Highlights of the American Psychiatric Association (APA) 167th annual meeting, New York NY, May 3-7, 2014 – The following is a summary of some noteworthy studies presented at this year’s APA annual meeting. Please go to Part 1 to read our coverage of antidepressant treatment trials.
Caraprazine is a dopamine D3/D2 partial agonist currently in development for schizophrenia and bipolar mania. Phase II results in schizophrenia were recently published (Durgam et al. Schizophr Res 2014;152:450-457). A new phase III trial in bipolar I disorder randomized 497 patients to placebo or caraprazine 3-6 mg/day or 6-12 mg/day for three weeks (Calabrese et al. APA 2014; NR8-03). Both active treatment arms showed significant improvements from baseline to week 3 in Young Mania Rating Scale scores (mean difference vs. placebo: low dose, 6.1 points; high dose 5.9 points). Significantly more patients had a YMRS response or remission with treatment compared to placebo. The most common adverse effects were akathisia, nausea, and constipation. One-third of patients receiving caraprazine experienced extrapyramidal symptom-related adverse effects. Discontinuation rates were higher in both active treatment groups (9%, 15%) versus placebo (5%).
STEP-BD (Systematic Treatment Enhancement Program for Bipolar Disorder) reported that antidepressants confer little additional benefit when used concomitantly with mood stabilizers in bipolar disorder (Ghaemi et al. J Clin Psychiatry 2010;71:372-380). A single-centre retrospective study compared outcomes in 337 patients on a mood stabilizer or atypical antipsychotic with or without an antidepressant prescribed at hospital discharge (Warner et al. APA 2014; P1-13). Concomitant antidepressant use was associated with no benefit with respect to time to hospital readmission or mean time to readmission, even in patients with significant anxiety. In the subgroup with anxiety, patients were more likely to be readmitted if they received venlafaxine at discharge (hazard ratio 2.35 vs. no antidepressant; HR 5.38 vs. another antidepressant).
The time course of treatment response to antipsychotics was evaluated in the French ESPASS follow-up study (Nordon et al. APA 2014; abstract 48). A total of 467 treatment-naïve patients were followed-up for six months after starting therapy. Five trajectories of treatment response were observed: rapid response (9.6%), gradual response (43.7%), patients who remained mildly ill (28.5%), patients who remained severely ill (4.9%), and patients with an unsustained clinical response (13.3%). Predictors of a response at 6 months were baseline CGI-S score (odds ratio 3.1) and negative symptoms (OR 1.5).
A Canadian study analysed factors affecting insight, uncooperativeness and self-assessed performance using data from the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study (Siu et al. APA 2014; abstract 18). Insight was evaluated using the Insight and Treatment Attitudes Questionnaire (ITAQ) and the PANSS item G12. Uncooperativeness was assessed with the PANSS item G8. Patients with higher ITAQ scores (better insight) had higher functioning and reductions in uncooperativeness symptoms over time, but lower self-reported well-being and higher levels of depressive symptoms.
The safety of rapid clozapine dose escalation was evaluated in a single-centre study of 111 consecutive patients with schizophrenia at high risk of harming themselves or others (Ifteni et al. APA 2014; P3-18). The mean PANSS score at admission was 104. The starting dose of clozapine was 1.25 to 25 mg, with additional doses of 25-50 mg given, as needed, every 6 hours. In the subgroup that had previously received clozapine, symptom control was achieved after 4.1 days with a maximum clozapine dose of 352.7 mg. In clozapine-naive patients who had failed prior antipsychotic therapy, symptom control was achieved in 7.1 days with a maximum dose of 408.6 mg. The mean PANSS score at discharge was 60. No significant adverse drug reactions were observed.
Phase II results have now been reported for ITI-007, a novel drug in development for the treatment of schizophrenia. The drug acts as a post-synaptic dopamine D2 antagonist, a pre-synaptic D2 partial agonist, a serotonin 5HT2A antagonist, an inhibitor of the serotonin transporter, and a modulator of glutamatergic function (Li et al. J Med Chem 2014;57:2670-2682; Snyder & Vanover. Curr Pharm Des 2013; epublished December 15, 2013). The trial randomized patients with an acute exacerbation of schizophrenia to ITI-007 60 mg or 120 mg, risperidone 4 mg or placebo for 28 days (Vanover et al. APA 2014; abstract 172). ITI-007 60 mg was superior to placebo in the change from baseline to Day 28 in total PANSS score; there was no significant difference with the 120 mg dose. There was greater improvement in negative symptoms and depression with ITI-007 60 mg compared to risperidone in the subgroups with prominent negative symptoms or depression at entry. Treatment appeared to be well-tolerated.
Miscellany and curiosities
A case series of five patients with schizophrenia or schizoaffective disorder and deep-vein thrombosis observed remission of comorbid psychotic symptoms after warfarin was administered (Hoirisch-Clapauch et al. APA 2014; NR3-014). The author hypothesized that tissue plasminogen activator (tPA) , which promotes clot dissolution as well as neurogenesis/neuronal plasticity, may be the common link. Warfarin inhibits thrombin activatable fibrinolysis inhibitor (TAFI), thereby increasing tPA levels. They speculated that normalizing plasminogen activator function may help to induce long-term remission of psychotic symptoms.
A Canadian meta-analysis of 15 studies recently concluded that repetitive transcranial magnetic stimulation (rTMS) is a promising intervention for treating major depression and schizophrenia (Hovington et al. Ann Med 2013;45:308-321). A new study in 18 patients with stable schizophrenia has reported that 10 daily sessions of rTMS (20 Hz applied over the left dorsolateral prefrontal cortex) produced significant short-term increases in brain-derived neurotrophic factor (BDNF) (Hwang et al. APA 2014; NR3-045). Effects were not sustained at two-week follow-up.
A majority of people in the world speak a tonal language (e.g. Mandarin or Cantonese, many African languages), in which a change in pitch confers different meanings. A new study has found that patients with schizophrenia may have disease-related features (e.g. monotonous speech) that can impair their ability to speak a tonal language and which may complicate other speech difficulties they may have (Chiao-Li et al. APA 2014; NR3-089).
Several small studies of depression have used an outside-in approach, injecting worry lines with botulinum toxin to improve mood (Hawlik et al. Fortschr Neurol Psychiatr 2014;82:93-9). The latest randomized 30 patients to adjunctive botulinum toxin or saline injections to the glabellar region (Kruger et al. APA 2014; NR3-030). There was a mean 47% improvement in HAM-D scores with botulinum toxin at 6 weeks, with sustained improvement at 16 weeks. Improvement was also seen on other measures (BDI, CGI). The effect of treatment was larger in women compared to men. These results appear to support the facial feedback theory: the facial musculature regulates mood as well as expressing it.
A retrospective analysis of emergency room visits at two tertiary care hospitals reported that there was no difference in psychiatric presentations when there was a full moon (Parmar et al. APA 2014; NR5-21). Other studies have also debunked the full-moon effect (McLay et al. Mil Med 2006;171:1239-1242; Gorvin & Roberts. Psychol Rep 1994;75:1435-1440). There was a greater tendency for adolescents to be lunatics, as parents have previously observed.