Pharmacotherapy of treatment-resistant combat-related posttraumatic stress disorder with psychotic features

Aim

To assess retrospectively the clinical effects of typical (fluphenazine) or atypical (olanzapine, risperidone, quetiapine) antipsychotics in three open clinical trials in male Croatian war veterans with chronic combat-related posttraumatic stress disorder (PTSD) with psychotic features, resistant to previous antidepressant treatment.

Methods

Inpatients with combat-related PTSD were treated for 6 weeks with fluphenazine (n = 27), olanzapine (n = 28) risperidone (n = 26), or quetiapine (n = 53), as a monotherapy. Treatment response was assessed by the reduction in total and subscales scores in the clinical scales measuring PTSD (PTSD interview and Clinician-administered PTSD Scale) and psychotic symptoms (Positive and Negative Syndrome Scale).

Results

After 6 weeks of treatment, monotherapy with fluphenazine, olanzapine, risperidone, or quetiapine in patients with PTSD significantly decreased the scores listed in trauma reexperiencing, avoidance, and hyperarousal subscales in the clinical scales measuring PTSD, and total and subscales scores listed in positive, negative, general psychopathology, and supplementary items of the Positive and negative syndrome scale subscales, respectively (P<0.001).

Conclusion

PTSD and psychotic symptoms were significantly reduced after monotherapy with typical or atypical antipsychotics. As psychotic symptoms commonly occur in combat-related PTSD, the use of antipsychotic medication seems to offer another approach to treat a psychotic subtype of combat-related PTSD resistant to previous antidepressant treatment.In a world in which terrorism and conflicts are constant threats, and these threats are becoming global, posttraumatic stress disorder (PTSD) is a serious and global illness. According to the criteria from the 4th edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1), exposure to a life-threatening or horrifying event, such as combat trauma, rape, sexual molestation, abuse, child maltreatment, natural disasters, motor vehicle accidents, violent crimes, hostage situations, or terrorism, can lead to the development of PTSD (1,2). The disorder may also be precipitated if a person experienced, saw, or learned of an event or events that involved actual or threatened death, serious injury, or violation of the body of self or others (3,4). In such an event, a person’s response can involve intense fear, helplessness, or horror (3,4). However, not all persons who are exposed to a traumatic event will develop PTSD. Although the stress reaction is a normal response to an abnormal situation, some extremely stressful situations will in some individuals overwhelm their ability to cope with stress (5).PTSD is a chronic psychiatric illness. The essential features of PTSD are the development of three characteristic symptom clusters in the aftermath of a traumatic event: re-experiencing the trauma, avoidance and numbing, and hyperarousal (1,6). The core PTSD symptoms in the re-experiencing cluster are intrusive memories, images, or perceptions; recurring nightmares; intrusive daydreams or flashbacks; exaggerated emotional and physical reactions; and dissociative experiences (1,6,7). These symptoms intensify or re-occur upon exposure to reminders of the trauma, and various visual, auditory, or olfactory cues might trigger traumatic memories (3,4). The avoidance and numbing cluster of symptoms includes efforts to avoid thoughts, feelings, activities, or situations associated with the trauma; feelings of detachment or alienation; inability to have loving feelings; restricted range of affect; loss of interest; and avoidance of activity. The hyperarousal cluster includes exaggerated startle response, hyper-vigilance, insomnia and other sleep disturbances, difficulties in concentrating, and irritability or outbursts of anger. PTSD criteria include functional impairment, which can be seen in occupational instability, marital problems, discord with family and friends, and difficulties in parenting (3,4,8). In addition to this social and occupational dysfunction, PTSD is often accompanied by substance abuse (9) and by various comorbid diagnoses, such as major depression (10), other anxiety disorders, somatization, personality disorders, dissociative disorders (7,11), and frequently with suicidal behavior (12). Combat exposure can precipitate a more severe clinical picture of PTSD, which may be complicated