The Use of Biomarkers in Psychiatric Research: How Serotonin Transporter Occupancy Explains the Dose-Response Curves of SSRIs

  title={The Use of Biomarkers in Psychiatric Research: How Serotonin Transporter Occupancy Explains the Dose-Response Curves of SSRIs},
  author={Sheldon H. Preskorn},
  journal={Journal of Psychiatric Practice},
  • S. Preskorn
  • Published 1 January 2012
  • Medicine, Psychology
  • Journal of Psychiatric Practice
This column reviews why signal detection in psychiatric research has been problematic, how the use of biomarkers can help, how and why fixed dose studies are done, and how these studies differ from what clinicians do in practice. The fixed dose studies done with selective serotonin reuptake inhibitors (SSRIs) are used to illustrate general points about clinical trial research methodology relevant to clinical practice. Studies with SSRIs have yielded flat dose-response curves with regard to… 

How Biomarkers Will Change Psychiatry: From Clinical Trials to Practice. Part I Introduction

Part I of this series defines biomarkers and discusses their research utility and potential application in clinical practice. To provide a frame of reference, biomarkers commonly used in general

Raising the Minimum Effective Dose of Serotonin Reuptake Inhibitor Antidepressants: Adverse Drug Events

  • D. Safer
  • Medicine, Psychology
    Journal of clinical psychopharmacology
  • 2016
Strong evidence from fixed-dose trial data for the efficacy of nonascendant, minimum effective doses of SRIs was found for the treatment of both major depression and anxiety disorders, and the finding that most SRI ADEs have an ascending dose-response curve was particularly important.

Declining Differences in Response Rates with Antidepressants versus Placebo: A Modest Proposal for Another Contributing Cause

  • S. Preskorn
  • Psychology
    Journal of psychiatric practice
  • 2013
This column discusses declining differences in response rates between sequentially introduced selective serotonin reuptake inhibitors (SSRI) and placebo, and proposes that another factor may be responsible.

Circulating tumour necrosis factor is highly correlated with brainstem serotonin transporter availability in humans

How Biomarkers Will Change Psychiatry. Part II: Biomarker Selection and Potential Inflammatory Markers of Depression

The authors first discuss the rationale for selecting a biomarker and the potential use of inflammatory biomarkers in depression, with a specific focus on derivatives of the inflammatory biomarker, thromboxane, to illustrate how biomarkers can be developed for use in clinical practice.

Serotonin Hypothesis of Autism: Implications for Selective Serotonin Reuptake Inhibitor Use during Pregnancy

Though the majority of studies conducted in infants and children suggest prenatal exposure to SSRIs does not affect neurodevelopment, interpretation must be tempered given small sample sizes, and Obstacles that will be faced in future research are isolating medication effects from maternal depression and obtaining an adequate sample size.

A comparative review of escitalopram, paroxetine, and sertraline: are they all alike?

Overall, as an allosteric serotonin reuptake inhibitor that is somewhat different from classical SSRIs, escitalopram is the first choice judged by combined efficacy and tolerability, and nonclinical data have offered possible mechanisms through which escITALopram could be more efficacious.

The SOFIA Study: Negative Multi-center Study of Low Dose Fluoxetine on Repetitive Behaviors in Children and Adolescents with Autistic Disorder

A RCT of fluoxetine in 158 individuals with ASD found no significant differences on the Children’s Yale-Brown Obsessive Compulsive Scale, and results are consistent with other SSRI RCTs treating RRBs in ASD.

Serotonin and emotion, learning and memory

The major aim of this paper is to re-examine some recent advances regarding mammalian 5-HT receptors and transporter in light of their physiological, pathophysiological and therapeutic implications for memory.



Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study.

Occupancy of 80% across five SSRIs occurs at minimum therapeutic doses, which suggests that 80% 5-HTT blockade is important for therapeutic effect.

Occupancy of serotonin transporters by paroxetine and citalopram during treatment of depression: a [(11)C]DASB PET imaging study.

During treatment with clinical doses of paroxetine or citalopram, approximately 80% of 5-HTT receptors are occupied, which is greater than the known physiological range of changes in 5- HTT binding potential but may be necessary for some therapeutic effects.

Imaging the serotonin transporter during major depressive disorder and antidepressant treatment.

  • J. Meyer
  • Psychology
    Journal of psychiatry & neuroscience : JPN
  • 2007
5-HTT imaging findings for understanding major depressive disorder and antidepressant treatment will be discussed, and a strong relation between plasma level and occupancy that is not predictable based on affinity alone is discussed.

Relationship between clinical effects, serum drug concentration and serotonin uptake inhibition in depressed patients treated with citalopram

The relationship between improvement and serum level of citalopram indicated a lower limit of effect in endogenous depression at about 100 nM, corresponding to an average dose of 15 mg, and no significant correlation was found between serum drug level and the few reported side effects.

Biomarkers in development of psychotropic drugs

  • K. Wiedemann
  • Psychology
    Dialogues in clinical neuroscience
  • 2011
With a view to developing more individually tailored therapeutic strategies, the characterization of patients and the courses of different types of treatment will become even more important in the future.

Drug plasma levels and platelet 5-HT uptake inhibition during long-term treatment with fluvoxamine or lithium in patients with affective disorders.

Plasma levels and platelet 5-HT uptake characteristics were determined at baseline and at various times during a long-term study comparing fluvoxamine and lithium prophylaxis, which had to be discontinued prematurely for some patients due to apparent lack of efficacy, unwanted effects or a combination of both.

Evidence of the dual mechanisms of action of venlafaxine.

This study provides the first in vivo evidence in healthy humans that both 5-HT uptake and NE uptake inhibition are mechanisms of action sequentially engaged by venlafaxine over its clinically relevant dose range.

The human platelet. A diagnostic and research tool for the study of biogenic amines in psychiatric and neurologic disorders.

  • S. Stahl
  • Medicine, Psychology
    Archives of general psychiatry
  • 1977
Experimental evidence is reviewed, which uses the human platelet model to investigate neurotransmitter-related abnormalities in Down syndrome, mental retardation, infantile autism, hyperactivity syndromes, schizophrenia, affective disorders, Duchenne muscular dystrophy, Parkinson disease, Huntington chorea, and migraine headaches.