In apostgradmed.com article there is a description of chronic post traumatic stress disorder:
Persons with chronic PTSD have unusually high rates of associated psychiatric conditions throughout life, including substance abuse and dependence (23%), major depression (20%), alcohol dependence (75%), and personality disorder (20%) (4-6). Other comorbid psychiatric conditions include panic disorder, agoraphobia, generalized anxiety disorder, social phobia, and bipolar disorder (5,6). When such conditions are identified and treated, the intensity of PTSD symptoms usually decreases (4,7).
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Prevention Plan and Model for Post-Traumatic Stress Disorder (PTSD) from Burns and Other Physical Trauma
Conrad M. Swartz, Ph.D., M.D. and Karen Whitehorn, M.D.
Department of Psychiatry, Southern Illinois University School of Medicine, Springfield, IL
"Sympatholytics such as beta-blockers and alpha-1 antagonists reduce emotional intensity by inhibiting sympathetic nervous system activation and tone; so do benzodiazepine and barbiturate tranquilizers and several other anticonvulsants. Decreasing emotional excitement around the time of trauma exposure should diminish both memory acquisition of trauma details and the emotional unpleasantness remembered with the details. Moreover, sympatholytics and tranquilizers can cause somnolence, which itself impairs learning. A few drug trials attempted to prevent PTSD with propranolol; a few more examined stress-related learning, postulating extrapolation to PTSD, although PTSD is pathological and stress-related learning is not. "
Am J Psychiatry 2003 Feb;160(2):371-3 : Reduction of Nightmares and Other PTSD Symptoms in Combat Veterans by Prazosin: A Placebo-Controlled Study.
Raskind MA, Peskind ER, Kanter ED, Petrie EC, Radant A, Thompson CE, Dobie DJ, Hoff D, Rein RJ, Straits-Troster K, Thomas RG, McFall MM.
OBJECTIVE: Prazosin is a centrally active alpha(1) adrenergic antagonist. The authors' goal was to evaluate prazosin efficacy for nightmares, sleep disturbance, and overall posttraumatic stress disorder (PTSD) in combat veterans. METHOD: Ten Vietnam combat veterans with chronic PTSD and severe trauma-related nightmares each received prazosin and placebo in a 20-week double-blind crossover protocol. RESULTS: Prazosin (mean dose=9.5 mg/day at bedtime, SD=0.5) was superior to placebo for the three primary outcome measures: scores on the 1) recurrent distressing dreams item and the 2) difficulty falling/staying asleep item of the Clinician-Administered PTSD Scale and 3) change in overall PTSD severity and functional status according to the Clinical Global Impression of change. Total score and symptom cluster scores for reexperiencing, avoidance/numbing, and hyperarousal on the Clinician-Administered PTSD Scale also were significantly more improved in the prazosin condition, and prazosin was well tolerated. CONCLUSIONS: These data support the efficacy of prazosin for nightmares, sleep disturbance, and other PTSD symptoms.
Inhibition of norepinephrine uptake in patients with major depression treated with paroxetine
OBJECTIVE: The study examined whether paroxetine inhibits the human norepinephrine transporter in addition to the human serotonin (5-HT) transporter in patients with major depressive disorder. METHOD: In an open-label, parallel-group, forced-titration study, 52 outpatients with DSM-IV major depressive disorder and a baseline Montgomery Asberg Depression Rating Scale score > or =20 were randomly assigned to treatment with paroxetine (to 60 mg/day) or desipramine (to 30 mg/day) in a 3-to-1 ratio, respectively. Norepinephrine and 5-HT transporter function were assayed by using human transporter transfected cells in the presence of serum collected at baseline and the end of each treatment week. Data from 36 patients were analyzed. RESULTS: Paroxetine decreased norepinephrine uptake to 73% of control (27% inhibition) at an average serum concentration of 100 ng/ml and 57% of control (43% inhibition) at 200 ng/ml. Uptake of 5-HT was decreased to less than 15% (greater than 85% inhibition) of control at these paroxetine concentrations. Desipramine decreased norepinephrine uptake to near maximal 15% of control (85% inhibition) at 100 ng/ml. Uptake of 5-HT was decreased to 82% of control (18% inhibition) at 100 ng/ml and 49% of control (51% inhibition) at 500 ng/ml. CONCLUSIONS: Paroxetine, currently classified as a selective 5-HT reuptake inhibitor, can act as a 5-HT/norepinephrine uptake inhibitor in vivo. The clinical significance of this action on norepinephrine uptake is currently unknown, but this action may contribute to the broad therapeutic efficacy of paroxetine in the treatment of depression, panic disorder, social anxiety disorder, posttraumatic stress disorder, and generalized anxiety disorder.
Periactin (Cyproheptadine) 4 mg 100 $34.29
Eur Neuropsychopharmacol. 2003 Oct;13(5):313-20. : D2 dopamine receptor gene polymorphism: paroxetine and social functioning in posttraumatic stress disorder.
Lawford BR, McD Young R, Noble EP, Kann B, Arnold L, Rowell J, Ritchie TL.
Greenslopes Private Hospital, Queensland, Brisbane, Australia.
This study examined whether allelic status of the D2 dopamine receptor (DRD2) gene was associated with response to a selective serotonin reuptake inhibitor, paroxetine, in the treatment of posttraumatic stress disorder (PTSD). Sixty-three Caucasian war veterans with combat-related PTSD were treated with paroxetine for 8 weeks. Patients were assessed at baseline and at follow-up using the General Health Questionnaire-28 (GHQ). TaqI A DRD2 alleles were determined by PCR. Before paroxetine treatment, patients with the DRD2 A1+ allele (A1A2 genotype) compared to those with the A1- allele (A2A2 genotype) had higher total GHQ psychopathological scores (P=0.040) and higher GHQ subscale scores for anxiety/insomnia (0.046), social dysfunction (P=0.033) and depression (P=0.011). In an intention-to-treat analysis, paroxetine was associated with significant improvement in total GHQ scores (P=0.014) and in the factor scores of social dysfunction (P=0.033), anxiety (P=0.009) and depression (P=0.026). Furthermore, there was a significant allele by time interaction on the social dysfunction scale, with A1+ allelic patients showing significant improvement in social functioning compared to A1- allelic patients (P=0.031), an effect independent of changes in depression or anxiety. This suggests changes in social functioning induced by paroxetine may be, in part, mediated via D2 dopamine receptors. The DRD2 A1 allele may prove to be a useful marker to assist clinicians in predicting which patients with PTSD are likely to obtain improvements in social functioning with paroxetine treatment.
Psychopharmacology (Berl). 2003 Oct 30 [Epub ahead of print]. : Topiramate attenuates exaggerated acoustic startle in an animal model of PTSD.
Khan S, Liberzon I.
Department of Psychiatry, University of Michigan, 1500 E Medical Center Drive, MI 48109, Ann Arbor, USA.
