Dragica KOZARIC-KOVACIC31' Nela PIVACb
"Referral Centre for the Stress Related Disorders of the Ministry of Health of the Republic of Croatia, Department of Psychiatry, Dubrava University Hospital, Avenija Gojka Suska 12, HR-10000 Zagreb, Croatia, bDivision of Molecular Medicine, Rudjer Boskovic Institute, POBox 180, HR-10002
Abstract. Combat-related posttraumatic stress disorder (PTSD) is a severe debilitating psychiatric illness associated with different comorbidities. When complicated with comorbid psychotic features, PTSD is usually refractory to treatment and requires the use of other pharmacotherapeutic strategies, i.e. typical or atypical antipsychotics. In 81 male war veterans with chronic combat related PTSD with psychotic features, treatment response, clinical symptoms and adverse events were assessed using Watson's PTSD questionnaire, Positive and Negative Syndrome Scale (PANSS), Hamilton Rating Scale for Depression (HAMD), Clinical Global Impression Severity Scale (CGI-S), CGI-Improvement (CGI-I), Patient Global Impression Improvement Scale (PGI-I) and Drug Induced ExtraPyramidal Symptoms Scale (DIEPSS). War veterans were treated for 6 weeks with fluphenazine (27 patients), olanzapine (28 patients) in a dose range of 5-10 mg/day, or risperidone (26 patients) at a dose of 2-4 mg/day, as monotherapy. Treatment with the atypical antipsychotic olanzapine or risperidone for 6 weeks improved significantly most of the PTSD and psychotic symptoms in war veterans with combat-related chronic psychotic PTSD. Olanzapine and risperidone showed similar efficacy and tolerability and induced fewer side effects than fluphenazine, suggesting that atypical antipsychotics might have beneficial effects in war veterans with treatment-resistant psychotic PTSD. In an open study the effect of clozapine was evaluated in war veterans with combat-related PTSD complicated with severe insomnia and nightmares: 34 patients were treated for 7 days with clozapine, and 37 patients with sedatives. Clozapine was shown to be effective in veterans with PTSD as well as in severe sleep disorders and nightmares, due to its strong sedative and anxiolytic effect.
Keywords. Combat related Posttraumatic Stress Disorder, War veterans, Psychotic features, Treatment, Atypical Antipsychotics, Olanzapine, Risperidone, Clozapine
1 Corresponding author: Dragica KOZARIC-KOVACIC, Referral Centre for the Stress Related Disorders of the Ministry of Health of the Republic of Croatia, Department of Psychiatry; Dubrava University Hospital, Avenija Gojka Suska 6, HR-10000 Zagreb, Croatia, E-mail: [email protected]
Epidemiologic and clinical studies have shown that posttraumatic stress disorder (PTSD) commonly occurs with other psychiatric disorders [1-5]. The rate of comorbidity is especially high in combat-related PTSD. A recent epidemiological survey indicated that approximately 80% of combat veterans with PTSD meet criteria for at least one psychiatric diagnosis. The most frequent diagnoses are major depressive disorder, other anxiety disorders, substance abuse, somatization, personality disorders, and dissociative disorders .
Comorbidity patterns in combat-related PTSD have been suggested to be socio-culturally and geographically specific . There are also atypical clinical pictures of PTSD, as well as the difference in clinical presentation of symptoms. Recently, it has been shown that 30-40% of combat related PTSD patients have psychotic symptoms [3,8,9]. Psychotic features add to the severity of symptoms in combat related PTSD patients .
Some studies show different subtypes of PTSD with depressive, psychotic, and panic features. Levels of cognitive, emotional, and behavioral disturbances in patients with comorbid PTSD and psychotic disorders exceed those seen in patients with PTSD without psychosis, or in patients with only another psychotic disorder. The question is whether a patient had any psychotic episode before his current diagnosis, i.e. current and chronic PTSD, or the psychotic episode occurred after the development of PTSD. There is active debate regarding whether the psychotic symptoms should be recognized as an unique entity, a malignant form of a disorder, or psychosis comorbid with PTSD or major depressive disorder. Before the incorporation of PTSD into American Diagnostic Nomenclature (DSM-III), patients suffering from PTSD were diagnosed with schizophrenia or other psychotic disorders. Many of these patients presented hallucinations, paranoid ideation, or disorganized behavior.
