Suicidal behavior is a major problem worldwide and, at the same time, has received relatively little empirical attention. This relative lack of empirical attention may be due in part to a relative absence of theory development regarding suicidal behavior. The current article presents the interpersonal theory of suicidal behavior. We propose that the most dangerous form of suicidal desire is caused by the simultaneous presence of two interpersonal constructs—thwarted belongingness and perceived burdensomeness (and hopelessness about these states)—and further that the capability to engage in suicidal behavior is separate from the desire to engage in suicidal behavior. According to the theory, the capability for suicidal behavior emerges, via habituation and opponent processes, in response to repeated exposure to physically painful and/or fear-inducing experiences. In the current article, the theory’s hypotheses are more precisely delineated than in previous presentations (Joiner, 2005), with the aim of inviting scientific inquiry and potential falsification of the theory’s hypotheses.

/pdf/the-interpersonal-theory-of-suicide-38t99pb95m.pdf

The Interpersonal Theory of Suicide

Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT2A receptors and D2-type receptors. Predominant 5HT2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D2 antagonism is required for the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D3 and in particular D4 receptors has been proposed.

Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding

Background and Purpose— This guideline provides an overview of the evidence on various established and potential stroke risk factors and provides recommendations for the reduction of stroke risk. M...

https://www.ahajournals.org/doi/pdf/10.1161/01.STR.32.1.280

Primary Prevention of Ischemic Stroke A Statement for Healthcare Professionals From the Stroke Council of the American Heart Association

The neurotransmitter transporters (NTTs) belonging to the solute carrier 6 (SLC6) gene family (also referred to as the neurotransmitter-sodium-symporter family or Na(+)/Cl(-)-dependent transporters) comprise a group of nine sodium- and chloride-dependent plasma membrane transporters for the monoamine neurotransmitters serotonin (5-hydroxytryptamine), dopamine, and norepinephrine, and the amino acid neurotransmitters GABA and glycine. The SLC6 NTTs are widely expressed in the mammalian brain and play an essential role in regulating neurotransmitter signaling and homeostasis by mediating uptake of released neurotransmitters from the extracellular space into neurons and glial cells. The transporters are targets for a wide range of therapeutic drugs used in treatment of psychiatric diseases, including major depression, anxiety disorders, attention deficit hyperactivity disorder and epilepsy. Furthermore, psychostimulants such as cocaine and amphetamines have the SLC6 NTTs as primary targets. Beginning with the determination of a high-resolution structure of a prokaryotic homolog of the mammalian SLC6 transporters in 2005, the understanding of the molecular structure, function, and pharmacology of these proteins has advanced rapidly. Furthermore, intensive efforts have been directed toward understanding the molecular and cellular mechanisms involved in regulation of the activity of this important class of transporters, leading to new methodological developments and important insights. This review provides an update of these advances and their implications for the current understanding of the SLC6 NTTs.

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

https://tauruspet.med.yale.edu/staff/edm42/IUPUI-website/emorris.tar/emorris/emorris/PETjournalCLub/Drevets/biol_psych_5ht1a%20in%20depression-sdarticle.pdf

PET imaging of serotonin 1A receptor binding in depression

High affinity binding of [3H]paroxetine and [3H]imipramine to human platelet membranes

High-affinity binding of 3 H-imipramine to platelet membranes from control subjects and psychiatric patients was studied. Maximal binding (βmax) in depressed manic-melancholic patients was higher than in euthymic manic- melancholic patients, psychiatric controls, and normal controls.

3H-imipramine binding sites in platelets from psychiatric patients

Brain 5-HT1A, 5-HT1D, and 5-HT2 Receptors in suicide victims

The serotonin transporter (SERT), which belongs to a family of sodium/chloride-dependent transporters, is the major pharmacological target in the treatment of several clinical disorders, including depression and anxiety. In the present study we show that the dissociation rate, of [3H]S-citalopram from human SERT, is retarded by the presence of serotonin, as well as by several antidepressants, when present in the dissociation buffer. Dissociation of [3H]S-citalopram from SERT is most potently inhibited by S-citalopram followed by R-citalopram, sertraline, serotonin and paroxetine. EC50 values for S- and R-citalopram are 3.6 +/- 0.4 microm and 19.4 +/- 2.3 microm, respectively. Fluoxetine, venlafaxine and duloxetine have no significant effect on the dissociation of [3H]S-citalopram. Allosteric modulation of dissociation is independent of temperature, or the presence of Na+ in the dissociation buffer. Dissociation of [3H]S-citalopram from a complex with the SERT double-mutant, N208Q/N217Q, which has been suggested to be unable to self-assemble into oligomeric complexes, is retarded to an extent similar to that found with the wild-type, raising the possibility that the allosteric mechanism is mediated within a single subunit. A species-scanning mutagenesis study comparing human and bovine SERT revealed that Met180, Tyr495 and Ser513 are important residues in mediating the allosteric effect, as well as contributing to high-affinity binding at the primary site.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1471-4159.2004.02835.x

Characterization of an allosteric citalopram-binding site at the serotonin transporter

Paroxetine is the most potent and one of the most specific serotonin uptake inhibitors. High-affinity3H-paroxetine and3H-imipramine binding was compared in rat neuronal membranes.

Per Plenge

Papers

High affinity binding of [3H]paroxetine and [3H]imipramine to human platelet membranes

3H-imipramine binding sites in platelets from psychiatric patients

Brain 5-HT1A, 5-HT1D, and 5-HT2 Receptors in suicide victims

Characterization of an allosteric citalopram-binding site at the serotonin transporter

High affinity binding of 3H-paroxetine and 3H-imipramine to rat neuronal membranes.