In his 1967 article, Gordon Paul raised an iconic question: ‘What treatment, by whom, is most effective for this individual with that specific problem, and under which set of circumstances?’ ^{Reference Paul1} This article has been cited almost 1800 times since it was published, but it is almost always cited to convey how much we still do not know about what works for whom and why, with a count of years to indicate the elapsed time and our continued lack of definitive answers. Indeed, meta-analyses document no improvement in treatment efficacy over the past decades. ^{Reference Cuijpers, Miguel, Ciharova, Harrer, Basic and Cristea2} One potential contributor to the lack of improvement is the limited progress that has been made in understanding the factors contributing to effective treatments. Referring to common factors across psychotherapies, Cuijpers et al ^{Reference Cuijpers, Reijnders and Huibers3} summarised decades of empirical research by stating: ‘Although hundreds of correlational studies have been conducted during the past decades, little progress has been made in understanding the mechanisms of change of therapies.’ This is not to suggest that decades of psychotherapy research have yielded no progress. Much progress has been made in treatment package development, psychotherapy design and measurements. However, insufficient progress has been made in understanding the mechanisms that drive treatment efficacy; thus, there has been insufficient improvement in treatment efficacy rates. Drawing on both human and animal research, we propose that an important factor contributing to this gap is neglect of the parental context, particularly from an intergenerational perspective (Fig. 1).

Fig. 1

The present and future of clinical diagnosis. While in the present (top panel) diagnosis of depression is performed based on the state at intake, future diagnosis will hopefully take into account variables such as parental, early and lifetime experience as well as genetic predisposition, leading to more effective treatment.

For the past 50 years, most psychotherapy research has assessed mental health before treatment using self-report questionnaires and clinical interviews, followed by treatment allocation through randomisation or other methods. Traditionally, the next measurement occurs post-treatment and focuses on how much change has taken place. Recent advances have led to the introduction of repeated measurements throughout treatment, providing a clearer understanding that change is often nonlinear and varies among individuals. Despite this, baseline assessments still serve as the primary indicator of pre-treatment traits.

More recently, there has been recognition that mental health and other traits exhibit dynamic patterns even before treatment begins. State-of-the-art psychotherapy research has started to capture these characteristics through measurements taken at multiple time points before treatment, enabling researchers to address critical questions such as whether treatment alters pre-existing patterns into more adaptive ones. Although research in this area is still emerging, it has provided fascinating insights. ^{Reference Zilcha-Mano4} In this letter, we aim to expand the scope from pre-treatment time points to the individual’s lifespan and intergenerational (or even transgenerational) contexts.

Empirical human and animal studies have shown that trauma experienced in previous generations can affect an individual’s traits. For example, Yehuda et al ^{Reference Yehuda, Daskalakis, Lehrner, Desarnaud, Bader and Makotkine5} showed that pre-conception post-traumatic stress disorder increases the prevalence of depression and anxiety in children. Rodent studies, which enable the use of proper control groups and investigation of mechanisms, have confirmed the impact of trauma on behaviour and brain function for up to four generations. ^{Reference Jawaid, Roszkowski and Mansuy6} Moreover, an individual rodent’s ‘anxiogenic’ behaviour is a product of both its own stress exposure levels and its mother’s exposure to stress. ^{Reference Zaidan, Leshem and Gaisler-Salomon7} Intergenerational (F0 to F1) or transgenerational (F0 to F2 and onward) transmission of experience can occur as a result of gestational changes and/or the social environment in early life. A third mechanism, the biological embedding of experience and its transmission via epigenetic changes to the germline, has gained recent support with respect to both males and females experiencing stress.

Epigenetic mechanisms involve transient or long-lasting heritable changes in the absence of modifications to the genetic code itself. Common examples of epigenetic modifications include DNA methylation, histone modifications and changes to non-coding RNA. Epigenetic modifications in rodent germline cells have been found to account for transgenerational transmission of experience and were also altered in the brains of the offspring, ^{Reference Jawaid, Roszkowski and Mansuy6} indicating a putative mechanism for behavioural changes in progeny. Although much of our knowledge on epigenetics and transgenerational inheritance comes from rodent studies, human studies have also shown that lifetime experience is registered in germ cells, possibly leading to an altered epigenetic profile in the germline and allowing transmission of such epigenetic signals to the next generation. Recent evidence also indicates that epigenetic markers can be used as predictors of clinical progress following psychotherapy in individuals with post-traumatic stress disorder. ^{Reference Yehuda, Daskalakis, Desarnaud, Makotkine, Lehrner and Koch8} This demonstrates the intergenerational and transgenerational impact of the previous generation’s context on an individual’s traits and the putative role of epigenetics in diagnosis and treatment.

We propose that considering intergenerational influences on an individual could provide new insights into their traits before the start of treatment. By examining how parental experiences shape the individual’s characteristics, we could gain a more nuanced understanding of their presenting issues and treatment needs. For example, animal studies have shown that maternal exposure to stress profoundly alters dam–pup interactions, leading to long-term changes in the offspring’s affective state and epigenetic landscape. ^{Reference Kappeler and Meaney9} Translational research in clinical settings that builds on this knowledge may enable us to explore how intergenerational trauma and epigenetic modifications contribute to interpersonal synchrony patterns. Patients’ ability to synchronise with their therapist may be shaped, in part, by epigenetic mechanisms linked to early parental attachment and stress regulation. By investigating a patient’s epigenetic landscape pre-treatment, we can examine its influence on key therapeutic mechanisms, such as therapist–patient synchrony in arousal levels. These mechanisms may, in turn, provide a meaningful window into the patient’s broader interpersonal functioning, including their ability to engage in healthy social interactions outside the clinical setting.

This broader perspective on epigenetic and intergenerational factors could enable more comprehensive assessment of the influences shaping an individual’s mental health, psychopathology and well-being, ultimately informing more tailored and effective treatment strategies. Such factors may include the individual’s genetic background, early life environment, lifetime experiences and – as argued in this letter – intergenerational context. For example, classical long-term psychotherapy approaches emphasise the importance of understanding how past experiences shape present and future functioning. As contemporary treatments become shorter and more focused, the question arises as to whether and how addressing the past, particularly intergenerational history, should be integrated within time-limited therapeutic frameworks. Epigenetic research may offer insights into mechanisms of intergenerational influence, helping clinicians to refine their focus within time-limited treatments. Research on the impact of parental trauma on maladaptive stress regulation patterns in offspring, for instance, could support the integration of targeted intake questions about parental trauma history and encourage a curious, exploratory stance in therapy regarding the relevance of such trauma to the patient’s current coping mechanisms – a potentially crucial contribution to both psychotherapy research and clinical practice.