Up to 40% of combat veterans with PTSD may have comorbid psychotic symptoms or meet criteria for a comorbid psychotic disorder diagnosis. PTSD with psychotic features may be a distinct subtype of the disorder [8, 10-15], and it has been found that psychotic features may occur in 30-40% of patients with combat PTSD . Positive symptoms of psychosis, e.g. hallucinations that are moderate to severe in intensity, are now included as an aspect of "flashbacks" in the re-experiencing phenomena of the diagnostic criterion in PTSD. The avoidance symptoms of PTSD— avoidance of activities, places, or people reminiscent of the trauma, feeling detached or estranged from others, restricted range of affect, and diminished interest or participation in significant activities—resemble the negative symptoms associated with schizophrenia.
2. Clinical picture of psychotic symptoms in PTSD and psychometric assessment
Combat veterans with PTSD on the Minnesota Multiphasic Personality Inventory (MMPI / MMPI-2) have their highest mean elevation on clinical scale 8 (the "schizophrenia" scale), suggesting prominent symptoms of thought disturbances and psychosis . Patients with psychotic features scored at least 4 (moderate severity) on the Positive and Negative Syndrome Scale (PANSS) positive items (delusions, conceptual disorganization, hallucinatory behavior, suspiciousness/persecution) . Hamner et al.  described psychotic features in PTSD which include auditory and visual hallucinations and delusional thinking. The content of hallucinations may refer to the traumatic experience ("soldiers screaming" or "incoming rockets"), but also may include not readily identifiable content (the sounds of "garbled voices" or "shadows seen out of the corner of patient's eye"). Delusions are generally paranoid or persecutory in nature. PTSD patients are generally distressed by the psychotic symptoms and retain some reality testing and insight. They do not have the characteristic disturbances(e.g., constricted or inappropriate) of affect or thought disorder (e.g., loose associations or disorganized responses). Complex, bizarre, or absurd delusions, which are common in schizophrenia, are rare in PTSD.
In studies of Croatian war veterans with combat-related PTSD, Kozaric-Kovacic and Borovecki  found that 57-62 % of patients met criteria for comorbid diagnoses. The most prevalent diagnoses were: alcohol abuse, major depressive disorder, anxiety disorders, panic disorder and phobia, psychosomatic disorder, psychotic disorders, substance abuse, and dementia. The study included 680 men who experienced combat stress and had diagnoses of PTSD. The psychotic symptoms in PTSD consisted of two types: depressive or schizophrenia-like. Psychotic disorders were confirmed in 17% and major depressive disorder with psychotic features in 15% of patients with PTSD. Psychotic symptoms were accompanied by auditory or visual hallucinations in 68% of patients. Delusional paranoid symptoms occurred in 32% of patients.
4. Are there implications of comorbid psychotic features for understanding the biology of PTSD?
The concentration of plasma dopamine beta-hydroxylase (DBH) is elevated in psychotic vs. nonpsychotic PTSD and normal control subjects , a finding directly opposed to the findings observed in psychotic depression, i.e. a reduced DBH concentration. Altered DBH may be a biological marker reflecting the increased risk to develop psychotic symptoms in the context of trauma. Since DBH catalyzes the conversion of norepinephrine to dopamine, higher DBH would yield more norepinephrine relative to dopamine biosynthesis. Higher norepinephrine biosynthesis may be characterized by more severe PTSD symptoms and consequent psychotic symptoms.
In extensive studies evaluating the activity of the hypothalamic-pituitary-adrenal (HPA) axis in PTSD, Yehuda and her group [19,20] demonstrated that some aspects of the biology of PTSD differ from that of major depression. PTSD is associated with alterations in the HPA axis, including increased concentrations of cerebrospinal fluid (CSF) corticotrophin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH), low baseline urinary cortisol, and alterations in the secretion and metabolism of norepinephrine and dopamine [20,21]. CRF is released throughout the brain during stress, and mediates endocrine and behavioral responses to stress. CRF released from the hypothalamus increases the release of ACTH from the anterior pituitary, which subsequently stimulates the release of cortisol from the adrenal gland . In PTSD, CRF is elevated, as demonstrated by high basal CSF concentrations of CRF obtained via a single lumbar puncture , and from serial lumbar puncture sampling . The finding that PTSD with psychotic symptoms is associated with elevated CRF shows that PTSD with psychotic features is characterized by extreme perturbations of the neuroendocrine system, supporting the hypothesis that PTSD with psychotic symptoms is a distinct subtype of PTSD .
