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The Lilly Suicides - Adbusters | Journal of the mental environment

Reports that Prozac might be unsafe at any dose had Lilly running scared. As early as 1990, one executive stated in an internal memo that, if Prozac is taken off the market, the company could “go down the tubes.” With the US Food and Drug Administration asking questions, Lilly was pressed to show that their drug was safe. The result was published on September 21, 1991. Authored by Lilly employees, the report claimed to represent all existing data comparing Prozac with either older antidepressants or placebos. In fact, the data had been handpicked to favor the drug and the company. The analysis dealt with 3,065 patients, less than 12 percent of the total data from Prozac studies at the time. Among those whose data were left out was the very population most likely to become suicidal –the five or so percent of patients who dropped out of the clinical trials because they experienced unpleasant side effects after taking Prozac.

Happy drug Prozac can bring on impulse to suicide, study says | Science | The Guardian

Volunteers taking part in the early trials were never asked whether they experienced any suicidal feelings or the restless agitation which can be the precursor of a suicide attempt. If patients in later trials said they felt suicidal, it was recorded as part of their depression.

Sexual Consequences of Post-SSRI Syndrome

There are some indications that antidepressant-emergent sexual dysfunctions do not always resolve after discontinuation of the medication and can persist indefinitely in some individuals. Although some or all sexual side effects that start with the use of SSRIs might continue after stopping the medication, other sexual complaints can develop. Decreased capacity to experience sexual pleasure is the most frequent characteristic of this syndrome.

Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration

Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.

Mice Genetically Depleted of Brain Serotonin Do Not Display a Depression-like Behavioral Phenotype - ACS Chemical Neuroscience (ACS Publications)

Reductions in function within the serotonin (5HT) neuronal system have long been proposed as etiological factors in depression. Selective serotonin reuptake inhibitors (SSRIs) are the most common treatment for depression, and their therapeutic effect is generally attributed to their ability to increase the synaptic levels of 5HT. Tryptophan hydroxylase 2 (TPH2) is the initial and rate-limiting enzyme in the biosynthetic pathway of 5HT in the CNS, and losses in its catalytic activity lead to reductions in 5HT production and release. The time differential between the onset of 5HT reuptake inhibition by SSRIs (minutes) and onset of their antidepressant efficacy (weeks to months), when considered with their overall poor therapeutic effectiveness, has cast some doubt on the role of 5HT in depression. Mice lacking the gene for TPH2 are genetically depleted of brain 5HT and were tested for a depression-like behavioral phenotype using a battery of valid tests for affective-like disorders in animals. The behavior of TPH2–/– mice on the sucrose preference test, tail suspension test, and forced swim test and their responses in the unpredictable chronic mild stress and learned helplessness paradigms was the same as wild-type controls. While TPH2–/– mice as a group were not responsive to SSRIs, a subset responded to treatment with SSRIs in the same manner as wild-type controls with significant reductions in immobility time on the tail suspension test, indicative of antidepressant drug effects. The behavioral phenotype of the TPH2–/– mouse questions the role of 5HT in depression. Furthermore, the TPH2–/– mouse may serve as a useful model in the search for new medications that have therapeutic targets for depression that are outside of the 5HT neuronal system.

Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response - ScienceDirect

The role of serotonin in depression and antidepressant treatment remains unresolved despite decades of research. In this paper, we make three major claims. First, serotonin transmission is elevated in multiple depressive phenotypes, including melancholia, a subtype associated with sustained cognition. The primary challenge to this first claim is that the direct pharmacological effect of most symptom-reducing medications, such as the selective serotonin reuptake inhibitors (SSRIs), is to increase synaptic serotonin. The second claim, which is crucial to resolving this paradox, is that the serotonergic system evolved to regulate energy. By increasing extracellular serotonin, SSRIs disrupt energy homeostasis and often worsen symptoms during acute treatment. Our third claim is that symptom reduction is not achieved by the direct pharmacological properties of SSRIs, but by the brain's compensatory responses that attempt to restore energy homeostasis. These responses take several weeks to develop, which explains why SSRIs have a therapeutic delay. We demonstrate the utility of our claims by examining what happens in animal models of melancholia and during acute and chronic SSRI treatment.