T91. DEVELOPMENT OF NOVEL BIS-AMIDINES FOR THE TREATMENT OF TOXOPLASMOSIS

Abstract Background Toxoplasma infections constitute a worldwide public health problem responsible for significant morbidity. Symptoms of acute infection by the agent, the apicomplexan parasite Toxoplasma gondii, can range from mild to life-threatening depending upon the immune status of the host. Toxoplasma infections are often unrecognized in immune competent hosts but infection can lead to the long-term establishment of cysts in the brain and thus a persistent infection. Such tissue cysts are associated with altered behavior and cognition in mouse models. Furthermore, serological evidence of Toxoplasma infection has been associated with an increased risk of recent onset psychosis, schizophrenia, and other psychiatric disorders in humans. Adjunct treatment of Toxoplasma-seropositive individuals afflicted with schizophrenia with effective anti-parasitic medications could be beneficial by eliminating the parasite cysts, thereby possibly alleviating psychiatric symptoms. However, currently available medications are ineffective against the cyst form of the organism responsible for persistent infection. Others have published the anti-Toxoplasma potential of derivatives of the bis-amidine pentamidine. We designed and synthesized a panel of novel bis-amidines and explored their anti-Toxoplasma efficacy. Methods We designed and synthesized an array of twelve novel bis-amidines. These compounds were examined for in vitro activity against T. gondii tachyzoites first using a colorimetric assay employing the β-gal producing strain RH-2F to examine the effect of the compounds over 5 days of parasite growth in human fibroblast host cells. This was followed by several immunofluorescence-based assays to determine if compounds can directly act on tachyzoites (red/green invasion assay), on an established infection of host cells (replication assay), and whether the compounds are parasiticidal, ie. can rid the host cells of tachyzoite infection after one dose (recovery assay). A rodent model of acute toxoplasmosis was established for examining in vivo efficacy of lead compounds. Results Four of these compounds proved highly efficacious in vitro with 50% inhibitory (IC50) values ranging from 200 nM to 1.3 µM. Therapeutic indices based on the ratio between the median cell cytotoxic dose and the IC50 ranged from 4 to 84. These four compounds all inhibited tachyzoite invasion and significantly inhibited in vitro replication over a 24-hour period at nanomolar concentrations. Additionally, two of the compounds evaluated thus far appear to be parasiticidal in vitro at 1 - 2 µM. Discussion Our results suggest that bis-amidines can be designed to be effective against experimental Toxoplasma infections. The parasiticidal activity of some of the compounds make them serious candidates for further drug development. Further experiments to determine 1) in vivo efficacy in mouse models of persistent infection, and 2) synergy with antipsychotics and mood stabilizers will investigate the possibility that these compounds could be used as adjunct treatment in Toxoplasma-positive individuals suffering with schizophrenia and other psychiatric disorders.

with relatively normal cognitive performance. However, the prevalence and implications of these subgroups for understanding schizophrenia are unclear because "normality" criteria vary. Estimates of the frequency of normal range performance in the patient population are as low as 0% and as high as 89%. This study examines the relation between different normality criteria and normality prevalence. It also assesses functional outcome and symptom severity in cognitively normal and impaired subgroups. Methods: "Narrow" (IQ) and "broad" (MATRICS Consensus Cognitive Battery; MCCB) cognitive normality criteria were applied to data from schizophrenia (n = 99) and healthy control samples (n = 80). Functional outcome was assessed with the Multidimensional Scale of Independent Functioning (MSIF). The Positive and Negative Syndrome Scale (PANSS) was administered to measure symptom severity. Results: Cognitive normality ranged from 13% (broad criterion) to 47% (narrow criterion) among patients. Patients meeting both broad (MCCB) and narrow (IQ) definitions were functionally disadvantaged compared to cognitively normal controls (t(63) = 7.05, p < .01; t(72) = 9.97, p < .01, respectively). However, cognitively normal patients showed no functional (MSIF) advantage relative to cognitively impaired patients based on both broad and narrow definitions of cognitive normality (t(95) = .43, p = .67; t(74) = -1.04, p = .30, respectively). Functioning did not differ between IQ and MCCB based cognitively normal patients (t(51) = .61, p = .55). Moreover, broad and narrow definitions of cognitive normality were not associated with differences in symptom severities relative to cognitively impaired patients. This held true for both positive (t(97) = 1.39, p = .17; t(76) = -.72, p = .47, broad and narrow definitions, respectively) and negative (t(97) = .98, p = .33; t(76) = -1.07, p = .29, broad and narrow definitions, respectively) symptom severity on the PANSS. Discussion: Our data show that the prevalence of cognitive performance normality varies widely with the breadth of the normality criterion. However, regardless of the criterion applied, cognitively normal patients remain functionally disadvantaged relative to cognitively normal controls. Perhaps more importantly, however defined, cognitively normal patients demonstrate no advantage in functionality relative to cognitively impaired patients. Thus, patients meeting the broad definition of cognitive normality are not functionally advantaged relative to those meeting the narrow definition. We also found that varying definitions of cognitive normality/impairment have no implications for the severity of psychotic psychopathology in treated outpatients. Overall, the current study suggests that the reported prevalence of cognitive normality in schizophrenia is largely a product of definitional approaches. At the same time, the data cast doubt on the functional importance of preserved and proficient cognition regardless of definition and suggest that cognitive normality does not confer an advantage in terms of reduced symptom severity.

