Schizophrenia remains one of the most severe medical diseases. Current dopamine modulating first-generation and second-generation antipsychotics target mainly positive symptoms, but not/inadequately negative and cognitive symptoms. Additional challenges include non-adherence and adverse effects, especially cardiometabolic dysregulation. This review evaluates new/emerging pharmacological treatments for schizophrenia. Therapies targeting total symptoms include cannabidiol, D3 antagonist/5-HT1A partial agonist F17464, lumateperone (ITI-007), phosphodiesterase 10A (PDE10A) inhibitors MK-8189 and TAK-063, sodium nitroprusside, and trace amine-associated receptor-1 (TAAR1) agonist RO5263397 and SEP-363856. Treatments targeting negative symptoms include the PDE10A inhibitor LuAF-11167, 5-HT2A inverse agonist pimavanserin, sigma-2/5-HT2A antagonist roluperidone (MIN-101), and d-amino acid oxidase (DAAO) inhibitor TAK-831. Agents targeting primarily cognitive dysfunction are the glycine transporter-1 inhibitor BI-425809 and cannabidiol. Therapies targeting residual positive symptoms/treatment-resistant schizophrenia include pimavanserin, dopamine D1/D2 antagonist LuAF-35700, and DAAO inhibitor sodium benzoate. Two new long-acting injectable antipsychotic formulations, Aripiprazole Lauroxil NanoCrystal® and the first subcutaneous injectable LAI Perseris (RBP-7000), were recently approved by U.S. Food and Drug Administration, and positive results were announced for Risperidone ISM®, each achieving therapeutic levels within 24 hours, without need for initial oral cotreatment/loading injection-strategies. Paliperidone palmitate 6-monthly intramuscularly injectable and Risperidone subcutaneously injectable TV46000 are currently under investigation. Finally, the samidorphan+olanzapine combination targets reduced weight gain liability, while maintaining olanzapine’s efficacy. Most of these trial programs are still ongoing or have yielded mixed or even negative results. Thus, additional mechanisms of action and agents require study to improve schizophrenia outcomes for total/positive symptoms with reduced adverse effects, but also cognitive symptoms, negative symptoms, and treatment resistance, the areas of greatest need in schizophrenia currently.

BackgroundThere is increasing evidence that regulatory problems (RPs), such as excessive crying, sleeping or feeding problems in infancy, could be associated with the development of behavioral problems in childhood. In this meta-analysis we aimed to investigate the strength and characteristics of this association.MethodsA systematic literature search (PubMed/PsycInfo, until 15/08/2021) for longitudinal prospective studies of infants with RPs and at least one follow-up assessment reporting incidence and/or severity of behavioral problems was conducted. The primary outcomes were (i) the cumulative incidence of behavioral problems in children (2–14 years) with previous RPs and (ii) the difference between children with/without previous RPs with regard to the incidence and severity of externalizing, internalizing and/or attention-deficit/hyperactivity disorder (ADHD) symptoms. Additionally, we analyzed behavioral problems of children with previous single, multiple or no RPs and with respect to age at follow-up. Subgroup and meta-regression analyses were added.Results30 meta-analyzed studies reported on 34,582 participants (nRP = 5091, ncontrol = 29,491; age: baseline = 6.5 ± 4.5 months, follow-up = 5.5 ± 2.8 years) with excessive crying (studies = 13, n = 1577), sleeping problems (studies = 9, n = 2014), eating problems (studies = 3, n = 105), any single (studies = 2, n = 201) or multiple RPs (studies = 9, n = 1194). The cumulative incidence for behavioral problems during childhood was 23.3% in children with RPs. Behavioral problems were significantly more pronounced in infants with RPs compared to healthy controls (SMD = 0.381, 95% CI = 0.296–0.466, p < .001), particularly with multiple RPs (SMD = 0.291, p = 0.018).ConclusionsFindings suggest that RPs in infancy are associated with overall behavioral problems (externalizing or internalizing behavior and ADHD symptoms) in childhood. Our data cannot explain linked developmental trajectories and underlying factors. However, detection of affected infants may help to adapt supportive measures to the individual familial needs to promote the parent-child-relationship and prevent the development of child behavioral problems from early on.

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