The Use of SSRIs to Treat Conditions Other Than Depression

One of the major spin-offs to occur as a result of the overwhelming commercial success of the SSRIs has been the spread of their use not only for severe depression to mild dysthymia, but also to other psychiatric, e.g., bulimia, panic disorder, obsessive-compulsive disorder, anxiety, and non-psychiatric conditions, e.g., obesity, premature ejaculation, Raynaud's syndrome, headache. The distinction between anxiety and depression was not recognized in the 1950s and it is fair to say that the...

Criteria for Selection of Preferred Treatment

Melancholic or Endogenous Depression Depression with melancholic features is classified as a loss of pleasure in all or almost all activities, or lack of reactivity to usually pleasurable stimuli, and three of the following distinct quality of depressed mood, depression worse in the morning, early morning awakening, marked psychomotor retardation or agitation, significant anorexia or weight loss, and excessive or inappropriate guilt. Traditionally, endogenous depression has responded poorly to...

HT1 Receptor Agonist Challenge

The azapirones (buspirone, ipsapirone, gepirone) are partial 5-HT1A receptor agonists that stimulate PRL, GH and cortisol secretion and lower body temperature.40 5-HT1A receptors are sited both presynaptically (cell body autoreceptors) and postsynaptically41-44 so that responses to challenge by these compounds could reflect pre- and or postsynaptic receptor stimulation. Pindolol has been shown to antagonize the GH response to buspirone, the cortisol response to ipsapirone and the hypothermic...

Learned Helplessness and 5HT

5-HT plays a major role in learned helplessness.6,7 Briefly, micro-injection of 5-HT into the medial prefrontal cortex reverses established helpless behavior and does so on an acute basis. That is to say, repeated injections over several days are not required for behavioral activity. Interestingly, micro-injection of a TCA had the same effect, suggesting a serotonergic mechanism for their behavioral action. Further support for this idea is derived from in vivo microdialysis experiments which...

The Relationship Between Depression and Suicide

Estimates of the 12-month prevalence rate for diagnosed depression in the USA range from 20 to 250 per 1000.1,2 Each year, 2-3 million people in Britain suffer from depression requiring medical care.3,4 This is equivalent to a 12-month prevalence rate of 30-50 per 1000.3,4 Depression is associated with a risk of suicide between 13-30 times higher than for the overall population.5 This figure does not include those with undiagnosed depression. For 60-70 of...

Tricyclic Antidepressants TCAs

Although TCAs are traditionally considered as a group, individual drugs differ in important properties and receptor binding profiles. Clomipramine and, to a lesser extent, amitriptyline and imipramine have greater 5-HT reuptake inhibiting properties than other TCAs. Sedative and non-sedative TCAs differ in H1 receptor antagonism and 5-HT2 receptor antagonism varies between drugs.83 The property most shared is their ability to inhibit noradrenaline reuptake.83 TRP challenge generally reveals a...

Obsessive Compulsive Disorder

The most convincing evidence for the use of SSRIs in this group is in obsessive-compulsive disorder (OCD), and this would concur with the evidence for serotonergic dysfunction in this disorder. Fluoxetine is the SSRI most studied in this area but unfortunately there are very few trials. The only published randomized, double-blind, placebo-controlled trial involved a fixed dose of fluoxetine (20 mg day) in 14 patients with OCD (aged 8-15 years).8 The study, which lasted for 20 weeks with a...

Evidence Linking 5HT Dysfunction and Suicide

The SSRIs share a common mechanism of action, despite their remarkably differing chemical structures (fluvoxamine is a monocyclic agent, fluoxetine a bicyclic agent, sertraline a naphthylamine derivative, paroxetine a phenyl piperidine derivative and citalopram a bicyclic isobenzo-furan derivative). The number of deaths per million prescriptions of antidepressants has been shown to be inversely related to their serotonin (5-HT) reuptake inhibition activity31 but this relationship may be...

Actions of Drugs at 5HT1 Receptors

Systemic administration of 5-HT1A receptor agonists such as 8-OH-DPAT in rats reduces penile erections induced by 5-HT2C agonists36 and facilitates ejaculation by decreasing ejaculatory threshold and latency (Table 6.1).37 Administration of 8-OH-DPAT causes a Table 6.1. Summary of the effects of 5-HT receptor activation in male and female rats Reduces erection & increases ejaculation Increases erection & reduces ejaculation Receptive Non-Receptive Inhibits lordosis stimulates lordosis...

Appraisal of Evidence for Prevention versus Aggravation of Suicide by SSRIs Comparison with Other Antidepressant Agents

The irony that patients may kill themselves with the drugs prescribed to treat their depression and its complications (which includes suicide) is especially great because one measure of their efficacy in clinical trials is their performance on the suicide item of the Hamilton rating scale for depression. Almost every antidepressant has occasionally been associated with the intensification of suicidal ideation, or even the emergence of suicidal thoughts in the patient being treated. In the...

Development of the First SSRI Zimelidine

Even before the introduction of clomipramine into the clinic, our research group had proceeded with attempts to develop a 5-HT-selective reuptake inhibitor. We discovered a number of non-tricyclic agents with amine-uptake inhibitory properties, acting on both noradrenergic and serotonergic neurons. Some of these agents were found among the addictive analgesics, e.g., pethidine, while others were antihistamines.23 Especially potent among the latter were pheniramine and its bromine- and...