RATIONALE. Exaggerated acoustic startle is a prominent symptom of post-traumatic stress disorder (PTSD); however, its physiological basis is not well understood, and there are few available treatments. Neurobiological research has suggested that anti-kindling agents and/or glutamate antagonists can attenuate the acoustic startle response (ASR) in animal models. The anticonvulsant topiramate is an AMPA antagonist that also demonstrates potent anti-kindling effects and may, therefore, have promise in treating trauma-enhanced ASR. OBJECTIVE. To evaluate the ability of topiramate to attenuate stress-induced increases in ASR in a previously validated animal model of PTSD. METHODS. Male Sprague-Dawley rats ( n=36) served as controls or received single prolonged stress (SPS). SPS consisted of 2 h restraint, forced swim and ether anesthesia, then a 7-day "undisturbed" period. Animals then received vehicle, 10 mg/kg or 30 mg/kg of topiramate orally, twice daily for 7 days. ASR was assessed for all animals before and after the study, in light and dark environments. RESULTS. SPS produced a sustained increase in the ASR in both environments, an effect that was significantly reduced by topiramate. Meanwhile the ASR of control animals remained unaffected by topiramate. CONCLUSIONS. The current results provide one of the few demonstrations of a single stress episode producing sustained enhancement of ASR. In addition, topiramate demonstrates promise in treating exaggerated acoustic startle symptoms in PTSD or other stress-related disorders.
Expert Opin Pharmacother. 2003 Oct;4(10):1829-38. : Paroxetine in the treatment of post-traumatic stress disorder: pooled analysis of placebo-controlled studies.
Stein DJ, Davidson J, Seedat S, Beebe K.
MRC Unit on Anxiety Disorders, University of Stellenbosch, Cape Town and University of Florida, Gainesville, PO Box 19063, Tygerberg 7505, Cape Town, South Africa.
js2@sun.ac.za
Post-traumatic stress disorder (PTSD) is increasingly understood to be a medical disorder characterised by particular psychobiological dysfunctions that respond to specific treatments. Paroxetine is a selective serotonin re-uptake inhibitor that has been found effective in the treatment of major depression as well as a range of anxiety disorders. This paper reviews data on the use of paroxetine for the treatment of adult PTSD. There have been three 12-week, placebo-controlled studies of paroxetine in PTSD. As these followed a partly similar design, a pooled analysis of the studies is possible and is reported here. Paroxetine is effective in the short-term treatment of PTSD, resulting in significantly better response and remission rates than placebo, improving sleep disturbance and reducing each of the symptom clusters of PTSD, as well as the disability associated with this condition. The medication is effective in both male and female PTSD patients and whether or not there are comorbid disorders such as depression.
Compr Psychiatry 1998 May-Jun;39(3):160-4 : Efficacy of cyproheptadine for nightmares associated with posttraumatic stress disorder.
Gupta S, Popli A, Bathurst E, Hennig L, Droney T, Keller P.
Department of Psychiatry, Olean General Hospital, NY, USA.
A retrospective review of the psychiatric records of nine patients with posttraumatic stress disorder (PTSD) was conducted to determine the efficacy of cyproheptadine in relieving nightmares. The treatment dose was 4 to 12 mg at bedtime. The response varied from complete remission to a decrease in the intensity and frequency of nightmares.
Mil Med 1991 Feb;156(2):100-1 : Cyproheptadine for combat nightmares in post-traumatic stress disorder and dream anxiety disorder.
Brophy MH.
Psychiatry Service, Veterans Administration Medical Center, Dallas, TX 75216.
Pharmacologic treatment of patients with post-traumatic stress disorder often involves antidepressant drugs. Combat nightmares often persist. The addition of cyproheptadine, in a median dose of 16-24 mg orally at night, controls the nightmares.
Ann Pharmacother 2002 Dec;36(12):1875-8 : Quetiapine therapy for posttraumatic stress disorder.
Sattar SP, Ucci B, Grant K, Bhatia SC, Petty F. S Pirzada Sattar MD, Assistant Professor of Psychiatry, School of Medicine,
Creighton University; Director, Psychiatric Services, Substance Abuse Treatment Center,
Omaha Veterans Affairs Medical Center, Omaha, NE.
OBJECTIVE: To report a case of improvement in posttraumatic stress disorder (PTSD) after adjunctive therapy with quetiapine. CASE SUMMARY: A 49-year-old white man witnessed a traumatic event and experienced severe PTSD. He was started on paroxetine, with increases in dosage and no significant improvement. Quetiapine was added to his regimen, with increased doses resulting in improvement of PTSD symptoms, both clinically and as measured on the Hamilton-D rating scale for depression and the clinician-administered PTSD screen. DISCUSSION: This is the first case published in the English language literature describing improvement in PTSD symptoms after treatment with quetiapine. There are several treatment options for PTSD, but some severe cases may require treatment with antipsychotic medications. Because of the lower risks of serious adverse effects, the newer atypical antipsychotics are much safer than the older antipsychotics. Although use of risperidone and olanzapine in the successful treatment of PTSD has been reported in the literature, there are no reports of quetiapine use in this clinical condition. CONCLUSIONS: Quetiapine appeared to improve clinical signs and symptoms of PTSD in this patient. It may be a treatment option in other severe cases of PTSD.
J Clin Psychopharmacol 2003 Feb;23(1):15-20 : Quetiapine treatment in patients with posttraumatic stress disorder: an open trial of adjunctive therapy.
Hamner MB, Deitsch SE, Brodrick PS, Ulmer HG, Lorberbaum JP
In this 6-week, open-label trial, combat veterans meeting DSM-IV criteria for posttraumatic stress disorder (PTSD) were treated with the atypical antipsychotic quetiapine. The starting dose was 25 mg at bedtime with subsequent titration based on tolerability and clinical response. Primary outcome was measured using the Clinician Administered PTSD Scale (CAPS). Secondary assessments of efficacy included the Positive and Negative Symptom Scale (PANSS), the Hamilton Rating Scale for Depression, and the Clinical Global Impression Scale. Safety and tolerability evaluations included neurologic ratings, vital signs, and assessment of treatment-emergent side effects. Eighteen of 20 patients enrolled in the study completed 6 weeks of open-label treatment. The dose range of quetiapine was 25 to 300 mg daily, with an average of 100+/-70 mg/d. There was significant improvement in CAPS scores, from 89.8+/-15.7 to 67.5+/-21.0 (t=4.863, df=18, <0.005), and composite PANSS ratings from baseline to endpoint. General psychopathology (PANSS) and depressive symptoms (HRSD) were also reduced at the 6-week end point. There were no serious adverse events and no clinically significant changes in vital signs or neurologic ratings. This preliminary open trial suggests that quetiapine is well tolerated and may have efficacy in reducing PTSD symptoms in patients who have not had an adequate response other medications. Studies utilizing a randomized, controlled trial design and larger sample sizes are needed to better define the potential role of quetiapine and other atypical antipsychotics in the treatment of PTSD.
Int Clin Psychopharmacol 2003 Jan;18(1):1-8 : Adjunctive risperidone treatment in post-traumatic stress disorder: a preliminary controlled trial of effects on comorbid psychotic symptoms.
Hamner MB, Faldowski RA, Ulmer HG, Frueh BC, Huber MG, Arana GW.
Positive and negative symptoms of psychosis may be common in patients with chronic post-traumatic stress disorder (PTSD), but few studies have investigated the use of antipsychotic agents in these patients. This preliminary study examined the potential efficacy of risperidone in treating psychotic symptoms associated with chronic PTSD. In a 5-week, prospective, randomized, double-blind, placebo-controlled trial, adjunctive risperidone treatment was assessed in 40 combat veterans with chronic PTSD and comorbid psychotic features. Most patients were receiving antidepressants and some other psychotics with doses of concurrent medications held constant for at least 1 month prior to and during the study. Thirty-seven patients completed at least 1 week of treatment with risperidone or placebo. The Positive and Negative Syndrome Scale (PANSS) and the Clinician Administered PTSD Scale (CAPS) were used to assess symptoms. The PANSS was the primary outcome measure. At treatment endpoint, risperidone-treated patients showed a significantly greater decrease from baseline, albeit modest, in psychotic symptoms (PANSS total scores) than placebo-treated patients ( <0.05). CAPS ratings declined significantly in both groups but did not differ significantly between groups. However, CAPS re-experiencing subscale scores had greater improvement in the risperidone-treated patients at week 5 ( <0.05, completer analysis) with a trend towards greater improvement versus placebo a endpoint ( <0.1, LOCF). Risperidone was well tolerated with minimal extrapyramidal symptoms. These preliminary results support studying the potential efficacy of risperidone for treating global psychotic symptoms associated with chronic PTSD with a suggestion that core re-experiencing symptoms may also be responsive. Further research using randomized, controlled trial designs in larger patient groups are needed to define more adequately the role of risperidone and other atypical agents in PTSD.
