Gregory M. Asnis

Denosologization of biological psychiatry or the specificity of 5-HT disturbances in psychiatric disorders

5-Hydroxytryptamine (5-HT) disorders have been reported to occur in a variety of psychiatric disorders. The situation has been called chaotic, the disturbances non-specific. We reject this viewpoint. 5-HT disturbances are non-specific only from a nosological/categorical viewpoint; they seem rather specific from a functional/dimensional point of view, correlating as they do with particular psychopathological dimensions, i.e. aggression-, anxiety- and possibly mood-disregulation, across diagnosis. The evolution of 5-HT research in psychiatry illustrates the importance of what we have called the functional approach, implying dissection of a given psychopathological syndrome in its component parts, i.e., the psychological dysfunctions, and searching for correlations between biological and psychological dysfunctions. The rigid preoccupation of biological psychiatry with the search for markers of disease entities has hampered progress. The functional approach should be incorporated in biological psychiatry, not as an alternative for the nosological approach but as its complement.

Serotonin and anxiety revisited

Serotonin (5hydroxytryptamine; 5-HT) was first discovered in 1948 in blood platelets and a few years later in the brain. Since then, investigations of 5-HT involvement in mental disorders have contributed to major advances in psychiatry. 5-m distances were initially linked to the p~ogenesis of depression. A subgroup of depressed patients was noted to have decreased 5-HT metabolism in the central nervous system (CNS) (van Praag and Korf 1971). Further studies indicated that lowered 5-HT metabolism correlated with particular dimensions of psychopathology that may occur within depressive disorders but likewise within other syndromes. One of these dimensions is dyscontrol of aggression, leading to suicide or to outwardly directed aggression (van Praag 1986). A second psychopathological dimension appears to be related to anxiety. Evidence relevant to this latter conclusion will be summarized in this article. Most data on the relationship of 5-HT to anxiety are derived from animal studies. Research using human subjects has only recently begun. We think that the substanti~ body of animal findings and the exciting new human data warrant a reexamination of the role of 5-HT in the pathogenesis of anxiety. We will propose a 5-HT hypothesis of anxiety that takes into account 5-HT availability as well as receptor sensitivity. H-IT Systems in the Brain The raphe nuclei in the brain stem, encompassing the dorsal raphe and medial raphe nuclei, contain the cell bodies of 5-HT-producing neurons. From there, six major projections ascend to the forebrain, two tracts within the median forebrain bundle and four outside of it. Cortex, hypothalamus, thalamus, basal ganglia, substantia nigra, caudate, putamen, amygdala, hippocampus, septum, tegmentum, and mamillary bodies are all innervated by 5-HT neurons (Azmitia and Segal 1978). Two major subcategories of 5HT receptors have been identified in the CNS, labeled 5-HTr (Perot&a 1984) and 5-HT2 (Leysen et al. 1984). 5-HTr receptors are further su~Iassifi~ as 5-HTr,, 5-HTu,, 5HTr,, and 5-HTrd receptors. 5-HT,, receptors display a very high affinity for 8-hydroxyNJV-dipropyl-2-aminotetralin (80HDAP) and are found in the human frontal cortex and

Neuroendocrine evidence for serotonin receptor hypersensitivity in panic disorder

Normal controls (NC) (n=15), patients with panic disorder (PD) (n=13) and patients with major depression (MD) (n=17) were challenged with a single, oral dose (0.25 mg/kg) of the selective 5HT agonist m-chlorophenyl-piperazine (MCPP) or placebo. Blood samples were assayed for cortisol and MCPP levels every 30 min. The PD group had an augmented cortisol release when compared to the other two groups. Finally, a significant correlation was found across all subjects between clinical anxiety level and cortisol release on MCPP. These data support the hypothesis of 5HT receptor hypersensitivity in PD.

