients were started on either 50 mg/day sertraline or 300 mg/day moclobemide. If the therapeutic response was not satisfactory after 4 weeks, the dose could be increased to either 100 mg/day sertraline or 450 mg/day moclobemide. Primary efficacy evaluations were the 29-item Hamilton Psychiatric Rating Scale for Depression (HAM-D) and the Clinical Global Impression of Improvement (CGI-I) response rate (much or very much improved) at study endpoint. Secondary efficacy evaluations included the ADDS, the Hamilton Anxiety Scale (HAMA), the Leeds Sleep Scale, and the Battelle Quality of Life Battery (BQOLB). In the analysis of the 172 patient efficacy-evaluable population, there was significant baseline to endpoint improvement in all primary and secondary efficacy assessments after treatment with either sertraline or moclobemide. At the endpoint, the proportion of responders on CGI-I, was 77.5% in the sertraline group and 67.5% in the moclobemide group (p=0.052). The baseline to endpoint mean 29-item HAM-D score decreased from 35.9 to 14.5 in the sertraline group and from 36.3 to 16.1 in the moclobemide group. Sertraline also resulted in a significantly (p < 0.05) greater degree of improvement at the endpoint, compared with moclobemide, in the proportion of remitters on the HAMA (total score < or = 7), ADDS Category IID (Rejection Sensitivity), Leeds Sleep Factor 4 (Integrity of Behaviour Following Awakening), and on three dimensions of the BQOLB (Energy/Vitality, Social Interaction and Life Satisfaction). There were no other significant differences between treatment groups. Overall, both medications were well tolerated. In this study, both sertraline and moclobemide improved the symptoms of atypical depression.

Responsiveness of observer rating scales by analysis of number of days until improvement in patients with major depression.

Several well-known observer scales, including the Hamilton Depression Scale (HAM-D), Montgomery-Asberg Scale (MADRS), Major Depression Rating Scale (MDS), Melancholia Scale (MES), and Inventory for Depressive Symptomatology (IDS) used for measuring severity of depressive states have been compared by their responsiveness in an open trial including patients treated with a combination of citalopram and mianserin. The patients fulfilled the Diagnostic and Statistical Manual (DSM)-IV criteria for major depressive episode, and all scored 18 or more on the HAM-D before treatment. Onset of antidepressant action was defined as an improvement of rating scale scores of 25% or more of pre-treatment scores. A response to treatment was defined as a reduction of 50% or more on the pre-treatment scores. The results showed that the number of treatment days until improvement was 11 to 13 with no difference between the scales. The days until response were between 18 and 21 with no difference between the scales. In conclusion, the depression scales were found to be equal in their ability to detect changes in depressive symptoms during treatment. The mean of days to response was 19 for the combination of citalopram and mianserin. This is similar to the response for the combination of fluoxetine and pinolol.

The effects of extrusion processing of carbohydrate sources on weanling pig performance.

Three experiments were conducted to study the effects of extrusion processing on growth performance of weanling pigs. In Exp. 1, 350 weanling pigs (initially 4.4 +/- 1.0 kg BW and 10 +/- 2 d of age) were used to study the effects of various carbohydrate sources (corn, cornstarch, broken rice, wheat flour, and grain sorghum), with or without moist extrusion processing, on growth performance in a 5 x 2 factorial arrangement of treatments. No carbohydrate source x extrusion processing interactions were observed (P > .10). Growth performance was not affected by extrusion processing; however, pigs fed corn had poorer growth performance (P < .05) than those fed other carbohydrate sources. In Exp. 2, 360 weanling pigs (initially 5.0 +/- .5 kg BW and 10 +/- 2 d of age) were used to determine the interactive effects of ingredient processing and diet complexity on growth performance. Three processing combinations were used with either a simple or complex diet formulation in a 3 x 2 factorial arrangement of treatments. The three processing conditions were 1) pelleted only (control); 2) corn that was moist-extruded and then the complete diet was pelleted (extruded); or 3) the complete diet was expanded and then pelleted (expanded). Pigs fed extruded diets had a greater improvement in ADG as diet complexity increased than those fed other diets (processing x diet complexity interaction, P < .10). Pigs fed moist-extruded corn had the best growth performance (P < .01). In Exp. 3, 210 weanling pigs (initially 6.8 +/- 1.5 kg BW and 21 +/- 2 d of age) were fed pelleted diets containing nonextruded corn (14.5% gelatinization; control) or corn extruded to provide 38.7, 52.7, 64.4, or 89.3% gelatinization. Average daily gain and ADFI decreased and then increased (P < .05), but apparent digestibility of DM, CP, and energy (P < .01) increased and then decreased with increasing gelatinization. These results indicate that moist extrusion processing of carbohydrate sources has variable effects on growth performance of early-weaned pigs and that the degree of gelatinization does not seem to be a major factor in explaining this variation.

Effect of steam-flaked sorghum grain density on performance, mill production rate, and subacute acidosis in feedlot steers.