Spotlight on paroxetine in psychiatric disorders in adults
Paroxetine is a selective serotonin reuptake inhibitor (SSRI), with antidepressant and anxiolytic activity. In 6- to 24-week well designed trials, oral paroxetine 10 to 50 mg/day was significantly more effective than placebo, at least as effective as tricyclic antidepressants (TCAs) and as effective as other SSRIs and other antidepressants in the treatment of major depressive disorder. Relapse or recurrence over 1 year after the initial response was significantly lower with paroxetine 10 to 50 mg/day than with placebo and similar to that with imipramine 50 to 275 mg/day. The efficacy of paroxetine 10 to 40 mg/day was similar to that of TCAs and fluoxetine 20 to 60 mg/day in 6- to 12-week trials in patients aged > or = 60 years with major depression. Paroxetine 10 to 40 mg/day improved depressive symptoms to an extent similar to that of TCAs in patients with comorbid illness, and was more effective than placebo in the treatment of dysthymia and minor depression. Paroxetine 20 to 60 mg/day was more effective than placebo after 8 to 12 weeks' treatment of obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder (social phobia), generalised anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). Improvement was maintained or relapse was prevented for 24 weeks to 1 year in patients with OCD, panic disorder, social anxiety disorder or GAD. The efficacy of paroxetine was similar to that of other SSRIs in patients with OCD and panic disorder and similar to that of imipramine but greater than that of 2'chlordesmethyldiazepam in patients with GAD. Paroxetine is generally well tolerated in adults, elderly individuals and patients with comorbid illness, with a tolerability profile similar to that of other SSRIs. The most common adverse events with paroxetine were nausea, sexual dysfunction, somnolence, asthenia, headache, constipation, dizziness, sweating, tremor and decreased appetite. In conclusion, paroxetine, in common with other SSRIs, is generally better tolerated than TCAs and is a first-line treatment option for major depressive disorder, dysthymia or minor depression. Like other SSRIs, paroxetine is also an appropriate first-line therapy for OCD, panic disorder, social anxiety disorder, GAD and PTSD. Notably, paroxetine is the only SSRI currently approved for the treatment of social anxiety disorder and GAD, which makes it the only drug of its class indicated for all five anxiety disorders in addition to major depressive disorder. Thus, given the high degree of psychiatric comorbidity of depression and anxiety, paroxetine is an important first-line option for the treatment of major depressive disorder, OCD, panic disorder, social anxiety disorder, GAD and PTSD.
Paroxetine: a review.
Paroxetine is a potent and selective serotonin reuptake inhibitor (SSRI) with currently approved indications for the treatment of depression, obsessive-compulsive disorder, panic disorder and social phobia. It is also used in the treatment of generalized anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder and chronic headache. Paroxetine, a phenylpiperidine derivative, is the most potent inhibitor of the reuptake of serotonin (5-hydroxytryptamine, 5-HT) of all the currently available antidepressants including the class of SSRIs. It is a very weak inhibitor of norepinephrine (NE) uptake but it is still more potent at this site than the other SSRIs. The selectivity of paroxetine, i.e., the ratio of inhibition of uptake of norepinephrine to serotonin (NE/5-HT) is amongst the highest of the SSRIs. Paroxetine has little affinity for catecholaminergic, dopaminergic or histaminergic systems and by comparison with tricyclic antidepressants (TCAs) has, therefore, a reduced propensity to cause central and autonomic side effects. Paroxetine exhibits some affinity for the muscarinic cholinergic receptor but much less than the TCAs. In addition, the adaptive changes of somatodendritic (5-HT(1A)) and terminal (5-HT(1B/1D)) autoreceptors observed with paroxetine are different to those observed with TCAs; it also inhibits nitric oxide synthase. It is both a substrate and an inhibitor of cytochrome isoenzyme P450 2D6. Paroxetine is well absorbed orally and undergoes extensive first pass metabolism that is partially saturable. Its metabolites are pharmacologically inactive in vivo. Steady state levels are achieved after 4-14 days and an elimination half-life of 21 h is consistent with once-daily dosing. There is wide inter-individual variation in the pharmacokinetics of paroxetine in adults as well as in the young and the elderly with higher plasma concentrations and slower elimination noted in the latter. Elimination is also reduced in severe renal and hepatic impairment. Serious adverse events are, however, extremely rare even in overdose. In summary, paroxetine is well tolerated and effective in the treatment of both depressive and anxiety disorders across the age range.
Posttraumatic stress disorder and quality of life: results across 64 weeks of sertraline treatment.
OBJECTIVE: The goal of the current study was to characterize the quality of life (QOL) and functional impairment associated with posttraumatic stress disorder (PTSD) and to report the QOL/functional response over the course of long-term treatment. METHOD: QOL and psychosocial functioning were analyzed in 359 randomly assigned patients across a 3-phase study of sertraline in the treatment of chronic DSM-III-R-defined PTSD: (1) 12 weeks of double-blind, placebo-controlled acute treatment with sertraline in flexible doses of 50 to 200 mg/day, (2) 24 weeks of open-label continuation treatment with sertraline among all study completers (regardless of initial study drug assignment or endpoint responder status), and (3) 28 weeks of double-blind, placebo-controlled maintenance treatment with sertraline in continuation phase responders. Assessments included the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), emotional role functioning and mental health subscales of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), as well as the occupational and social functioning items on the Clinician-Administered PTSD Scale, Part 2 (CAPS-2). RESULTS: At acute phase baseline, QOL was significantly impaired as reflected by a mean Q-LES-Q score of 56% of the total possible score and a CAPS-2 social/occupational impairment composite score of 4.4. Sertraline treatment was associated with marked improvement on all QOL/functional measurements: at the end of the acute treatment phase, 58% of responders on treatment with sertraline had achieved Q-LES-Q total scores within 10% of community norms. Twenty-four weeks of continuation treatment led to an additional 20% improvement in QOL and measures of functioning. Double-blind discontinuation of sertraline resulted in recurrence of PTSD symptoms and a worsening of QOL and functional measures, although the degree of exacerbation in symptomatology and psychosocial impairment was notably less than at study entry. CONCLUSION: Sertraline treatment of chronic PTSD is associated with rapid improvement in quality of life that is progressive and sustained over the course of more than 1 year of treatment.
Triiodothyronine augmentation of selective serotonin reuptake inhibitors in posttraumatic stress disorder.
