👤 Peter Wad Sackett

Serotonergic psychedelics are re-emerging as therapeutic candidates across psychiatry, particularly for treatment-resistant depression. Their rapid and sustained antidepressant effects, alongside evidence for neuroplastic, dopaminergic, and glutamatergic modulation, have prompted interest in whether they could address depressive and negative symptoms in schizophrenia spectrum disorders (SSDs). This narrative review summarizes mechanistic, preclinical, and early clinical findings relevant to psychedelic use in SSDs. Schizophrenia and major depressive disorder share disturbances in dopamine, glutamate, and neuroplasticity, and both involve large-scale network abnormalities. Schizophrenia is associated with widespread dysconnectivity, mesocortical hypodopaminergia, and striatal hyperdopaminergia linked to NMDA receptor hypofunction. Depression is characterized by fronto-limbic and default mode network hyperconnectivity, mesolimbic hypodopaminergia, and reduced cortical glutamatergic tone. Depressive symptoms within SSDs may reflect an intermediate phenotype combining depressive-like hyperconnectivity with schizophrenia-related global dysconnectivity, suggesting that psychedelics' capacity to transiently increase network flexibility and recalibrate maladaptive connectivity may be clinically relevant. Preclinical studies show increased dendritic spine density, enhanced BDNF expression, restored reward sensitivity, and modulation of network dynamics after psychedelic administration. Clinically, uncontrolled exposure appears associated with increased psychosis-related presentations, whereas limited case reports suggest controlled administration may be tolerated in carefully selected, clinically stable individuals with SSDs. To date, only one early-phase trial (MDMA in schizophrenia) is ongoing, and no randomized trials have evaluated psilocybin or LSD in SSDs. Overall, psychedelics are biologically and mechanistically plausible but remain unproven for depressive and negative symptoms in SSDs, which partially overlap. Carefully designed, safety-focused early-phase studies in clinically stable patients are therefore a prerequisite for broader clinical application. Show less

Ancient DNA is highly degraded, resulting in very short sequences. Reads generated with modern high-throughput sequencing machines are generally longer than ancient DNA molecules, therefore the reads often contain some portion of the sequencing adaptors. It is crucial to remove those adaptors, as they can interfere with downstream analysis. Furthermore, overlapping portions when DNA has been read forward and backward (paired-end) can be merged to correct sequencing errors and improve read quality. Several tools have been developed for adapter trimming and read merging, however, no one has attempted to evaluate their accuracy and evaluate their potential impact on downstream analyses. Through the simulation of sequencing data, seven commonly used tools were analyzed in their ability to reconstruct ancient DNA sequences through read merging. The analyzed tools exhibit notable differences in their abilities to correct sequence errors and identify the correct read overlap, but the most substantial difference is observed in their ability to calculate quality scores for merged bases. Selecting the most appropriate tool for a given project depends on several factors, although some tools such as fastp have some shortcomings, whereas others like leeHom outperform the other tools in most aspects. While the choice of tool did not result in a measurable difference when analyzing population genetics using principal component analysis, it is important to note that downstream analyses that are sensitive to wrongly merged reads or that rely on quality scores can be significantly impacted by the choice of tool. Show less