Psychobiology and Psychopharmacology

Borgheini, G. (2003) 'The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs', Clinical Therapeutics 25(6): 1578-92. [available online]

This article suggests that present standards for determining bioequivalence between branded and generic medications may be inadequate; from the article's abstract, "Specifically, 1 study found that plasma levels of phenytoin were 31% lower after a switch from a brand-name to a generic product. Several controlled studies of carbamazepine showed a recurrence of convulsions after the shift to a generic formulation. After a sudden recurrence of seizures when generic valproic acid was substituted for the brand-name product, an investigation by the US Food and Drug Administration found a difference in bioavailability between the 2 formulations." The article concludes that "The essential-similarity requirement should be extended to include more rigorous analyses of tolerability and efficacy in actual patients as well as in healthy subjects".

Klein, L.C. and E.J. Corwin (2002) 'Seeing the Unexpected: How Sex Differences in Stress Responses May Provide a New Perspective on the Manifestation of Psychiatric Disorders', Current Psychiatry Reports 4: 441-8.

This excellent review article is co-authored by one leader of the investigation (Taylor et al. 2000) which first suggested a significant hormonally-mediated sex difference in responses to stress. After reviewing the physiology of stress responses and the 'tend and befriend' theory developed in the earlier paper, the authors explore the notion that the observable diagnostic criteria for some psychiatric disorders may not apply equally to both sexes. Focusing in particular on major depressive disorder and attention deficit hyperactivity disorder (ADHD), the paper examines the implications of a differential response to stress in the manifestation, diagnosis and treatment of psychiatric disorders.

Nemeroff, C.B. (1996) 'The Corticotropin-Releasing Factor (CRF) Hypothesis of Depression: New Findings and New Directions', Molecular Psychiatry 1: 336-42.

Excellent review article on CRF and hyperactivity of the HPA axis. Particularly notable results include the notion that elevated CRF levels not only stimulate the HPA axis but also act on extra-pituitary brain sites. Also, evidence suggests that undue stress early in an organism's life may sensitise CRF neurons, and paraventricular nucleus (PVN) hypothalamic tissue in particular, leading to CRF hypersecretion in response to stresses later in life. This appears linked to an increase in CRF mRNA expression. Selective serotonin reuptake inhibitors appear remarkably effective in normalising ACTH and corticosterone responses to stress, as well as normalising mRNA expression in the PVN and other areas.

Nemeroff, C.B. (1998) 'The Neurobiology of Depression', Scientific American 278(6): 28-35.

This accessible article reviews the chemical pathways implicated in depression, ranging from norepinephrine and other monoamines, to serotonin (produced in neurons projecting from the raphe nuclei to many areas, including those which affect the release of norepinephrine), to hormonal disturbances in the HPA (hypothalamic-pituitary-adrenal) axis and the stress-diathesis model, which predicts that early childhood stress can permanently increase CRF gene expression. For more details, see Owens and Nemeroff (1994) and Nemeroff (1996).

Owens, M.J. and C.B. Nemeroff (1994) 'Role of Serotonin in the Pathophysiology of Depression: Focus on the Serotonin Transporter', Clinical Chemistry 40(2): 288-95.

This article reviews evidence on the role of inhibitory neurotransmitter 5-hydroxytryptamine -- 5-HT, or serotonin -- and its relevance to depression. Notable results include experimental evidence that a special diet deficient in tryptophan (the central metabolic precursor of 5-HT) and high in neutral amino acids which compete with existing tryptophan for carrier-mediated brain uptake, precipitated a rapid relapse in depressed patients within hours of ingestion. (Who volunteers for studies like this??) The article also discusses, from the transport point of view, the effect of selective reuptake inhibitors in increasing serotonergic neurotransmission and the effect of some amphetamine derivatives, including 3,4-methylene-dioxymethamphetamine (MDMA, or 'ecstasy'), in creating a large wash of synaptic 5-HT. Also notes that 5-HT transporter mRNA has been observed in areas altogether devoid of serotonergic perikarya as well as the finding that this mRNA expression can apparently be controlled by both nonselective and selective reuptake inhibitors. Interestingly (to the uninitiated such as myself), much of the work on 5-HT transporters is actually performed on platelets, which apparently have identical 5-HT transporter sequences.

Taylor, S.E.; L.C. Klein, B.P. Lewis, T.L. Gruenewald, R.A.R. Gurung and J.A. Updegraff (2000) 'Female Responses to Stress: Tend and Befriend, Not Fight or Flight', Psychological Review 107(3): 411-29.

While most biobehavioural studies on human stress responses have been performed on men (because women's cyclical variations in neuroendocrine responses yield data which are much more difficult to interpret), this analysis and theoretical model proposes and offers an explanation for a significant difference in how the two sexes respond to stress. Tracing the results in part to the buffering effects of the posterior pituitary hormone oxytocin, plus estrogen and endogenous opioid mechanisms in down-regulating the sympathetic and HPA responses to stress, the authors suggest that the familiar 'fight or flight' response is largely replaced in women with a 'tend and befriend' response, encouraging them to tend children and gather together with other women. Note that some secondary commentary on this article floating around on the internet is prone to poorly-grounded extrapolations from the actual data. Also see Klein and Corwin (2002).