BACKGROUND: There is considerable comorbidity of major depression and posttraumatic stress disorder (PTSD), and antidepressants have been reported to be effective in treating PTSD. Addition of triiodothyronine (T3) to ongoing antidepressant treatment is considered an effective augmentation strategy in refractory depression. We report the effect of T3 augmentation of antidepressants in patients with PTSD. METHOD: T3 (25 microg/day) was added to treatment with a selective serotonin reuptake inhibitor (SSRI) (paroxetine or fluoxetine, 20 mg/day for at least 4 weeks and 40 mg/day for a further 4 weeks) of 5 patients who fulfilled DSM-IV criteria for PTSD but not for major depressive disorder (although all patients had significant depressive symptoms). The Clinician-Administered PTSD Scale, the 21-item Hamilton Rating Scale for Depression, and the Clinical Global Impressions-Severity of Illness scale were administered every 2 weeks, and self-assessments were performed with a 100 mm visual analog mood scale. RESULTS: In 4 of the 5 patients, partial clinical improvement was observed with SSRI treatment at a daily dose of 20 mg with little further improvement when the dose was raised to 40 mg/day. This improvement was substantially enhanced by the addition of T3. Improvement was most striking on the Hamilton Rating Scale for Depression. CONCLUSION: T3 augmentation of SSRI treatment may be of therapeutic benefit in patients with PTSD, particularly those with depressive symptoms. Larger samples and controlled studies are needed in order to confirm this observation.
Effects of comorbid diagnoses on sleep disturbance in PTSD.
OBJECTIVE: Patients with post-traumatic stress disorder (PTSD) are frequently diagnosed with other psychiatric comorbid conditions. This study tested the hypothesis that PTSD patients suffer a greater proportion of sleep problems according to comorbid diagnoses. METHOD: National Comorbidity Survey (NCS) data from 591 individuals diagnosed with PTSD were analyzed. Revised versions of the Diagnostic Interview Schedule and Composite International Diagnostic Interview were administered to a representative sample of males and females. Groups consisted of patients diagnosed with lifetime PTSD and with current comorbid panic disorder, major depressive disorder, generalized anxiety disorder, and alcohol dependence. RESULTS: Patients diagnosed with PTSD/panic disorder reported a significantly greater proportion of nightmare complaints (96%) and insomnia (100%) compared with the other comorbid groups. CONCLUSIONS: A greater proportion of PTSD patients with comorbid panic disorder complain of sleep-related problems than other comorbid groups. This effect appears unique to panic, rather than other general anxiety disorder or depression. Prospective sleep studies are needed to differentiate the role of sleep in PTSD and PD, as well as to examine the role of psychiatric comorbidity in worsening sleep in PTSD patients.
REM sleep and the early development of posttraumatic stress disorder
OBJECTIVE: The potential for chronicity and treatment resistance once posttraumatic stress disorder (PTSD) has become established has stimulated interest in understanding the early pathogenesis of the disorder. Arousal regulation and memory consolidation appear to be important in determining the development of PTSD; both are functions of sleep. Sleep findings from patients with chronic PTSD are complex and somewhat contradictory, and data from the acute phase are quite limited. The aim of the present study was to obtain polysomnographic recordings during an acute period after life-threatening experiences and injury and to relate measures of sleep duration and maintenance and the timing, intensity, and continuity of REM sleep to the early development of PTSD. METHOD: Twenty-one injured subjects meeting study criteria received at least one polysomnographic recording close to the time of medical/surgical stabilization and within a month of injury. PTSD symptoms were assessed concurrently and 6 weeks later. Sleep measures were compared among injured subjects with and without significant PTSD symptoms at follow-up and 10 noninjured comparison subjects and were also correlated with PTSD severity. RESULTS: There was more wake time after the onset of sleep in injured, trauma-exposed patients than in noninjured comparison subjects. Development of PTSD symptoms was associated with shorter average duration of REM sleep before a stage change and more periods of REM sleep. CONCLUSIONS: The development of PTSD symptoms after traumatic injury is associated with a more fragmented pattern of REM sleep.
Abnormal stimulus-response intensity functions in posttraumatic stress disorder: an electrophysiological investigation.
OBJECTIVE: The purpose of this study was to explore the relationship between combat-related posttraumatic stress disorder (PTSD) and specific augmentation versus reduction patterns for the N100 and P200 components of auditory event-related potentials evoked by tones of increasing intensity. METHOD: Event-related potentials of subjects with PTSD (N=36), subjects with no psychopathology (N=20), subjects with major depression but no PTSD (N=10), and subjects with a history of chronic alcohol abuse but no PTSD (N=8) were recorded. Brain responses were evoked by a 2000-Hz tone presented in intensity blocks of 65, 72.5, 80, 87.5, and 95 dB (SPL). RESULTS: Evoked data from five PTSD subjects were of poor quality and excluded from further analyses. For all but one subject with no psychopathology and for all subjects with a history of alcohol abuse or major depression (but no PTSD), the Cz amplitude of the P200 response component showed augmentation as a nearly linear function of tone intensity. As a group, subjects with PTSD showed no such increase in P200 response magnitude. Examination of the data from individual subjects with PTSD showed that 42% exhibited augmentation patterns similar to those seen for subjects in the comparison groups. However, 58% showed evidence of P200 reduction, with the response to the loudest tone being smaller than responses to tones of intermediate intensity. CONCLUSIONS: The data suggest that there is a significant subgroup of patients with combat-related PTSD who enter into a state of protective inhibition at relatively low stimulus intensities. It is hypothesized that this is an appropriate adaptive mechanism for these subjects rather than an indication of a core neurobiological abnormality.
Serotonergic and noradrenergic markers of post-traumatic stress disorder with and without major depression.
Some studies have suggested that disorders in the peripheral and central metabolism of serotonin (5-HT) and noradrenaline (NE) may play roles in the pathophysiology of post-traumatic stress disorder (PTSD). This study examines (1) the availability of plasma total tryptophan, the precursor of 5-HT, and tyrosine, the precursor of NE; and (2) the platelet 5-HT transporter and alpha 2-adrenoceptor (alpha 2-AR) binding sites in patients with PTSD and healthy volunteers. High-performance liquid chromatography (HPLC) was employed to measure plasma tryptophan and tyrosine as well as amino acids known to compete with the same cerebral transport system; that is, valine, leucine, phenylalanine, and isoleucine. The maximum number of binding sites (Bmax) and their affinity (Kd) for binding to [3H]-paroxetine and [3H]-rauwolscine, a selective alpha 2-AR antagonist, were determined. [3H]-paroxetine and [3H]-rauwolscine binding Kd values were significantly higher in patients with PTSD than in healthy volunteers. [3H]-rauwolscine binding Kd values were significantly higher in patients with PTSD and concurrent major depression (MD) than in PTSD patients without MD and healthy volunteers. Plasma tyrosine concentrations and the ratio of tyrosine/valine + leucine + isoleucine + phenylalanine + tryptophan were significantly higher in PTSD patients with MD than in those without MD and healthy volunteers. The results show that PTSD is accompanied by lower affinity of paroxetine binding sites and that PTSD with concurrent MD is accompanied by lower affinity of alpha 2-ARs and increased plasma tyrosine availability to the brain. The results suggest that (1) serotonergic mechanisms, such as defects in the 5-HT transporter system, may play a role in the pathophysiology of PTSD; and (2) that catecholaminergic mechanisms, such as increased precursor availability and lowered affinity of alpha 2-ARs, may play a role in the pathophysiology of PTSD with concurrent MD.
Open trial of fluvoxamine treatment for combat-related posttraumatic stress disorder.