Noradrenergic dysregulation has long been implicated in PTSD , with exaggerated norepinephrine responses to pharmacological , psychological , and physical  stressors. Yehuda et al.  reported a positive correlation between urinary norepinephrine excretion and PTSD symptoms. Severe PTSD symptoms in patients with psychotic PTSD, reflected by the strong correlation between CAPS and PANSS ratings, may be mediated by norepinephrine dysregulation, and elevated DBH concentrations support this hypothesis.
PTSD with secondary psychotic symptoms (PTSD-SP) is associated with increased somatotropin-release-inhibiting hormone (SRIF), an inhibitory peptide that has wide cortical and limbic distribution. SRIF is released from the anterior pituitary and serves to inhibit the secretion of growth hormone-releasing factor, ACTH, and other pituitary hormones. High levels of SRIF, that covary with CRF , have been reported in PTSD .
5. The relationship between PTSD-SP and schizophrenia
It is important to determine whether the psychotic symptoms that occur in PTSD with psychotic features are similar to schizophrenia, or are unique to PTSD. PTSD-SP is not associated with a family history of schizophrenia, hence it has been proposed that PTSD with psychotic features may be a severe subtype of the disorder that is distinct from the primary psychosis . These findings are supported by other studies, showing a high prevalence of psychotic symptoms in combat PTSD patients, assessed with a strict exclusion criteria for schizophrenia [3,8,15,17].
6. Possible etiologies of psychotic symptoms in psychotic PTSD
The increased activation of CRF circuitry could produce psychotic symptoms by several different mechanisms .
One hypothesis is that the increased activation of the neuroendocrine axis in PTSD-SP causes psychosis by increasing activity of the mesocortical dopaminergic system. Increased secretion of hypothalamic CRF would produce increased cortisol secretion from the adrenal gland, which would increase CNS dopamine activity. This hypothesis is supported by findings from animal studies showing that the peripheral administration of corticosterone leads to the release of dopamine in the prefrontal cortex , and increases in homovanillic acid (HVA) concentration from the caudate nucleus . The intraperitoneal administration of dexamethasone increases dopamine metabolites in the nucleus accumbens and hypothalamus . Clinical studies supporting this hypothesis have demonstrated that the administration of ACTH and cortisol leads to delayed increases in plasma HVA in normal control subjects . Other studies have shown that psychotic depression is associated with more prominent activity of the HPA axis , and higher plasma HVA levels , than non-psychotic depression.
A second hypothesis is that the higher levels of CRF found in PTSD-SP patients produce psychotic symptoms through the mechanism of CRF achieved at the cyclic adenosine monophosphate (cAMP) level in the frontal cortex . This hypothesis presumes that high levels of CRF in PTSD-SP augment dopaminergic stimulation of cyclic AMP in frontal cortex, because both CRF receptor subtypes use G-protein stimulatory receptors that increase cyclic AMP levels when activated by CRF. Stimulation of the D1 dopamine receptor, but not the D2 receptor, increases levels of cAMP. The D1 receptor is most often associated with antipsychotic effects after pharmacologic blockade, which decreases the intraneuronal levels of cAMP when activated by dopamine.
The third hypothesis: since CRF brain circuits are located outside the HPA axis, which mediate emotional responses and arousal, it is possible that increase in frontal dopamine circuit activity during psychotic symptomatology activates some of these systems, resulting in increased secretion of CRF in the CSF of patients with PTSD-SP. Regions outside of the hypothalamus that contain CRF include the locus ceruleus (LC), cortical areas, bed nucleus of the stria terminalis, amygdala and hippocampus. Psychological stressors can activate some of these circuits without involving the hypothalamic CRF neuroendocrine system .
Since PTSD is classified as an anxiety disorder, the treatment of PTSD includes the use of specific psychotherapeutic and pharmacotherapeutic interventions, primarily antidepressants such as tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), adrenergic and antianxiety agents, benzodiazepines, and mood stabilizers [41,42].
Due to the occurrence of psychotic symptoms in PTSD, and/or persistence and refractoriness of the symptoms, thymoleptics or atypical neuroleptics might be used. The presence of psychotic symptoms in PTSD is often associated with treatment resistance, and requires additional pharmacological strategies, such as the use of neuroleptics or atypical antipsychotics. There are few studies assessing the efficacy of different neuroleptics [43-45], or antipsychotics such as risperidone [46-50], olanzapine [44,51-55] or quetiapine [56,57] in PTSD. Hamner  reported a good response to clozapine in a veteran with comorbid PTSD and psychosis.