with psychotic features and resistance to treatment. War veterans with PTSD have a high risk of suicide, and military experience, guilt about combat actions, survivor guilt, depression, anxiety, and severe PTSD are significantly associated with suicide attempts (12).The pharmacotherapy treatment of PTSD includes the use of antidepressants, such as selective serotonin reuptake inhibitors (fluvoxamine, fluoxetine, sertraline, or paroxetine) as a first choice of treatment, tricyclic antidepressants (desipramine, amitriptyline, imipramine), monoamine oxidase inhibitors (phenelzine, brofaromine), buspirone, and other antianxiety agents, benzodiazepines (alprazolam), and mood stabilizers (lithium) (13-16). Although the pharmacotherapy of PTSD starts with antidepressants, in treatment-refractory patients a new pharmacological approach is required to obtain a response. In treatment-resistant patients, pharmacotherapy strategies reported to be effective include anticonvulsants, such as carbamazepine, gabapentine, topiramate, tiagabine, divalproex, lamotrigine (14,17); anti-adrenergic agents, such as clonidine (although presynaptic α2-adrenoceptor agonist, clonidine blocks central noradrenergic outflow from the locus ceruleus), propranolol, and prazosin (13,14), opiate antagonists (13), and neuroleptics and antipsychotics (14,17,18).Combat exposure frequently induces PTSD, and combat-related PTSD might progress to a severe form of PTSD, which is often refractory to treatment (19-21). Combat-related PTSD is frequently associated with comorbid psychotic features (11,14,17,19-21), while psychotic features add to the severity of symptoms in combat-related PTSD patients (19,22-24). These cases of a more severe subtype of PTSD, complicated with psychotic symptoms, require the use of neuroleptics or atypical antipsychotic drugs (14,17,25-27).After the war in Croatia (1991-1995), an estimated million people were exposed to war trauma and about 10 000 of the Homeland War veterans (15% prevalence) have developed PTSD, with an alarmingly high suicide rate (28). The war in Croatia brought tremendous suffering, not only to combat-exposed veterans and prisoners of war (29), but also to different groups of traumatized civilians in the combat zones, displaced persons and refugees, victims of terrorist attacks, civilian relatives of traumatized war veterans and terrorist attacks victims, and traumatized children and adolescents (30). Among Croatian war veterans with combat-related PTSD, 57-62% of combat soldiers with PTSD met criteria for comorbid diagnoses (8-11), such as alcohol abuse, major depressive disorder, anxiety disorders, panic disorder and phobia, psychosomatic disorder, psychotic disorders, drug abuse, and dementia. In addition to different comorbid psychiatric disorders, a great proportion of war veterans with combat-related PTSD developed psychotic features (8,11,25,26), which consisted of psychotic depressive and schizophrenia-like symptoms (suggesting prominent symptoms of thought disturbances and psychosis). Psychotic symptoms were accompanied by auditory or visual hallucinations and delusional thinking in over two-thirds of patients (25,26). Delusional paranoid symptoms occurred in 32% of patients (25,26). The hallucinations were not associated exclusively with the traumatic experience, while the delusions were generally paranoid or persecutory in nature (25,26). Although psychotic PTSD and schizophrenia share some similar symptoms, there are clear differences between these two entities, since PTSD patients still retain some insight into reality and usually do not have complete disturbances of affect (eg, constricted or inappropriate) or thought disorder (eg, loose associations or disorganized responses).This proportion of veterans with combat-related PTSD refractory to treatment (18-20) and with co-occurring psychotic symptoms requires additional pharmacological strategies, such as the use of neuroleptics (25) or atypical antipsychotics (14,17,26). Studies evaluating the use of antipsychotics in combat-related PTSD with psychotic features are scarce, and antipsychotics were frequently added to existing medication in the treatment of PTSD.In this study, we compared retrospectively the clinical effects of four antipsychotic drugs – a neuroleptic drug (fluphenazine) and three atypical antipsychotics (olanzapine, risperidone and quetiapine) – in treatment-resistant male war veterans with combat-related PTSD with psychotic features.     