A 10-week open-label trial of fluvoxamine was conducted for male Vietnam combat veterans with chronic PTSD. Subjects were excluded if they met full current criteria for panic disorder or agoraphobia, and lifetime criteria for psychosis, bipolar disorder, or organic mental syndrome. Repeated MANOVA was performed to determine change over time. Fluvoxamine was well tolerated; side effects were observed primarily early in treatment with headache, insomnia, sedation, and gastrointestinal distress being most frequent. Fluvoxamine was effective for treating the core intrusion, avoidance, and arousal symptoms of PTSD. Large treatment effects were seen by 4-6 weeks, and maintained at 10 weeks. The magnitude of change was greater than has been previously reported for antidepressant treatment of male Vietnam combat veterans with PTSD.
CNS Drugs 2002;16(6):425-34 : Spotlight on paroxetine in psychiatric disorders in adults.
Wagstaff AJ, Cheer SM, Matheson AJ, Ormrod D, Goa KL.
Paroxetine is a selective serotonin reuptake inhibitor (SSRI), with antidepressant and anxiolytic activity. In 6- to 24-week well designed trials, oral paroxetine 10 to 50 mg/day was significantly more effective than placebo, at least as effective as tricyclic antidepressants (TCAs) and as effective as other SSRIs and other antidepressants in the treatment of major depressive disorder. Relapse or recurrence over 1 year after the initial response was significantly lower with paroxetine 10 to 50 mg/day than with placebo and similar to that with imipramine 50 to 275 mg/day. The efficacy of paroxetine 10 to 40 mg/day was similar to that of TCAs and fluoxetine 20 to 60 mg/day in 6- to 12-week trials in patients aged > or = 60 years with major depression. Paroxetine 10 to 40 mg/day improved depressive symptoms to an extent similar to that of TCAs in patients with comorbid illness, and was more effective than placebo in the treatment of dysthymia and minor depression. Paroxetine 20 to 60 mg/day was more effective than placebo after 8 to 12 weeks' treatment of obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder (social phobia), generalised anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). Improvement was maintained or relapse was prevented for 24 weeks to 1 year in patients with OCD, panic disorder, social anxiety disorder or GAD. The efficacy of paroxetine was similar to that of other SSRIs in patients with OCD and panic disorder and similar to that of imipramine but greater than that of 2'chlordesmethyldiazepam in patients with GAD. Paroxetine is generally well tolerated in adults, elderly individuals and patients with comorbid illness, with a tolerability profile similar to that of other SSRIs. The most common adverse events with paroxetine were nausea, sexual dysfunction, somnolence, asthenia, headache, constipation, dizziness, sweating, tremor and decreased appetite. In conclusion, paroxetine, in common with other SSRIs, is generally better tolerated than TCAs and is a first-line treatment option for major depressive disorder, dysthymia or minor depression. Like other SSRIs, paroxetine is also an appropriate first-line therapy for OCD, panic disorder, social anxiety disorder, GAD and PTSD. Notably, paroxetine is the only SSRI currently approved for the treatment of social anxiety disorder and GAD, which makes it the only drug of its class indicated for all five anxiety disorders in addition to major depressive disorder. Thus, given the high degree of psychiatric comorbidity of depression and anxiety, paroxetine is an important first-line option for the treatment of major depressive disorder, OCD, panic disorder, social anxiety disorder, GAD and PTSD. Adis International Limited, Auckland, New Zealand.
demail@adis.co.nz
Psychosocial outcomes following long-term, double-blind treatment of chronic depression with sertraline vs placebo
BACKGROUND: Chronic forms of depression are associated with significant functional and psychosocial impairments. To date, no study has measured psychosocial functioning in this population during long-term maintenance antidepressant treatment or following the double-blind discontinuation of treatment. METHODS: Patients with chronic major or double depression completed 12 weeks of short-term treatment followed by 16 weeks of continuation treatment with sertraline hydrochloride. Responders at the end of the continuation phase were randomized, double-blind, to 18 months of maintenance therapy with either sertraline (n = 77) or placebo (n = 84). Multiple domains of psychosocial functioning were assessed during double-blind therapy. RESULTS: Substantial worsening in psychosocial function measures occurred in patients taking placebo compared with sertraline during maintenance. Patients with reemergence of depression lost psychosocial gains regardless of treatment. In the subsample of patients who remained in remission throughout maintenance, most of the observed improvement in psychosocial functioning occurred during short-term treatment. By maintenance end point, normalization of functioning was achieved by 58% to 84% of remitters, depending on the outcome measure used. CONCLUSIONS: These results indicate that long-term treatment of chronic forms of depression can result in sustained psychosocial benefits. Discontinuation of treatment results in frequent reemergence of symptoms and loss of psychosocial gains. Long-term treatment resulted in only modest further improvement of psychosocial measures over that achieved in the short-term phase.
Sertraline, paroxetine, and venlafaxine in refugee posttraumatic stress disorder with depression symptoms.
Three new antidepressants were used in treating posttraumatic stress disorder (PTSD) and symptoms of depression in Bosnian refugees. Thirty-two Bosnian refugees seeking treatment at a mental health clinic participated in a case series study. All received open trials of Sertraline (n = 15), Paroxetine (n = 12), or Venlafaxine (n = 5), with standard clinical doses. Overall, Sertraline and Paroxetine produced statistically significant improvement at 6 weeks in PTSD symptom severity in depression, and in Global Assessment of Functioning. Venlafaxine produced improvement in PTSD symptom severity and in Global Assessment of Functioning, did not yield improvement in symptoms of major depressive disorder; and had a high rate of side effects. Notwithstanding improvement of symptoms, all 32 refugees remained PTSD positive at the diagnostic level at the 6-week follow-up.
Venlafaxine-EFFEXOR
Dose-response relationship of selective serotonin reuptake inhibitors treatment-emergent hypomania in depressive disorders.
OBJECTIVE: The notion that antidepressant treatment-associated hypomania or mania being pharmacologically induced has been challenged. To determine whether selective serotonin reuptake inhibitors (SSRI) induced hypomania is secondary to medication effects, we examined the dose-response relationship of SSRI-induced hypomania in two patients with depressive disorder. METHOD: Case study. RESULT: Hypomanic symptoms emerged during treatment with sertraline at the dose of 300 mg per day in a 45-year-old male with major depression. Paroxetine treatment at the dose of 80 mg per day induced hypomania in a 37-year-old female with dysthymia and trichitillomania. These patients have no family or personal history of bipolar disorder. Hypomania resolved when sertraline was decreased to 200 mg per day and paroxetine to 40 mg per day. No hypomanic switch was observed during 18-24 months follow-up. CONCLUSION: In the absence of risk factors for manic switch, SSRI-induced hypomania may be dose-dependent medication effects.
BACKGROUND: The hypothesis that exposure to traumatic events may sensitize or kindle limbic nuclei has led to efforts to treat posttraumatic stress disorder (PTSD) with anticonvulsants. Based on the kindling hypothesis of PTSD, this open-label study assesses clinical response to topiramate as a potential treatment for DSM-IV PTSD. METHOD: A naturalistic data review was conducted of medical records of all adult outpatients (9 men. 26 women symptomatic for a mean +/- SD of 18 +/- 15 years with DSM-IV chronic civilian PTSD) treated with topiramate, 12.5 to 500 mg/day, as add-on (N = 28) or monotherapy (N = 7). The last 17 patients completed the PTSD Checklist-Civilian Version (PCL-C) before treatment and at week 4. Dosage titration started at 12.5 to 25 mg/day and increased in 25- to 50-mg increments every 3 to 4 days until a therapeutic response was achieved or the drug was no longer tolerated. The mean duration of treatment was 33 weeks (range, 1-119 weeks). RESULTS: Topiramate decreased nightmares in 79% (19/24) and flashbacks in 86% (30/35) of patients, with full suppression of nightmares in 50% and of intrusions in 54% of patients with these symptoms. Nightmares or intrusions partially improved in a median of 4 days (mean = 11 +/- 13 days) and were fully absent in a median of 8 days (mean = 35 +/- 49 days). Response was seen in 95% of partial responders at a dosage of 75 mg/day or less, and in 91% of full responders at a dosage of 100 mg/day or less. Mean reductions in PCL-C score from baseline to week 4 were highly significant (baseline score = 60 vs. week 4 score = 39, p < .001), with similar reductions in reexperiencing, avoidance, and hyperarousal criteria symptoms. Thirteen patients discontinued for various reasons during the > 2-year study period. Except for a single instance of acute secondary narrow-angle glaucoma, there were no serious side effects. CONCLUSION: Topiramate appeared effective as add-on or monotherapy for chronic PTSD. It demonstrated a rapid onset of action and minimally serious, dose-related side effects without the development of tolerance. Double-blind studies are indicated.