Preliminary open-trial experience suggested that low doses of atypical antipsychotics may alleviate positive symptoms of psychosis in some PTSD patients. Initial reports suggest that atypical antipsychotics may be helpful either alone or as adjunct therapy to antidepressants or other agents, at least when targeting the comorbid psychosis.
In a preliminary open trial of add-on therapy , 20 combat veterans meeting DSM-IV criteria for PTSD were treated for 6 weeks with quetiapine. The starting dose was 25 mg at bedtime with subsequent titration based on tolerability and clinical response. Quetiapine demonstrated significant improvement in the core PTSD symptoms, positive and negative psychotic symptoms, general psychopathology, and depressive symptoms in war veterans. The tolerability of quetiapine was high with few reported side effects. Patients experiencing sedative effects noted increased duration of sleep and reduction in frequency and intensity of nightmares, other nocturnal anxiety symptoms, and night time awakenings.
8. Studies with Croatian war veterans
In the studies evaluating the effects of antipsychotics in the trials in Croatian war veterans with psychotic combat-related PTSD [44,50], 81 male war veterans with combat-related PTSD participated in the 6 weeks open studies (Figures 1-6, Table 1). War veterans (27 patients) were treated with fluphenazine, 28 patients received olanzapine (5-10 mg/day), and 26 patients were treated with risperidone (2-4 mg/day), as a monotherapy. Fluphenazine exhibits a high affinity of D2 and D1, and moderate affinity for H1 histaminergic receptors . Olanzapine has a high affinity for the 5-HT2A, 5-HT2C, 5-HT3, ^adrenergic, dopamine D1, D2 and D4, and muscarinic M1 to M5 receptors . Risperidone has the affinity for 5-HT2A, 5-HT7, dopamine D2, a1, a2 adrenergic receptors and its high 5-HT2A/D2 ratio is characteristic of the atypical antipsychotic profile .
The presence of psychotic symptoms in PTSD was associated with treatment resistance. Patients included in this study were those with current and chronic PTS who had comorbid psychotic symptoms. The diagnosis of current and chronic combat-related PTSD was confirmed by administration of the structured clinical interview for DSM-IV disorders. The existence of current PTSD was also assessed with Watson's PTSD questionnaire based on DSM-III-R. Patients were excluded from this study if they had any psychiatric disorder before the war, major depressive disorder, a primary diagnosis of another psychiatric disorder (currently or in the previous three months), a serious concomitant medical condition, clinically significant ECG or laboratory findings, serious risk of suicide, history of seizure, or misuse of alcohol or drugs.
Psychotic symptoms were evaluated by the PANSS in 4 categories: positive items (delusions, conceptual disorganization, hallucinatory behavior, suspiciousness/ persecution); negative items (emotional withdrawal, and passive/apathetic social withdrawal); the general psychopathology subscale (guilt feelings, depression, motor retardation, unusual thought content, disorientation, disturbance of volition, poor impulse control, and active social avoidance); and the supplementary subscale (anger and affective lability).
The clinical picture of psychotic symptoms could be categorized into a) the schizophrenia-like characterized mostly by conceptual disorganization, delusions and suspiciousness/persecution; b) the psychotic depression-like, manifest by hallucinatory behavior, depressive psychotic accusations, anddepressive delusions; and c) a mixed clinical picture, with conceptual disturbances and disorganization, persecutive and depressive delusions, visual and auditory hallucinations.
All patients were evaluated before and after 6 weeks of treatment. Instruments used to measure outcomes were: Watson's PTSD Scale to assess PTSD symptoms; Positive and Negative Syndrome Scale (PANSS) to assess change in positive psychotic symptoms, negative symptoms, global psychopathology, and supplementary items; Clinical Global Impression Severity Scale (CGI-S), Clinical Global Impression Improvement Scale (CGI-I), and Patient Global Impression Improvement Scale (PGI-I). For safety and tolerability assessments, vital signs and adverse events were recorded using the Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS).
Before treatment, the age of patients, duration of combat experience and scores in all measurement instruments were similar among veterans with combat-related PTSD receiving fluphenazine, olanzapine or risperidone treatment.
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