The role of central monoamine neurotransmitters and neglect of behavioural factors

In this respect, there are gaps in how these investigators attack this problem of identifying ‘biological markers’. One, despite the earlier discovery and establishment of drug therapeutic activity, there is no mention of the specific role that chemical neurotransmitters play in the disorder and in reactivity to the new drugs.

On the clinical side, there are missteps in the overall attack on the problem of uncovering biological markers. Katz and Maas (Reference Katz and Maas5) based on the National Institute of Mental Health (NIMH) collaborative study of the psychobiology of depression (Reference Maas, Koslow and Davis6) characterised the problem as follows: the common approach to investigate the ‘causes’ of a major mental disorder is to assess extent of a proposed dysfunctional biological system with the level that system functions in subjects who do not suffer from this disorder. The approach is the standard based on a ‘disease model’ suited to this type of investigation in most areas of medicine. The problem regarding mental disorders is the nature of psychopathology, generally, its ambiguities, and still incompletely reliable classification system. It is, therefore, premature to apply the medical model in such research.

Going beyond diagnosis and applying the theory of ‘opposed neurobehavioral states’

The NIMH collaborative study examined studies conducted over decades on clinical phenomenology of the affective disorders, prominently the work of Grinker et al. (Reference Grinker, Miller, Shabsin, Nunn and Nunnally7) and Kendell (Reference Kendell8). Critical to the NIMH collaborative study, launched in 1970 to test hypotheses linking dysfunction in central neurotransmitter and neurohormone systems to the disorder itself, was a diagnostic system that was reliable, so that results from this nationwide effort could be generalised across diverse clinical settings. Also necessary was going beyond selecting patients based only on diagnosis. The measurement of symptoms of the disorders as described had also to be reliable and quantitative, so that the validity of the specific hypotheses and the nature of drug actions could be adequately tested.

To achieve that, a set of clinical methods was developed to characterise major affective, behavioural, somatic, and cognitive aspects of a diverse range of depressive disorders. Working with the ‘components’ derived from analysing their application in a large sample (100+) of diagnosed depressed patients uncovered the structure of the clinical syndrome, identifying three major dimensions: the first, a core, depressed mood-motor retardation, second, a state of ‘arousal’, anxiety-agitation-somatisation, and third, hostility-interpersonal sensitivity (Reference Katz, Houston and Brannan9).

This system describes the depressive syndrome in terms of its major dimensions as against treating the disorder as a ‘whole’. It is similar, therefore, in its descriptive structure to how we identify the separate central monoamine transmitter systems. In follow-up investigations it was clear that more could be learned about mechanisms underlying the disorder and how the drugs acted on them, by examining the links between these neural systems and these clinical components directly, than if we adhered to the traditional model of viewing the disorder as a ‘whole’ entity, as a diagnosis. That position is in accord with the current movement towards the dimensional model adopted by the new Research Domain Criteria (RDoC) (Reference Cuthbert and Insel10) and away from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) approach, seeking a more reliable, categorical system for clinical studies. Critics, for example Weinberger (Reference Weinberger, Glick and Klein11), view the evidence on the RDoC as limited, not ready for broad application. Schmidt et al.’s (Reference Schmidt and Duman1) search for a ‘profile of biological markers’ for the depressive disorders, is equally limited, too early to apply.

Linking the neurochemical and behavioural systems

Linking the functioning of neurotransmitter systems to specific affects and behaviour, for example, to anxiety, hostility, depressed mood, results in generating patterns of neurotransmitter – behavioural associations that underlie the disorder. Decades of study of these linkages (see Morilak and Fraser (Reference Morilak and Frazer12) for review of basic studies) shows the serotonin system to be associated with regulation of aggression and anxiety, norepinephrine, with motor activity and ‘arousal’. The antidepressant drugs, such as the targeted selective serotonin reuptake inhibitors (SSRIs), significantly reduce the concentration of serotonin’s major metabolite, 5 hydroxyindoleacetic acid (5-HIAA), in cerebrospinal fluid (35%) (Reference Bowden, Koslow, Hanin, Davis and Robins13) and that effect was significantly associated with reducing anxiety, a major component of depression (Reference Katz, Maas and Frazer14). Although similarly, a selective norepinephrine drug, desipramine, resulted in a comparably large decrease in its 3 methoxy-4-hydroxyphenylethelylene (MHPG) metabolite, then found to be associated with a reduction in motor retardation.