Comparison with Other Antidepressants

In terms of tolerability and toxicity, the SSRIs appear to be more acceptable to both patients and their physicians than older antidepressants. Some investigators, however, believe that the TCAs and monoamine oxidase inhibitors (MAOIs) are more effective than the SSRIs in certain subtypes of depression. While the data are mixed, as will be discussed below, most studies indicate that the SSRIs and TCAs are equally efficacious. The influential studies from the Danish University Antidepressant...

Hyperkinetic Disorder

Biochemical research into neurotransmitters in this disorder has increased interest in drug treatments for these conditions.29 However, the use of psychostimulants for this heterogeneous group of behavior disorders differs markedly between the UK and the USA,30,31 with medication use much higher in the USA. Two open studies have used SSRIs in this group. Barrickman et al32 found that of the 19 (86 ) patients completing their trial of fluoxetine (20-60 mg day), 58 showed improvement with most...

Depression and Dementia

In a double-blind randomized trial of amitriptyline versus fluoxetine Taragano et al99 studied 37 patients with major depression complicating senile dementia of Alzheimer's type (SDAT). Significant improvements in HAM-D and Mini Mental State Examination (MMSE) ratings were observed in both groups completing treatment to day 45 but the groups were not significantly different from each other. A significant difference between groups was seen in the dropout rate 58 of amitriptyline-treated patients...

Impulse Control Disorders

Impairments of impulse control are seen in many psychiatric and neurological disorders and as resulting behaviors, such as aggression, may cause conflict with society they present an important potential use for SSRIs, although not a currently licensed one. There is now a body of literature exploring the relationship between 5-HT and aggression impulsive behaviors in both animals and humans. Mehlman et al65 measured the concentration of the 5-HT metabolite, 5-hydroyindoleacetic acid (5-HIAA), in...

Effects in the Noradrenergic Terminal Field

It has been acknowledged for many years that 5-HT alters release of catecholamines from peripheral neurons, particularly those in the cardiovascular and enteric systems. Although it is now apparent that extracellular 5-HT could have similar effects on catechola-minergic transmission in the brain, details of the type and location of the receptors which mediate these changes are far from clear. Judging by the little evidence gathered to date, 5-HT1A and 5-HT1B receptors in the terminal field seem...

Mechanism of Action of Pindolol

We hypothesized that pindolol could accelerate and or augment the effects of serotonergic antidepressants by preventing self-inhibition of cell firing and 5-HT release due to its ability to bind to 5-HT1A receptors. Indeed, single doses of racemic pindolol (e.g., 30 mg) prevent the fall in body temperature and the changes in hormonal secretion induced by 5-HT1A receptor agonists.79,80 This shows that, at this dosage, pindolol has 5-HT1A receptor antagonistic properties, despite reports of a...

Novel Neurotransmitter Balance and Equilibrium Theory of Mental Illness

From these data, we have formulated a neurotransmitter balance theory of mental illness (Fig. 11.2). In this model, three primary neurotransmitters are postulated to mediate specific dimensions of pathophysiology associated with mental illness. Dopamine, noradrenaline and GABA are conceived as mediating thought process, anxiety, and depression, respectively. In a situation of homeostasis and normothymia, the brain maintains a balance among these three neurotransmitters. When, due to stress,...

Ejaculation and Orgasm

Delayed orgasm or anorgasmia appears to be a relatively common side-effect of SSRIs and is also commonly reported with TCAs and MAOIs. Impairment of orgasm has been reported in 8-75 of patients taking fluoxetine87-90 and 6-9 of patients taking paroxetine.91-93 These are generally likely to represent low estimates as one open study above found a much higher rate of impairment of orgasm when subjects were asked specifically about this. Anorgasmia has been reported with all the commonly employed...

Premenstrual Dysphoric Disorder and 5HT

An interesting, and potentially important, model for the serotonergic balance theory of mood stability is found in premenstrual dysphoric disorder (PMDD). This condition, though often trivialized by the lay press, is a mental illness, often disabling, and occasionally life-threatening. The current psychiatric diagnostic category for severe premenstrual syndrome (PMS), PMDD, is categorized in DSM-IV as a 'Depressive Disorders Not Otherwise Specified,' in recognition of its close relationship...

Role for 5HT in Depression

Serotonergic neurons play a key role in the modulation, organization and coordination of appropriate responses to a wide variety of stimuli. As noted, 5-HT acts primarily as an inhibitory neurotransmitter, has a significant role in several behaviors that are consistently disturbed in many persons with depression (e.g., mood, sleep, sexual activity, appetite, circadian and seasonal rhythms, neuroendocrine functions, body temperature, motor activity, and cognitive function).14-17 Studies...

Other Antidepressants

Monoamine oxidase inhibitors (MAOIs) increase the PRL response to TRP106 and the cortisol response to 5-HTP107 in depressed patients suggesting they may increase 5-HT1A 5-HT2 receptor function but more specific challenge data are unavailable. Antidepressants which lack both 5-HT and noradrenaline reuptake inhibition such as mianserin and trazodone do not enhance the PRL response to TRP108,109 indicating that this is not a universal property of antidepressant drugs. Nefazodone, related to...

Analysis of the Impact of the SSRIs on the Antidepressants Market

The generic and trade names of the SSRIs which have received regulatory approval are given in Table 12.1, along with the indications for which they have been approved. Their chemical structures are shown in Figure 12.1. It is clearly evident from the data presented in Figure 12.2 that the antidepressants market has grown and continues to grow at a very substantial rate. In fact, between 1990 and 1997 total world sales of antidepressants increased by an average of 34 year on year, and in 1992,...