Posttraumatic stress disorder (PTSD) is a serious and debilitating mental condition that affects a significant proportion of the general population at some time in their lives. To date, however, the U.S. Food and Drug Administration has approved only 1 pharmacologic treatment for this indication. Additional effective therapies are urgently required to control the destructive symptoms experienced by individuals with PTSD. This article reviews the effects of the novel antiepileptic drug topiramate on 3 patients meeting DSM-IV criteria for chronic PTSD. In these previously treatment-refractory patients, topiramate had a marked effect: reducing and even eliminating trauma-related intrusive memories and nightmares and normalizing depressed mood. Adverse events were effectively controlled with careful drug titration and discontinuation of concomitant therapies. These findings, together with observations in more than 30 additional patients (reported elsewhere), suggest that further study of topiramate as a treatment for PTSD is warranted.
Does intolerance or lack of response with fluoxetine predict the same will happen with sertraline?
BACKGROUND: The purpose of this study was to determine whether sertraline would be well tolerated and effective in patients who had failed fluoxetine therapy or were unable to tolerate the medication. METHOD: Hospital records were reviewed for 88 consecutive patients started on sertraline treatment at McLean Hospital from February 11, 1992 to August 28, 1992. Forty-two patients were identified who had received sertraline treatment and who had had previous trials of fluoxetine. Patients were contacted after discharge to determine sertraline efficacy and side effects. A variety of patient characteristics and outcome measures were compared. RESULTS: Thirty-nine subjects (93%) were available for follow-up interviews. The DSM-III-R diagnoses at discharge were as follows: major depression (N=25), bipolar depression (N=6), schizoaffective disorder (N=4), and obsessive-compulsive disorder (N=4). The sertraline discontinuation rate was 64% (25/39) by a mean +/- SD of 2.3 +/- 2.1 months. In patients with major depression (N=25) and bipolar depression (N=6) discharged on sertraline, only 13 (42%) were considered responders to sertraline therapy, and at follow-up, only 8 (26%) of 31 were considered responders to sertraline therapy. Patients who had previously discontinued fluoxetine because of side effects were significantly more likely to have side effects during sertraline treatment (p = .027), and to have discontinued sertraline at follow-up (p = .018). CONCLUSION: Sertraline was found to be modestly efficacious and associated with numerous side effects and discontinuation rates in patients who had previously discontinued fluoxetine.
fluoxetine=Prozax
Paroxetine: a review
Paroxetine is a potent and selective serotonin reuptake inhibitor (SSRI) with currently approved indications for the treatment of depression, obsessive-compulsive disorder, panic disorder and social phobia. It is also used in the treatment of generalized anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder and chronic headache. Paroxetine, a phenylpiperidine derivative, is the most potent inhibitor of the reuptake of serotonin (5-hydroxytryptamine, 5-HT) of all the currently available antidepressants including the class of SSRIs. It is a very weak inhibitor of norepinephrine (NE) uptake but it is still more potent at this site than the other SSRIs. The selectivity of paroxetine, i.e., the ratio of inhibition of uptake of norepinephrine to serotonin (NE/5-HT) is amongst the highest of the SSRIs. Paroxetine has little affinity for catecholaminergic, dopaminergic or histaminergic systems and by comparison with tricyclic antidepressants (TCAs) has, therefore, a reduced propensity to cause central and autonomic side effects. Paroxetine exhibits some affinity for the muscarinic cholinergic receptor but much less than the TCAs. In addition, the adaptive changes of somatodendritic (5-HT(1A)) and terminal (5-HT(1B/1D)) autoreceptors observed with paroxetine are different to those observed with TCAs; it also inhibits nitric oxide synthase. It is both a substrate and an inhibitor of cytochrome isoenzyme P450 2D6. Paroxetine is well absorbed orally and undergoes extensive first pass metabolism that is partially saturable. Its metabolites are pharmacologically inactive in vivo. Steady state levels are achieved after 4-14 days and an elimination half-life of 21 h is consistent with once-daily dosing. There is wide inter-individual variation in the pharmacokinetics of paroxetine in adults as well as in the young and the elderly with higher plasma concentrations and slower elimination noted in the latter. Elimination is also reduced in severe renal and hepatic impairment. Serious adverse events are, however, extremely rare even in overdose. In summary, paroxetine is well tolerated and effective in the treatment of both depressive and anxiety disorders across the age range.
An open trial of paroxetine in patients with noncombat-related, chronic posttraumatic stress disorder.
The symptom overlap between posttraumatic stress disorder (PTSD) and other pharmacotherapy-responsive disorders suggests that pharmacotherapy might be effective. Nevertheless, of the eight published placebo-controlled trials investigating the pharmacotherapy of PTSD, only four found statistically significant efficacy for the treatment being studied. This literature possesses a number of methodologic limitations, including the fact that most studies have been conducted with war veterans, who may constitute a more treatment-refractory population. Several open trials and one controlled trial with selective serotonin reuptake inhibitors have reported improvement in some or all core PTSD symptoms (reexperiencing, avoidance, numbing, and hyperarousal). The authors hypothesized that paroxetine might be effective in PTSD, based on findings of its particular efficacy for anxiety and agitation in studies of depressed patients. The study presented here summarizes a 12-week, open-label trial of paroxetine among patients with noncombat-related, chronic PTSD. Outcome was assessed by an independent evaluator, the treating physician, and the patient, with the use of established rating scales for depression, anxiety, general symptoms, and PTSD core symptoms. A repeated-measures analysis of variance revealed highly significant improvement in all three symptom clusters, as well as in associated anxiety, depressive, and dissociative symptoms, with 11 of 17 (65%) patients rated as much or very much improved. The mean reduction in PTSD symptom scores was 48%. Exploratory analyses revealed that cumulative childhood trauma was negatively correlated with pharmacotherapy response (r = -0.52, p = 0.03). There was also significant variation in the time course of response across symptom clusters, which is suggestive of multiple mechanisms of response. Because paroxetine seems a highly promising treatment for all three symptom clusters of PTSD, a placebo-controlled clinical trial is warranted
Spotlight on paroxetine in psychiatric disorders in adults.
