The paper by Hasler et al. addresses the challenges in genetic studies of major depression and proposes strategies to improve the definition of genetically relevant phenotypes through the identification of endophenotypes. Endophenotypes are defined as internal phenotypes that bridge the gap between genetic markers and clinical symptoms, potentially reducing the complexity of the genetic basis of depression. The authors propose two levels of endophenotypes: psychopathological endophenotypes and biological endophenotypes. **Psychopathological Endophenotypes:** 1. **Depressed Mood (Mood Bias Toward Negative Emotions):** This involves attentional and mnemonic biases toward negative information, which are stable over time and show state-independence. 2. **Anhedonia (Impaired Reward Function):** Loss of interest and reactivity, associated with dysfunctions in the brain's reward system, including changes in neurotrophic factors and dopamine. 3. **Impaired Learning and Memory:** Cognitive deficits, particularly in long-term memory and working memory. 4. **Neurovegetative Signs:** Changes in appetite and weight, which may be useful for subtyping depressive episodes. 5. **Diurnal Variation:** Circadian rhythm abnormalities, which are genetically controlled and show state-independence. 6. **Impaired Executive Cognitive Function:** Response speed, which remains impaired in remitted patients. 7. **Psychomotor Change:** Retardation and agitation, which are specific to the melancholic subtype. 8. **Increased Stress Sensitivity:** Gender-specific stress sensitivity, influenced by gene-environment interactions. **Biological Endophenotypes:** 1. **REM Sleep Abnormalities:** Reduced latency, higher density, and increased amount of REM sleep, which are specific to unipolar major depression. 2. **Brain Structure and Function Abnormalities:** Changes in brain regions such as the amygdala, prefrontal cortex, and hippocampus, which are associated with depressive symptoms and show state-independence. 3. **Receptor Pharmacology:** Altered binding potential of serotonin 5-HT1A receptors, which is heritable and shows state-independence. 4. **Serotonin, Dopamine, and Norepinephrine:** Dysfunctions in monoaminergic neurotransmitter systems, which are implicated in the pathophysiology of depression. 5. **HPA Axis and CRH:** Altered cortisol and CRH responses, which are state-independent and show familial association. The authors emphasize the need for a new classification system to reduce the heterogeneity of depression, which is a major obstacle in understanding its genetic and neurobiological basis. They conclude by discussing the strengths and limitations of psychopathological and biological endophenotypes in major depression, highlighting their potential for genetic studies.The paper by Hasler et al. addresses the challenges in genetic studies of major depression and proposes strategies to improve the definition of genetically relevant phenotypes through the identification of endophenotypes. Endophenotypes are defined as internal phenotypes that bridge the gap between genetic markers and clinical symptoms, potentially reducing the complexity of the genetic basis of depression. The authors propose two levels of endophenotypes: psychopathological endophenotypes and biological endophenotypes. **Psychopathological Endophenotypes:** 1. **Depressed Mood (Mood Bias Toward Negative Emotions):** This involves attentional and mnemonic biases toward negative information, which are stable over time and show state-independence. 2. **Anhedonia (Impaired Reward Function):** Loss of interest and reactivity, associated with dysfunctions in the brain's reward system, including changes in neurotrophic factors and dopamine. 3. **Impaired Learning and Memory:** Cognitive deficits, particularly in long-term memory and working memory. 4. **Neurovegetative Signs:** Changes in appetite and weight, which may be useful for subtyping depressive episodes. 5. **Diurnal Variation:** Circadian rhythm abnormalities, which are genetically controlled and show state-independence. 6. **Impaired Executive Cognitive Function:** Response speed, which remains impaired in remitted patients. 7. **Psychomotor Change:** Retardation and agitation, which are specific to the melancholic subtype. 8. **Increased Stress Sensitivity:** Gender-specific stress sensitivity, influenced by gene-environment interactions. **Biological Endophenotypes:** 1. **REM Sleep Abnormalities:** Reduced latency, higher density, and increased amount of REM sleep, which are specific to unipolar major depression. 2. **Brain Structure and Function Abnormalities:** Changes in brain regions such as the amygdala, prefrontal cortex, and hippocampus, which are associated with depressive symptoms and show state-independence. 3. **Receptor Pharmacology:** Altered binding potential of serotonin 5-HT1A receptors, which is heritable and shows state-independence. 4. **Serotonin, Dopamine, and Norepinephrine:** Dysfunctions in monoaminergic neurotransmitter systems, which are implicated in the pathophysiology of depression. 5. **HPA Axis and CRH:** Altered cortisol and CRH responses, which are state-independent and show familial association. The authors emphasize the need for a new classification system to reduce the heterogeneity of depression, which is a major obstacle in understanding its genetic and neurobiological basis. They conclude by discussing the strengths and limitations of psychopathological and biological endophenotypes in major depression, highlighting their potential for genetic studies.