Sleep disturbances in patients with post-traumatic stress disorder: epidemiology, impact and approaches to management

Subjective reports of sleep disturbance indicate that 70–91% of patients with post-traumatic stress disorder (PTSD) have difficulty falling or staying asleep. Nightmares are reported by 19–71% of patients, depending on the severity of their PTSD and their exposure to physical aggression. Objective measures of sleep disturbance are inconsistent, with some studies that used these measures indicating poor sleep and others finding no differences compared with non-PTSD controls. Future research in this area may benefit from examining measures of instability in the microstructure of sleep. Additionally, recent findings suggest that sleep disordered breathing (SDB) and sleep movement disorders are more common in patients with PTSD than in the general population and that these disorders may contribute to the brief awakenings, insomnia and daytime fatigue in patients with PTSD. Overall, sleep problems have an impact on the development and symptom severity of PTSD and on the quality of life and functioning of patients.In terms of treatments, SSRIs are commonly used to treat PTSD, and evidence suggests that they have a small but significant positive effect on sleep disruption. Studies of serotonin-potentiating non-SSRIs suggest that nefazodone and trazodone lead to significant reductions in insomnia and nightmares, whereas cyproheptadine may exacerbate sleep problems in patients with PTSD. Prazosin, a centrally acting α1-adrenoceptor antagonist, has led to large reductions in nightmares and insomnia in small studies of patients with PTSD. Augmentation of SSRIs with olanzapine, an atypical antipsychotic, may be effective for treatment-resistant nightmares and insomnia, although adverse effects can be significant. Additional medications, including zolpidem, buspirone, gabapentin and mirtazapine, have been found to improve sleep in patients with PTSD. Large randomised, placebo-controlled trials are needed to confirm the above findings. In contrast, evidence suggests that benzodiazepines, TCAs and MAOIs are not useful for the treatment of PTSD-related sleep disorders, and their adverse effect profiles make further studies unlikely.Cognitive behavioural interventions for sleep disruption in patients with PTSD include strategies targeting insomnia and imagery rehearsal therapy (IRT) for nightmares. One large randomised controlled trial of group IRT demonstrated significant reductions in nightmares and insomnia. Similarly, uncontrolled studies combining IRT and insomnia strategies have demonstrated good outcomes.Uncontrolled studies of continuous positive airway pressure for SDB in patients with PTSD show that this treatment led to significant decreases in nightmares, insomnia and PTSD symptoms. Controlled studies are needed to confirm these promising findings.

Behavioral indications for serotonin receptor hypersensitivity in panic disorder

Immediate placebo-corrected behavioral responses to m-chlorophenylpiperazine (MCPP), a selective serotonin agonist, are reported in 11 normal controls, 10 patients with panic disorder, and 10 patients with major depression. Whereas the normal and depressed groups showed no noteworthy behavioral response, panic disorder patients became more anxious, depressed, and hostile, and 60% had panic attacks. These data suggest a hypersensitive postsynaptic serotonin receptor system in some panic disorder patients.

Interferon-induced depression in chronic hepatitis C: A review of its prevalence, risk factors, biology, and treatment approaches

Hepatitis C viral infection is a global health problem that affects approximately 4 million people in the United States. Combination treatment with pegylated interferon (IFN)-α plus ribavirin has been shown to be most effective in treating patients with chronic hepatitis C (CHC). Despite its efficacy, one of the most common side effects of this regimen is depression. Whereas IFN-α has been found to induce depression in chronic myelogenous leukemia, melanoma, and renal cell carcinoma, CHC patients may be especially prone to develop IFN-induced depression. This review includes a summary of differences between IFN-α and IFN-β and addresses whether pegylation of IFN (versus nonpegylated IFN) gives rise to a treatment with reduced potential to induce depressive symptoms. Consideration is also given to evidence showing that treatment with ribavirin may contribute to IFN-induced depression. Thyroid disorders and anemia (as well as other medical conditions) have also been associated with IFN exposure and may account for some incidences of depression in CHC patients. Evidence is reviewed indicating that prior psychiatric and mood disorders (especially previous episodes of major depressive disorder), just prior to IFN treatment, contribute to the propensity to develop depression during treatment. In addition, a brief description is provided of potential biological mechanisms of IFN-induced depression (ie, monoamines, hypothalamic-pituitary-adrenocortical [HPA] axis, proinflammatory cytokines, peptidases, intercellular adhesion molecule-1, and nitric oxide). Finally, a discussion is provided on the use of antidepressants as a preventative versus restorative treatment, including a commentary on risks of using antidepressants in this patient population.