T90. MEMBERSHIP IN A SCHIZOTYPY TAXON PREDICTS HOPELESSNESS AND THOUGHTS OF SELF-HARM 7 YEARS LATER
Richard Linscott* ,1 1 University of Otago Background: Expressions of liability for schizophrenia are associated with suicidal thinking and behaviour. This relationship appears not to be specific to different expressions of suicide, although there is evidence suggesting that schizophrenia liability is associated with greater lethality. The relationship is evident among help-seeking and non-help-seeking volunteers and using measures of psychosis experience or self-reported schizotypy; it persists despite controlling for other psychopathologies. Given these observations, the link between suicide and schizophrenia liability may be rooted in shared pathogenic mechanisms. With this in mind, I tested whether stress sensitivity could contribute to the link between schizophrenia liability and suicidality in a prospective study.
Methods: At baseline (T1), n = 1074 undergraduates (M = 19.8 years, SD = 3.1; 30% male) completed the Schizotypal Personality Questionnaire (SPQ) and the Acute Hassles Scale (AHS), a self-report measure of stress sensitivity. Participants were classified as schizotypal or non-schizotypal by taxometric analyses of items for specific SPQ facets (cognitive-perceptual, interpersonal, and disorganization) and a general SPQ item set. Participants were classified as schizotypal (n = 43) if they were classified to the general schizotypy class to two or more specific-facet classes. At followup (T2) 7.8 years later (SD = 1.9, range = 5.5 to 10.5 years), the T1 schizotypy group (n = 43) and an age-and sex-matched control group (n = 216) were invited to participate in an online follow-up study. Of those invited, n = 84 (M = 27.7 years, SD = 3.3; 26% male; n = 15 schizotypal at T1) provided consent and completed the SPQ and AHS. At T2, hopelessness was assessed using 3 items from the Depression, Anxiety, and Stress Scales and thoughts of self-harm were assessed with one item from DSM-5 Self-Rated Level 1 Cross-Cutting Symptom Measure for adults. The small n at T2 prevented taxometric analyses of SPQ ratings at T2. Results: At T2, 9.5% of participants reported thoughts of self-harm and 17.8% hopelessness. Cross-sectional regression analyses of T2 data showed that the SPQ and AHS total scores each predicted concurrent self-harm thoughts (β = .52, p < .001, and β = .45, p < .001, respectively) and hopelessness (β = .43, p < .001, and β = .24, p < .05, respectively). When T2 SPQ and AHS were entered simultaneously, only SPQ scores predicted selfharm thoughts (β = .39, p = .001 for SPQ; β = .20, p = .10, for AHS) and hopelessness (β = .46, p = .001, for SPQ; β = -.04, p = .74 for AHS). In longitudinal analyses, T1 taxon membership predicted T2 self-harm thoughts (β = .28, p = .011) and hopelessness (β = .33, p = .002) but T1 AHS did not (β = .09, p = .43, and β = .09, p = .40, respectively). T1 taxon membership remained a significant predictor of T2 self-harm thoughts (β = .28, p = .016) and hopelessness (β = .34, p = .004) when T1 AHS was entered as a concurrent predictor, whereas AHS predicted neither outcome (β = -.01, p = .95, and β = -.02, p = .84, respectively). Discussion: Schizotypy classification during the late teens or early 20s predicted hopelessness and thoughts of self-harm 5 to 10 years later. Although stress sensitivity was correlated with concurrent thoughts or self-harm, stress sensitivity could not have accounted for the link between schizotypy and self-harm thoughts or hopelessness. The study is limited by the rudimentary nature of the assessment of self-harm thinking, the modest sample size, and the large rate of loss to follow-up.