1: Paroxetine is a selective serotonin reuptake inhibitor (SSRI), with antidepressant and anxiolytic activity. In 6- to 24-week well designed trials, oral paroxetine 10 to 50 mg/day was significantly more effective than placebo, at least as effective as tricyclic antidepressants (TCAs) and as effective as other SSRIs and other antidepressants in the treatment of major depressive disorder. Relapse or recurrence over 1 year after the initial response was significantly lower with paroxetine 10 to 50 mg/day than with placebo and similar to that with imipramine 50 to 275 mg/day. The efficacy of paroxetine 10 to 40 mg/day was similar to that of TCAs and fluoxetine 20 to 60 mg/day in 6- to 12-week trials in patients aged > or = 60 years with major depression. Paroxetine 10 to 40 mg/day improved depressive symptoms to an extent similar to that of TCAs in patients with comorbid illness, and was more effective than placebo in the treatment of dysthymia and minor depression. Paroxetine 20 to 60 mg/day was more effective than placebo after 8 to 12 weeks' treatment of obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder (social phobia), generalised anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). Improvement was maintained or relapse was prevented for 24 weeks to 1 year in patients with OCD, panic disorder, social anxiety disorder or GAD. The efficacy of paroxetine was similar to that of other SSRIs in patients with OCD and panic disorder and similar to that of imipramine but greater than that of 2'chlordesmethyldiazepam in patients with GAD. Paroxetine is generally well tolerated in adults, elderly individuals and patients with comorbid illness, with a tolerability profile similar to that of other SSRIs. The most common adverse events with paroxetine were nausea, sexual dysfunction, somnolence, asthenia, headache, constipation, dizziness, sweating, tremor and decreased appetite. In conclusion, paroxetine, in common with other SSRIs, is generally better tolerated than TCAs and is a first-line treatment option for major depressive disorder, dysthymia or minor depression. Like other SSRIs, paroxetine is also an appropriate first-line therapy for OCD, panic disorder, social anxiety disorder, GAD and PTSD. Notably, paroxetine is the only SSRI currently approved for the treatment of social anxiety disorder and GAD, which makes it the only drug of its class indicated for all five anxiety disorders in addition to major depressive disorder. Thus, given the high degree of psychiatric comorbidity of depression and anxiety, paroxetine is an important first-line option for the treatment of major depressive disorder, OCD, panic disorder, social anxiety disorder, GAD and PTSD
Efficacy and safety of paroxetine treatment for chronic PTSD: a fixed-dose, placebo-controlled study
OBJECTIVE: This study evaluated the efficacy and safety of paroxetine for the treatment of patients with chronic posttraumatic stress disorder (PTSD). METHOD: Outpatients with chronic PTSD according to DSM-IV criteria and a score of 50 or more on the Clinician-Administered PTSD Scale, part 2, were randomly assigned to take placebo (N=186), 20 mg/day of paroxetine (N=183), or 40 mg/day of paroxetine (N=182) for 12 weeks. Efficacy was assessed by examining the change in total score from baseline to endpoint on the Clinician-Administered PTSD Scale, part 2, and rates of response ("very much improved" or "much improved") for global improvement on the Clinical Global Impression scale. RESULTS: Paroxetine-treated patients in both dose groups demonstrated significantly greater improvement on primary outcome measures compared to placebo-treated patients in the intent-to-treat analysis. Moreover, paroxetine treatment resulted in statistically significant improvement compared to placebo on all three PTSD symptom clusters (reexperiencing, avoidance/numbing, and hyperarousal), social and occupational impairment, and comorbid depression. Paroxetine was effective for both men and women. Treatment response did not vary by trauma type, time since trauma, or severity of baseline PTSD or depressive symptoms. Both doses were well tolerated. CONCLUSIONS: Doses of 20 and 40 mg/day of paroxetine are effective and well tolerated in the treatment of adults with chronic PTSD.
Paroxetine in the treatment of chronic posttraumatic stress disorder: results of a placebo-controlled, flexible-dosage trial.
. BACKGROUND: The objective of this double-blind, placebo-controlled study was to investigate the efficacy and safety of paroxetine in outpatients with posttraumatic stress disorder (PTSD). METHOD: Male and female outpatients 18 years and older who met DSM-IV criteria for PTSD and had baseline scores of 50 or greater on the Clinician Administered PTSD Scale (CAPS-2) were randomly assigned to treatment with paroxetine (20-50 mg/day) or placebo for 12 weeks. The primary efficacy variables were the change from baseline to the 12-week endpoint in the CAPS-2 total score and the proportion of responders on the Clinical Global Impressions-Global Improvement scale (CGI-1). Additional key outcome measures were the change from baseline in the reexperiencing, avoidance/ numbing, and hyperarousal scores of the CAPS-2 and in the total scores of the Treatment Outcome PTSD Scale and the patient-rated Davidson Trauma Scale and Sheehan Disability Scale (SDS). Depressive symptoms were assessed with the Montgomery-Asberg Depression Rating Scale. The proportion of patients achieving response and remission was also determined. RESULTS: 307 patients constituted the intent-to-treat population. At week 12, compared with the placebo group (N = 156), the paroxetine group (N = 151) showed significantly greater reduction of PTSD symptoms on both of the primary and all of the secondary outcome measures. Significantly greater improvement on the CAPS-2 total score was observed for paroxetine compared with placebo from week 4 (p < .05), and significantly greater proportions of paroxetine-treated patients achieved response (p < .001) and remission (p = .008) by week 12. The improvement in PTSD symptoms was similar in male and female patients. Functional improvement at the study endpoint was significantly greater (p < .05) in the paroxetine group in all 3 domains of the SDS (work, social life, family life). Treatment with paroxetine was well tolerated, with the frequency and type of adverse events recorded for the paroxetine group corresponding to the known safety profile of this medication. Conclusion: Paroxetine in doses of 20 to 50 mg once daily is effective as a treatment for chronic PTSD. Improvement is obtained for all 3 symptom clusters (reexperiencing, avoidance/numbing, hyperarousal) and is associated with significant reduction in disability after 12 weeks of treatment.
A post hoc comparison of paroxetine and nortriptyline for symptoms of traumatic grief.
BACKGROUND: This report presents the results of an open-trial pilot study of paroxetine for symptoms of traumatic grief, compared with the effects of nortriptyline in an archival contrast group. METHOD: Data are presented on 15 subjects (4 men, 11 women), ranging in age from 40 to 79 years (mean age = 57 years), who experienced the loss of a spouse (N = 8), child (N =5), grandchild (N = 1), or parent (N = 1). Subjects were required to have a baseline score on the Inventory of Complicated Grief (ICG) of > or = 20. Treatment with paroxetine began at a median of 17 months (range, 6-139 months) after the loss. Paroxetine-treated subjects received a psychotherapy tailored for traumatic grief. Depressive symptoms were assessed by using the Hamilton Rating Scale for Depression (HAM-D). The ICG and the HAM-D were administered weekly over 4 months of paroxetine treatment (median dose = 30 mg/day). The group receiving paroxetine were then compared with a group (N = 22) participating in a separate trial of nortriptyline (median dose = 77.5 mg/day) for treatment of bereavement-related major depressive episodes. RESULTS: Level of traumatic grief symptoms (ICG) decreased by 53%, and depression ratings (HAM-D) decreased by 54% in paroxetine-treated subjects. Nortriptyline showed clinical effects comparable to those of paroxetine. CONCLUSION: Paroxetine may be an effective agent in the treatment of traumatic grief symptoms. A comparison of the paroxetine-treated group with a nortriptyline-treated group suggests that both agents have comparably beneficial effects on the symptoms of traumatic grief (as well as those of depression). However, the higher rate of diagnostic comorbidity in the paroxetine-treated group, together with the greater chronicity of their symptoms and the greater safety of paroxetine in overdose, leads us to favor paroxetine over nortriptyline for traumatic grief symptoms in general psychiatric practice. Further controlled evaluation of paroxetine for traumatic grief is necessary.
nortriptyline-Pamelor, Aventyl
Common Reactions to Trauma
Edna B. Foa, Elizabeth A. Hembree, David Riggs, Sheila Rauch, and Martin Franklin
Center for the Treatment and Study of Anxiety
Department of Psychiatry, University of Pennsylvania
A traumatic experience produces emotional shock and may cause many emotional problems. This handout describes some of the common reactions people have after a trauma. Because everyone responds differently to traumatic events, you may have some of these reactions more than others, and some you may not have at all.