Two trials were conducted to determine the effects of steam-flaked sorghum grain bulk density on animal performance, cost of production, and propensity to induce ruminal acidosis in feedlot steers. In Trial 1, 336 yearling steers (343 kg; SEM = .346) were fed diets for 125 d that contained sorghum grain (82.5%, DM basis) flaked to .283 (L), .322 (M), or .361 (H) kg/L (i.e., 22, 25, and 28 lb/bu). Steers fed L consumed 3.2% less DM than those fed H (linear, P < .05), resulting in 6.9% lower ADG (linear, P = .02) and 3.6% lower gain efficiency (linear, P < .15). Sorghum grain flaked to M and L had 16 and 46% greater starch gelatinization than H (measured using differential scanning calorimetry; linear, P = .002). Dressing percentage increased linearly (P < .05) with increasing flake density, but no other carcass measurements were affected by treatment. Increasing flake density increased mill production rate linearly (P < .01), resulting in the lowest energy usage per unit of flaked grain for the H treatment. Trial 2 was an acidosis challenge study that incorporated six ruminally cannulated steers (422 kg; SEM = .129) into a replicated 3 x 3 Latin square experiment. Reducing flake density resulted in linear reductions in ruminal pH following intake challenge at 3, 33, and 36 h after the d-12 challenge (P < .05). There was a linear increase in the area between the pH vs time curve and a line at pH 5.5 (P < .01) and 5.0 (P = .09) with decreasing flake density (28.0, 25.2, and 18.2 pH-hours below 5.5 and 9.6, 7.3, and 3.9 pH-hours below 5.0 for L, M, and H, respectively). Cattle consuming L also tended to have higher VFA concentrations (mM) at 36 h after challenge (P = .12). There was no significant treatment effect on ruminal lactate. Flaking sorghum grain to .283 and .322 kg/L resulted in reduced intake and poorer animal performance compared with .361 kg/L (58.7% starch gelatinization), higher susceptibility to subacute acidosis, and higher costs of production.

Moclobemide for anxiety disorders: a focus on moclobemide for panic disorder.

Moclobemide is a reversible selective inhibitor of monoamine oxidase A. It has proven efficacy in a wide range of depressive disorders, including agitated anxious depression. In an international, multicentre, double-blind parallel-group study, the tolerability and efficacy of moclobemide were compared with that of the selective serotonin reuptake inhibitor fluoxetine. The target dose of moclobemide was 450 mg/day in the dose range of 300-600 mg/day, while the target dose for fluoxetine was 20 mg/day in the dose range of 10-30 mg/day. There were two consecutive studies. The first was an 8-week short-term study of acute adverse events, tolerability and efficacy. The efficacy data showed no significant difference between moclobemide and fluoxetine. Evaluation of the tolerability in a long-term study of up to 1 year is still in progress. A review of the moclobemide safety database for panic disorder with 624 patients showed a marginal increase in events with moclobemide compared with placebo for insomnia (11.2%), dizziness (4.5%) and dry mouth (3.7%), with rates for headaches and nausea lower for moclobemide than placebo. These data suggest moclobemide is a well tolerated and effective treatment for panic disorder.

Paroxetine and amitriptyline in the treatment of depression in general practice.

A total of 144 outpatients in general practice in Denmark, aged 18-65 years and diagnosed as suffering from depression with a HAMD-17 score of 15 or more, were included in this 8-week double-blind, randomised, multicentre, controlled, parallel group comparison of paroxetine versus amitriptyline. The purpose of the study was primarily to evaluate efficacy and tolerance of treatment. In addition, focus was added on weight change and subjective well-being. The efficacy results showed equal effect of both drugs. However, paroxetine was tolerated better than amitriptyline, and this difference reached the level of significance when four non-evaluable patients were taken out of the analysis. Moreover, there was a significant weight increase in the amitriptyline group and no significant weight change in the paroxetine group. There was no difference between the groups as regards subjective well-being as measured by the VAS. In conclusion, paroxetine is an effective and well-tolerated antidepressant, and well-suited for the treatment of depression in general practice.

Paroxetine in the treatment of panic disorder. A randomised, double-blind, placebo-controlled study.

BACKGROUND: This study compared the efficacy and tolerability of paroxetine with placebo in the treatment of panic disorder. METHOD: After three weeks of placebo, patients received 12 weeks of treatment with paroxetine (20, 40, or 60 mg) or placebo, and finally two weeks of placebo. Dosages were adjusted according to efficacy and tolerability. Standardised cognitive therapy was given to all patients. The primary measure of outcome was reduction in the number of panic attacks. RESULTS: Analysis of the results showed statistically significant differences in favour of paroxetine between the two treatment groups in two out of the three primary measures of outcome, i.e. 50% reduction in total number of panic attacks and number of panic attacks reduced to one or zero over the study period. For the third measure of outcome, the mean change in the total number of attacks from baseline, there was a positive trend in favour of paroxetine. The results of the primary measures of outcome were strongly supported by the results of the secondary efficacy measures of outcome. In addition, paroxetine, at all doses, was very well tolerated. CONCLUSION: Paroxetine plus cognitive therapy was significantly more effective than placebo plus cognitive therapy in the treatment of panic disorder.