cortisol Secretion in Relation to Age in Major Depression1

&NA; Twenty‐five unmedicated hospitalized patients, ages 26‐64, with severe major depressive disorders, endogenous subtype, were evaluated both clinically and endocrinologically. Although measures reflecting cortisol secretion did not correlate with symptom dimensions and diagnostic subtypes, we did find a significant relationship between cortisol secretion and age during endogenous depressive illness; this included the mean 24 hour plasma cortisol, assessed by sampling every 30 minutes for 24 hours, as well as other single plasma cortisol assessments on other days. After clinical recovery, when plasma cortisol levels returned to normal, there was no significant relationship between cortisol secretion and age. Replication is required of this apparent interaction among age, depressive illness, and cortisol secretion. The result may relate to the proposed role of brain noradrenalin in tonically inhibiting cortisol secretion, the decline of hypothalamic noradrenalin with age, and the hypothesized deficit in depressive illness.

Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C.

Background Whether antidepressants prevent depression during interferon‐alpha/ribavirin treatment for hepatitis C virus infection has yet to be established.

SSRIs versus non-SSRIs in post-traumatic stress disorder: An update with recommendations

Post-traumatic stress disorder (PTSD) is a highly prevalent (7.8% lifetime rate) anxiety disorder with impairment in daily functioning, frequent suicidal behaviour and high rates of co-morbidity. Fortunately, PTSD is responsive to pharmacotherapy and psychotherapy.The selective serotonin reuptake inhibitors (SSRIs) are the most studied medications for PTSD, with the largest number of double-blind, placebo-controlled trials. Of the SSRIs, sertraline, paroxetine and fluoxetine have been the most extensively studied, with sertraline and paroxetine being US FDA-approved for PTSD. These studies have demonstrated that SSRIs are effective in short-term trials (6–12 weeks). Furthermore, continuation and maintenance treatment for 6–12 months decrease relapse rates. Besides being the most studied and effective drugs for PTSD, SSRIs have a favourable adverse effect profile, making them the first-line treatment for PTSD. If SSRIs are not tolerated or are ineffective, non-SSRIs should be considered.Serotonin-potentiating non-SSRIs, such as venlafaxine, nefazodone, trazodone and mirtazapine, have been evaluated in PTSD only in open-label and case studies. Because of their promising results and relatively good safety profile, they should be considered as second-line treatment.Monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) have both been evaluated in a small number of double-blind, placebo-controlled studies. The results have been inconsistent but promising. In the limited comparative studies, MAOIs appeared superior to TCAs but patients continued to have residual symptoms. These drugs have significant adverse effects, such as cardiovascular complications, and safety issues, such as ease of overdose. Therefore, TCAs and MAOIs should be considered as third-line treatment.Anticonvulsants have been evaluated in PTSD in open-label studies and results have been positive for carbamazepine, valproic acid, topiramate and gabapentin. A small double-blind, placebo-controlled study demonstrated efficacy of lamotrigine for PTSD. Anticonvulsants should be considered where co-morbidity of bipolar disorder exists, and where impulsivity and anger predominate. Bupropion (amfebutamone), a predominantly noradrenergic reuptake inhibitor, was ineffective in PTSD in an open-label study. Benzodiazepines were ineffective in a double-blind, placebo-controlled study despite encouraging case reports. They should be avoided or used only short term because of potential depressogenic effects, and the possibility that they may promote or worsen PTSD. Buspirone, a non-benzodiazepine anxiolytic, was found to be effective in PTSD only in open-label studies. Recently, atypical antipsychotics were as effective as monotherapy and as an augmenter to SSRIs in open-label/case studies and small double-blind, placebo-controlled trials; atypical antipsychotics should be considered in PTSD where paranoia or flashbacks are prominent and in potentiating SSRIs in refractory cases.

Effect of age and sex on cortisol secretion in depressives and normals

The mean 24-hour plasma level of cortisol with plasma sampling every 20-30 minutes was determined in 32 normal women aged 12-73, 40 normal men aged 10-55, 21 depressed women aged 20-61, and 11 depressed men aged 22-66. The mean levels of cortisol were higher in the group of depressives compared with the controls. Cortisol levels showed a significant linear correlation with age in normal women but not in normal men. Both depressed women and men had a significant linear increase of cortisol levels with age. The finding that age substantially contributes to increased levels of cortisol calls for cautious interpretation of any data concerning that hormone when the variable of age is not adequately controlled. Furthermore, aging and depression may have some underlying mechanisms whose elucidation may contribute to the understanding of the pathophysiology of vulnerability to affective disorders.