That research led to a hypothesis about the neurobehavioral nature of the disorder that focussed on the internal conflict between the concurrent increases in the dimensions of depressed mood-retardation, a ‘down’ state, and anxiety-agitation, an ‘excited, aroused’ state, pointing to their ‘opposed’ nature relative to central nervous system functioning (Reference Katz15).

Whereas, this latter approach relies heavily on the role of chemical neurotransmitters, Schmidt et al. aim to uncover a profile of ‘biological markers’ based on dysfunctions in neuroplasticity, specific hormonal systems and stress factors.

Regarding their attempt to identify biological moderators of treatment response, Schmidt and Duman (Reference Schmidt, Shelton and Duman3) and Pizzagalli (Reference Pizzagalli2) appear to downgrade the value of clinical moderators. Pizzagalli refers to earlier reviews that showed little capacity of clinical variables to predict treatment outcome. ‘Early improvement’ (i.e. positive response within 2 weeks), however, is a ‘clinical’ moderator on which much evidence now exists demonstrating its potent role as a predictor. Improvement on severity of the disorder within that first 2 weeks of treatment is significantly related to positive outcome (Reference Stassen, Angst and Delini-Stula16,Reference Szegedi, Jansen and Van Wugenburg17). More compelling is the finding that failure to show any response during the first 2 weeks, that is, <20% change in severity of the disorder, will almost certainly result in failure to respond clinically (>90%), at outcome. The Stassen and Szegedi studies (Reference Stassen, Angst and Delini-Stula16,Reference Szegedi, Jansen and Van Wugenburg17) involving thousands of patients on diverse antidepressants and placebo clearly demonstrate these results.

The more direct approach

Why not then, monitor clinical changes along with biological changes, focussing on clinical measurement of specific psychopathological aspects before attempting to characterise biological profiles for the ‘whole’ disorder?

For example, the dimensional approach to addressing this issue would be to measure the relationship between changes in neural plasticity, not with the changes in the severity of the ‘whole’ depressive disorder, but specifically, with measures of the levels of major clinical components of the disorder. This could be accomplished by applying measures of these facets through use of the ‘multivantaged’ approach, a set of validated methods that includes standard tests, for example, the Symptom Checklist 90 and psychomotor performance tests, in addition to the Hamilton Rating Scale, described in detail by Katz et al. (Reference Katz, Houston and Brannan9). The multivantaged method provides measures for three major dimensions of the depressive disorder, depressed mood-retardation, anxiety-agitation, hostility-interpersonal sensitivity, and for a broader set of specific components to assess affective, motor, and cognitive aspects of the disorder. That approach makes possible correlating changes in neural functioning with the level of such specific major clinical components as anxiety or psychomotor or cognitive functioning of the disorder, before attempting to correlate such changes in neural functioning to the severity of the ‘whole’ depressive disorder.

The other question that remains unanswered is how neuroplasticity or peripheral growth factors are related to central neurotransmitter system functioning, Why have Schmidt et al. (Reference Schmidt and Duman1) and allied investigators not integrated the extensive body of research developed on these systems, into the interpretation of neurobehavioral mechanisms underlying the nature of the disorder and the reactivity to the drugs that target these systems?

Seeking markers for the disorder as a whole, is premature. Contrarily, the recommendation is that it will be more productive to complete the analysis of linkages between the elements of neurochemistry, of neuroendocrine factors on the one hand, and those of component behaviours and symptoms of the disorder, on the other – and for the present, to set aside the more ambitious aim of identifying ‘a panel of biological markers’ for the diagnosed disorder.