Recent advances in next generation sequencing (NGS) and human induced pluripotent stem cell (iPSC) technologies have allowed an unprecedented view into the transcriptional dynamics of the human brain. Particularly revealing has been the discovery of long non-coding RNAs (lncRNAs) that have substantially expanded in recent evolution, with >50,000 lncRNA genes identified in the human genome, one-third being primate-specific and the majority expressed predominantly in the brain. We employed whole transcriptome deep sequencing of activated neurons derived from human iPSCs (control and schizophrenia-associated) to investigate gene expression. We found that the expression of distinct subsets of mRNAs and lncRNAs are altered in response to neuronal depolarisation and these changes are strongly associated with metabolic systems. Altered metabolism may have significantly played a role in changes underpinning the substantial expansion of the human brain over the last 2 million years in response to changing diets and high energy foods obtained through the invention of tools and the domestication of fire for cooking. Furthermore, we find that there are significant differences in the robustness of transcriptomic responses between iPSC-derived neurons from schizophrenia patients compared with unaffected controls, which are only evident upon activity, suggesting that psychiatric conditions may arise from fragilities in newly evolved mechanisms relating to dynamic neural pathways. These results present evidence that metabolic pathways may be intimately involved in the recent sophistication of the human brain and dysregulation thereof may contribute to psychiatric disease.