Johns Hopkins University School of Medicine; 2 McMaster University
Background: Toxoplasma infections constitute a worldwide public health problem responsible for significant morbidity. Symptoms of acute infection by the agent, the apicomplexan parasite Toxoplasma gondii, can range from mild to life-threatening depending upon the immune status of the host. Toxoplasma infections are often unrecognized in immune competent hosts but infection can lead to the long-term establishment of cysts in the brain and thus a persistent infection. Such tissue cysts are associated with altered behavior and cognition in mouse models. Furthermore, serological evidence of Toxoplasma infection has been associated with an increased risk of recent onset psychosis, schizophrenia, and other psychiatric disorders in humans. Adjunct treatment of Toxoplasma-seropositive individuals afflicted with schizophrenia with effective anti-parasitic medications could be beneficial by eliminating the parasite cysts, thereby possibly alleviating psychiatric symptoms. However, currently available medications are ineffective against the cyst form of the organism responsible for persistent infection. Others have published the anti-Toxoplasma potential of derivatives of the bis-amidine pentamidine. We designed and synthesized a panel of novel bis-amidines and explored their anti-Toxoplasma efficacy. Methods: We designed and synthesized an array of twelve novel bisamidines. These compounds were examined for in vitro activity against T. gondii tachyzoites first using a colorimetric assay employing the β-gal producing strain RH-2F to examine the effect of the compounds over 5 days of parasite growth in human fibroblast host cells. This was followed by several immunofluorescence-based assays to determine if compounds can directly act on tachyzoites (red/green invasion assay), on an established infection of host cells (replication assay), and whether the compounds are parasiticidal, ie. can rid the host cells of tachyzoite infection after one dose (recovery assay). A rodent model of acute toxoplasmosis was established for examining in vivo efficacy of lead compounds. Results: Four of these compounds proved highly efficacious in vitro with 50% inhibitory (IC50) values ranging from 200 nM to 1.3 µM. Therapeutic indices based on the ratio between the median cell cytotoxic dose and the IC50 ranged from 4 to 84. These four compounds all inhibited tachyzoite invasion and significantly inhibited in vitro replication over a 24-hour period at nanomolar concentrations. Additionally, two of the compounds evaluated thus far appear to be parasiticidal in vitro at 1 -2 µM. Discussion: Our results suggest that bis-amidines can be designed to be effective against experimental Toxoplasma infections. The parasiticidal activity of some of the compounds make them serious candidates for further drug development. Further experiments to determine 1) in vivo efficacy in mouse models of persistent infection, and 2) synergy with antipsychotics and mood stabilizers will investigate the possibility that these compounds could be used as adjunct treatment in Toxoplasma-positive individuals suffering with schizophrenia and other psychiatric disorders.

T92. QUITLINK: ACCESSIBLE SMOKING CESSATION SUPPORT FOR PEOPLE LIVING WITH SEVERE AND ENDURING MENTAL ILLNESS
Background: People with severe mental illness (SMI) typically die 20 years earlier than the general population, largely due to smoking related diseases. Their smoking rate is alarmingly high and persistent, which contrasts sharply with the steady decline in the general population's smoking rate.
Smokers with SMI are equally motivated to quit smoking, but report less encouragement to quit by health professionals and are less able to succeed. When engaged in a program, some can quit successfully, but at lower rates than for the general population. Evidence-based smoking cessation interventions, such as quitlines, are underutilised by smokers with SMI. There is an urgent need to develop highly accessible, appropriately tailored cessation services for smokers with SMI to which mental health services can routinely refer smokers, and to explore why low smoking cessation rates persist among people with SMI receiving cessation treatment. Quitlink will utilise peer workers to identify, support, and refer smokers with SMI in mental health services to Quitline, who will deliver a tailored, proactive and accessible smoking cessation intervention. Additionally, we wish to investigate participant and health worker perceptions of the support provided by Quitlink, the nature of barriers encountered and their impact on initiating and succeeding with cessation. Methods: Design: A multi-centre prospective, randomised, open, blinded endpoint (PROBE) design will be utilised to compare standard smoking care alone against Quitlink. Assessments will be conducted at baseline, end of treatment, 3 months post treatment and 6 months post treatment. Setting and sample: 382 smokers will be recruited from three mental health services in Victoria: Mind Australia, Neami and Melbourne's St Vincent's hospital. Intervention: The manual guided Quitlink intervention consists of standard smoking care plus: Referral to Quitline, Quitline counselling, Quitline provision of NRT, Quitline engagement with mental health services, Quitline engagement of support network and peer worker help with participant contact. Results: As recommended by the Society for Research on Nicotine and Tobacco expert workgroup, the primary outcome measure in this study will be 6 months prolonged abstinence at the 8-month follow-up (allowing participants up to 2 months to stop). Prolonged 6-month abstinence will be defined as per the Russell Standard, i.e. self-report of abstinence for 6 months (allowing up to 5 cigarettes in total) and biochemical verification of self-reported abstinence (validated in a face-to-face visit using expired CO monitoring using a Micro+ Smokelyzer, with a reading of over 8ppm defined as a treatment failure). Discussion: Outcomes of the project will determine effectiveness and costeffectiveness of a novel and highly translatable intervention resulting from linking two existing services (Quitline and mental health peer workers). This will be the world first RCT of a Quitline intervention delivered to people with SMI that also includes a concurrent economic evaluation. As smoking is the leading cause of preventable death in people with SMI, if Quitlink is shown to be effective, it has the potential to greatly improve individuals' longevity, quality of life, mental health and reduce health care costs. This is an innovative and practical service delivery model that has the potential to ensure that smokers with SMI have access to best-practice smoking cessation treatment. Secondly, regardless of effectiveness outcomes, the project's qualitative study will provide greater insights into the barriers faced by smokers with SMI and will assist in the development of even more effective interventions.