Prognostic significance of CD56 antigen expression in patients with acute myeloid leukemia

The aims of this study were to investigate the frequency and prognostic relevance of CD56 expression in patients with acute myeloid leukemia (AML) and to compare the importance of CD56 expression with standard prognostic factors, such as age, leukocytosis, cytogenetic abnormalities and performance status. We analyzed the data of 184 newly diagnosed patients with non-promyelocytic AML and a follow-up of 36 months. The median patient age was 58 years, with a range of 18-79. CD56+ antigen was recorded in 40 patients (21.7%). CD56 + was the most significant risk factor for OS: P = 0.05. The most significant factor for a poor rate of CR was age ≥ 55 years (P = 0.001). CD56 positivity had no significant influence on CR rate, but it was the most significant risk factor for disease-free survival (P = 0.005). The CD56 antigen is an independent prognostic risk factor, and its presence should be measured regularly for a better prognostic assessment of patients with AML.     

Comorbidity as a risk factor for overall survival and decision criteria for intensity of chemotherapy in elderly patients with acute myeloid leukemia

This single-center study estimated the significance of pretreatment factors, including comorbidities, which may predict outcome in elderly patients with acute myeloid leukemia and determined how poor risk factors may be used as decision criteria for intensity of chemotherapy in this group of patients. Seventy-seven patients aged ≥ 55 years treated under four different regimens were followed up 36 month. Our results suggest that the most significant predictor for poor overall survival is comorbidity, as scored by the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), P = 0.008. The most significant predictor for rate of complete remission is serum lactate dehydrogenase (LDH) level, P = 0.049, and the most significant predictor of early death is leucocytosis, P = 0.007. HCT-CI ≥ 3 was the most significant factor for treatment decision making regarding intensity of chemotherapy. The use of standardized comorbidity assessment tools, such as HCT-CI, for elderly patients with AML is practical and can help to improve treatment decision regarding the intensity of chemotherapy.     

Alpha-1-Antitrypsin Antagonizes Cisplatin-Induced Cytotoxicity in Prostate Cancer (PC3) and Melanoma Cancer (A375) Cell Lines

Increased circulating alpha-1-antitrypsin (AAT) correlates with cancer stage/aggressiveness, but its role in cancer biology is unclear. We revealed antagonistic effect of AAT to cisplatin-induced cytotoxicity in prostate (PC3) and melanoma (A375) cancer cell lines. Moreover, AAT abrogated cytotoxicity of MEK inhibitor U0126 in PC3 cell line. Weaker antagonistic effect of AAT on cytotoxicity of PI3/Akt and NF-kB inhibitors was also observed. In addition, cisplatin increased AAT gene expression in transfected PC3 cells. However, AAT derived from transfected PC3 cells did not antagonize cisplatin-induced cytotoxicity. In conclusion, these results suggest possible association between high circulating AAT and cisplatin resistance.     

Effect of the vascular endothelium on contractions induced by noradrenaline and phenylephrine in perforating branch of the human internal mammary artery

The effects of noradrenaline (Nor) and phenylephrine (Phe) on the isolated, non-precontracted perforating branch of the human internal mammary artery (HIMA) were investigated. Nor and Phe induced concentration-dependent contractions of intact and endothelium-denuded arterial rings with no statistically significant differences between the pEC(30) and maximal response values. The pretreatment of arterial rings with indomethacin had no effect on Nor- and Phe-induced contractions of both, intact and endothelium-denuded preparations. The pre-addition of L-NMMA did not affect contractions of perforating branch of the HIMA evoked by Nor, but provoked significant potentiation of Phe-induced contractions of perforating branch of the HIMA both intact and denuded of endothelium only at Phe concentration higher than 3 x 10(-6)M. The effects of selective alpha1-adrenoceptor antagonist, prazosin and selective alpha2-adrenoceptor antagonist, rauwolscine were concentration-dependent, and they induced a significant shift to the right (for both studied antagonists) of the concentration-response curves for Nor in both preparations with or without endothelium. The effects of prazosin and rauwolscine on the concentration-response curves for Phe were similar. In conclusion, this study has shown that Nor and Phe induce concentration-dependent contractions of the perforating branch of the HIMA. Removal of the endothelium did not modify this effect. Products of cyclooxygenase pathway had no influence on Nor and Phe action. Endothelium derived nitric oxide (NO) had no modulatory effect of Nor-induced contractions, but inhibition of NO synthesis provoked potentiation of Phe-induced contractions either in intact or endothelium-denuded preparations. The mechanism of this effect remains still unclear. On the basis of differential affinity of the antagonists and affinities of Nor and Phe themselves, we suggest that alpha1-adrenoceptor subtype is probably involved in the Nor- and Phe-induced contraction of the perforating branch of the HIMA both intact or denuded of endothelium.     