Remember, many changes after a trauma are normal. In fact, most people who directly experience a major trauma have severe problems in the immediate aftermath. Many people then feel much better within three months after the event, but others recover more slowly, and some do not recover enough without help. Becoming more aware of the changes you've undergone since your trauma is the first step toward recovery.
Some of the most common problems after a trauma are described below.
1.Fear and anxiety. Anxiety is a common and natural response to a dangerous situation. For many it lasts
long after the trauma ended. This happens when views of the world and a sense of safety have
changed. You may become anxious when you remember the trauma. But sometimes anxiety may come from
out of the blue. Triggers or cues that can cause anxiety may include places, times of day, certain smells
or noises, or any situation that reminds you of the trauma. As you begin to pay more attention to the
times you feel afraid you can discover the triggers for your anxiety. In this way, you may learn that some
of the out-of-the-blue anxiety is really triggered by things that remind you of your trauma.
2.Re-experiencing of the trauma. People who have been traumatized often re-experience the traumatic
event. For example, you may have unwanted thoughts of the trauma, and find yourself unable to get rid
of them. Some people have flashbacks, or very vivid images, as if the trauma is occurring again.
Nightmares are also common. These symptoms occur because a traumatic experience is so shocking and
so different from everyday experiences that you can't fit it into what you know about the world. So in
order to understand what happened, your mind keeps bringing the memory back, as if to better digest it
and fit it in.
3.Increased arousal is also a common response to trauma. This includes feeling jumpy, jittery, shaky,
being easily startled, and having trouble concentrating or sleeping. Continuous arousal can lead to
impatience and irritability, especially if you're not getting enough sleep. The arousal reactions are due
to the fight or flight response in your body. The fight or flight response is the way we protect ourselves
against danger, and it occurs also in animals. When we protect ourselves from danger by fighting or
running away, we need a lot more energy than usual, so our bodies pump out extra adrenaline to help us
get the extra energy we need to survive.
People who have been traumatized often see the world as filled with danger, so their bodies are on
constant alert, always ready to respond immediately to any attack. The problem is that increased arousal
is useful in truly dangerous situations, such as if we find ourselves facing a tiger. But alertness becomes
very uncomfortable when it continues for a long time even in safe situations. Another reaction to danger
is to freeze, like the deer in the headlights, and this reaction can also occur during a trauma.
4.Avoidance is a common way of managing trauma-related pain. The most common is avoiding situations
that remind you of the trauma, such as the place where it happened. Often situations that are less
directly related to the trauma are also avoided, such as going out in the evening if the trauma occurred at
night. Another way to reduce discomfort is trying to push away painful thoughts and feelings. This can
lead to feelings of numbness, where you find it difficult to have both fearful and pleasant or loving
feelings. Sometimes the painful thoughts or feelings may be so intense that your mind just blocks them out
altogether, and you may not remember parts of the trauma.
5.Many people who have been traumatized feel angry and irritable. If you are not used to feeling angry
this may seem scary as well. It may be especially confusing to feel angry at those who are closest to
you. Sometimes people feel angry because of feeling irritable so often. Anger can also arise from a feeling
that the world is not fair.
6.Trauma often leads to feelings of guilt and shame. Many people blame themselves for things they did or
didn't do to survive. For example, some assault survivors believe that they should have fought off an
assailant, and blame themselves for the attack. Others feel that if they had not fought back they wouldn't
have gotten hurt. You may feel ashamed because during the trauma you acted in ways that you would
not otherwise have done. Sometimes, other people may blame you for the trauma.
Feeling guilty about the trauma means that you are taking responsibility for what occurred. While this may
make you feel somewhat more in control, it can also lead to feelings of helplessness and depression.
7.Grief and depression are also common reactions to trauma. This can include feeling down, sad, hopeless
or despairing. You may cry more often. You may lose interest in people and activities you used to enjoy.
You may also feel that plans you had for the future don't seem to matter anymore, or that life isn't worth
living. These feelings can lead to thoughts of wishing you were dead, or doing something to hurt or kill
yourself. Because the trauma has changed so much of how you see the world and yourself, it makes
sense to feel sad and to grieve for what you lost because of the trauma.
8.Self-image and views of the world often become more negative after a trauma. You may tell yourself,
"If I hadn't been so weak or stupid this wouldn't have happened to me." Many people see themselves as
more negative overall after the trauma ("I am a bad person and deserved this.").
It is also very common to see others more negatively, and to feel that you can't trust anyone. If you
used to think about the world as a safe place, the trauma may suddenly make you think that the world is
very dangerous. If you had previous bad experiences, the trauma convinces you that the world is
dangerous and others aren't to be trusted. These negative thoughts often make people feel they have
been changed completely by the trauma. Relationships with others can become tense and it is difficult to
become intimate with people as your trust decreases.
9.Sexual relationships may also suffer after a traumatic experience. Many people find it difficult to feel
sexual or have sexual relationships. This is especially true for those who have been sexually assaulted,
since in addition to the lack of trust, sex itself is a reminder of the assault.
10.Some people increase their use of alcohol or other substances after a trauma. There is nothing wrong
with responsible drinking, but if your use of alcohol or drugs changed as a result of your traumatic
experience, it can slow down your recovery and cause problems of its own.
Many of the reactions to trauma are connected to one another. For example, a flashback may make you
feel out of control, and will therefore produce fear and arousal. Many people think that their common
reactions to the trauma mean that they are "going crazy" or "losing it." These thoughts can make them
even more fearful. Again, as you become aware of the changes you have gone through since the trauma,
and as you process these experiences during treatment, the symptoms should become less distressing
Mol Pharmacol 2003 Jan;63(1):44-52 : Involvement of a calcineurin cascade in amygdala depotentiation and quenching of fear memory.
Lin CH, Lee CC, Gean PW.
Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan.
If fear memory is expressed by a long-term potentiation (LTP) of synaptic transmission in the amygdala, then reversal of LTP (depotentiation) in this area of the brain may provide an important mechanism for amelioration of anxiety and post-traumatic stress disorder. Herein, we show that low-frequency stimulation (LFS) of the external capsule elicits a depotentiation in the lateral nucleus of the amygdala. The induction of depotentiation requires activation of N-methyl-D-aspartate receptors and voltage-dependent calcium channels but is independent of adenosine A(1) and metabotropic glutamate group II receptors. Extracellular perfusion or loading cells with protein phosphatase (PP) 2B (calcineurin) inhibitors prevents depotentiation. The same stimulating protocol applied to the amygdala in vivo attenuates the expression of fear memory measured with fear-potentiated startle and reduces conditioning-elicited phosphorylation of Akt and mitogen-activated protein kinase (MAPK). This is paralleled by an increase in the activity of calcineurin. In addition, application of calcineurin inhibitor blocks LFS-induced extinction of fear memory and MAPK dephosphorylation. Taken together, this study characterizes the properties of LFS-induced depotentiation in the amygdala and suggests an involvement of calcineurin cascade in synaptic plasticity and memory storage.(calcineurin A)