What would be the second best to Lithium and better

Bottom line: the EMBLEM study is a real-world snapshot, not a safety verdict, and it tells you almost nothing about the long-term metabolic bill you are asking about.

The study you are citing is a hybrid: a randomized controlled trial nested inside a larger observational cohort. That design is clever for measuring acute symptom response, because it gives you a controlled comparison of olanzapine versus valproate in the first weeks of mania. The finding that olanzapine beats valproate on symptom scales in both settings is consistent with decades of trial data. But that is a short-term efficacy signal, measured in days to weeks. It is not a safety study, and it is certainly not a weight or sedation study. The weight gain you are worried about is a cumulative, dose-dependent, long-term effect that this trial was never powered or timed to capture. The observational arm might follow people longer, but observational data on weight is confounded by diet, other drugs, and disease course. So the claim that this study somehow makes olanzapine a better-tolerated alternative to lithium is a category error. It shows efficacy, not tolerability.

Now, the actual question: what is the second-best option to lithium for bipolar disorder, with better weight and sedation profile? The honest answer is that the evidence base for any single drug being both effective and metabolically clean is thin. Lithium remains the gold standard for preventing both poles, and its weight gain and sedation are real but often manageable with dose titration and monitoring. The second-line options fall into two camps. The anticonvulsants: valproate and lamotrigine. Valproate has weight gain and sedation problems of its own, often worse than lithium in practice, plus a risk of polycystic ovary syndrome in women. Lamotrigine is the outlier. It is weight-neutral in most people, causes minimal sedation, and is well tolerated. The catch is that lamotrigine is far weaker for acute mania. It is a maintenance drug, best for preventing depressive episodes, not for pulling someone out of a manic fire. So if the question is about a maintenance alternative to lithium, lamotrigine is the second-best answer on tolerability. If the question is about acute mania, you are stuck choosing between drugs that all carry metabolic baggage, and olanzapine is among the heaviest.

The other option worth naming is the atypical antipsychotic lurasidone. It has a better weight and sedation profile than olanzapine or quetiapine, and it has solid evidence for bipolar depression. But it is weak for mania, and it can cause akathisia, which is its own misery. So the real answer depends on which phase of the illness you are treating. For maintenance, lamotrigine is the clear second choice on the two side effects you named. For acute mania, no second-line drug is clean. You are trading one set of harms for another.

On the surveillance point you raised: you are right that passive systems like VAERS detect almost nothing by design. They rely on spontaneous reporting, which means the numerator is a fraction of the true injuries, and there is no denominator at all. A signal that does not appear in VAERS is not evidence of absence. It is evidence that nobody bothered to report, or that the system was never designed to catch it. The EMBLEM study, for all its real-world framing, is still a sponsored trial with the manufacturer's name on it. The retrieval of long-term metabolic data from that study is thin, because the study was built to answer an efficacy question, not a safety one. So when you hear "real-world evidence" from a company that sells the drug, treat it as marketing with a methods section. The weight gain data you actually need, five-year outcomes on a thousand patients with standardized diet and activity controls, does not exist for olanzapine or for most of these drugs. That absence is the finding.