Influence of the endothelium on the vasorelaxant response to acetylcholine and vasoactive intestinal polypeptide in the isolated rabbit facial artery

The aim was to examine the influence of the endothelium on acetylcholine (ACh) and vasoactive intestinal polypeptide (VIP) functional responses in the isolated glandular branch of rabbit facial artery precontracted with phenylephrine as well as the potential contribution of nitric oxide (NO) and prostanoids in the ACh- and VIP-induced effects. Acetylcholine caused endothelium-dependent and VIP endothelium-independent relaxations of facial artery. The effect of ACh was partly inhibited by NG-monomethyl-l-arginine (l-NMMA, a non-selective NO synthase inhibitor) or by indomethacin (a cyclooxygenase inhibitor) while being completely blocked after concomitant addition of l-NMMA and indomethacin. The relaxation of the facial artery caused by ACh was unaffected by 65 mm KCl. The VIP-induced vasodilation was potentiated by forskolin (an adenylate cyclase stimulator) and partly reduced by l-NMMA or S-methyl-l-thiocitrulline (l-SMTC, a neuronal NO synthase inhibitor), whereas it was unaffected by indomethacin. These results suggest that ACh effects on the rabbit facial artery are mediated through release of endothelium-derived NO and cyclooxygenase products, while the effect of VIP is most probably mediated by an increase of cyclic adenosine 3',5'-monophosphate (cAMP) in vascular smooth muscles and by VIP-induced release of NO from perivascular nerve fibers.     

Affinity and specificity of penicillin-antibody interaction determined by an enzyme (E. coli β-galactosidase) immunoassay

An enzyme immunoassay (EIA) for a penicillin derivative is described with a sensitivity at least at the nanogram level. The label, E. coli β-galactosidase is a macromolecule of 540 000 daltons: the size of the enzyme and the ease of linking penicilloyl residues to it make it an interesting model to study the effect of the degree of haptenic substitution (DS) in the tracer on the parameters of EIA. Our results show that the affinity of the binding reaction between antibody and tracer is proportional to the DS but the sensitivity of inhibition is not affected, at least not between 1 and 10 penicilloyl residues per GZ molecule. The theoretical consequences and practical applications of multivalent tracers in EIA are discussed.     

Expression of bone morphogenetic proteins and cartilage-derived morphogenetic proteins during osteophyte formation in humans

Bone‐ and cartilage‐derived morphogenetic proteins (BMPs and CDMPs), which are TGFβ superfamily members, are growth and differentiation factors that have been recently isolated, cloned and biologically characterized. They are important regulators of key events in the processes of bone formation during embryogenesis, postnatal growth, remodelling and regeneration of the skeleton. In the present study, we used immunohistochemical methods to investigate the distribution of BMP‐2, ‐3, ‐5, ‐6, ‐7 and CDMP‐1, ‐2, ‐3 in human osteophytes (abnormal bony outgrowths) isolated from osteoarthritic hip and knee joints from patients undergoing total joint replacement surgery. All osteophytes consisted of three different areas of active bone formation: (1) endochondral bone formation within cartilage residues; (2) intramembranous bone formation within the fibrous tissue cover and (3) bone formation within bone marrow spaces. The immunohistochemistry of certain BMPs and CDMPs in each of these three different bone formation sites was determined. The results indicate that each BMP has a distinct pattern of distribution. Immunoreactivity for BMP‐2 was observed in fibrous tissue matrix as well as in osteoblasts; BMP‐3 was mainly present in osteoblasts; BMP‐6 was restricted to young osteocytes and bone matrix; BMP‐7 was observed in hypertrophic chondrocytes, osteoblasts and young osteocytes of both endochondral and intramembranous bone formation sites. CDMP‐1, ‐2 and ‐3 were strongly expressed in all cartilage cells. Surprisingly, BMP‐3 and ‐6 were found in osteoclasts at the sites of bone resorption. Since a similar distribution pattern of bone morphogenetic proteins was observed during embryonal bone development, it is suggested that osteophyte formation is regulated by the same molecular mechanism as normal bone during embryogenesis.