Etiology Of Affective Disorders Research Articles

Pharmacological treatment of affective disorders: A review and guide for the non-medical practitioner

Abstract Mental health professionals who lack medical training may also lack knowledge and understanding of the potential utility of medications in the treatment of emotional disturbance. They may also lack information regarding the effects and side-effects of medications which their clients may already be taking, or be uncertain when the nature of their client's situation suggests a psychiatric assessment regarding drug therapy. This paper offers an educational review in one such area: the pharmacological treatment of depression. It includes a brief review of theories regarding the aetiology of affective disorder, examines the methodes, mechanisms and efficacy of anti-depressants, and draws conclusions regarding the appropriate use of pharmacological treatment.

The Second-Messenger Dysbalance Hypothesis of Affective Disorders

Proceeding from recent evidence about the mechanism of action of lithium and of the novel antidepressant rolipram, it is proposed that functional disturbances in intraneuronal signal transmission distal to the receptors of classic neurotransmitters (first messengers) play a role in the etiology of affective disorders. The second-messenger dysbalance hypothesis suggests that affective disorders are caused by the functional dysbalance of the two major intraneuronal signal-amplification systems (the adenylate-cyclase and the phospholipase-C system), with depression resulting from hypofunction of cyclic adenosine-3',5'-monophosphate-mediated effector cell responses together with an absolute or relative dominance of the inositoltriphosphate/diacylglycerol-mediated responses, and mania resulting from the converse. The usefulness of this hypothesis is discussed with respect to (a) the mechanism of action of current therapeutics and (b) the development of novel therapeutic approaches.

Dysbalance of neuronal second messenger function in the aetiology of affective disorders: A pathophysiological concept hypothesising defects beyond first messenger receptors

It is suggested that affective disorders arise from the dysbalance of the two major intraneuronal signal amplification systems, the adenylate cyclase and the phospholipase C system, with depression resulting from underfunction of cyclic adenosine 3',5'-monophosphate-mediated effector cell responses associated with an absolute or relative dominance of the inositoltriphosphate/diacylglycerol-mediated responses and mania resulting from the converse. The usefulness of this hypothesis is discussed with respect to (a) the mechanism of action of current therapeutic agents and (b) the development of novel therapeutic approaches.

Preliminary Evidence Points to Affective Disorder Triggered by Summer Weather

COLD SHOWERS, long a folk medicine to lessen libido, may become part of therapy to restore sexual desire, positive thinking, and motivation lost to some persons suffering from depression, according to a preliminary study by investigators at the National Institute of Mental Health in Rockville, Md ( Am J Psychiatry 1987;144:1602-1603). The report adds to a growing body of evidence incriminating dysfunctions of energy regulation in the etiology of affective disorders. It also raises the possibility of simple, nonpharmacologic treatments—such as partial sleep deprivation (please see accompanying article on p 959), phototherapy, or changes in ambient temperature—for at least some of them. This line of research garnered attention by introducing the syndrome known as seasonal affective disorder: recurring winter depression. The syndrome has been known for nearly 70 years (Kraepelin E [Barclay RM (trans)], in Robertson GM, Livingstone E, Livingstone S [eds]: Manic Depressive Illness and Paranoia . Edinburgh, E & S

Close linkage of c-Harvey-ras-1 and the insulin gene to affective disorder is ruled out in three North American pedigrees.

Affective disorder (AD) is one of the major forms of functional psychoses. Although the mode of transmission is uncertain, family, twin and adoption studies strongly suggest a genetic involvement. Because a basic biochemical abnormality is not known, direct analysis of the disease using a probe for the defective gene is not possible. However, a specific locus can be tested for its relevance to the aetiology of AD by genetic linkage, using restriction fragment length polymorphisms (RFLPs). Using probes for the c-Ha-ras-1 oncogene and the insulin gene, Gerhard et al. and Egeland et al. found convincing evidence for close linkage between these markers and a locus for AD in a large Old Order Amish pedigree. In an attempt to confirm this finding, we examined three bipolar pedigrees outside the Amish population. Our results indicate the absence of linkage from 0 to 15% recombination frequency between AD and the insulin gene-HRAS1 region in these pedigrees.

Interpreting data in aetiological studies of affective disorder: some pitfalls and ambiguities.

Although recent research in social psychiatry has produced an encouraging congruence of findings and conclusions, puzzling inconsistencies continue to be reported. One explanation which is often overlooked is that subtle differences in the way seemingly identical variables are grouped can produce sizeable, and sometimes dramatic, differences in the patterning of the same data. Re-examination of existing results can therefore often better clarify confusing inconsistencies than collection of new data. This is illustrated by examples from recent studies of affective disorder where the grouping of variables is discussed in three broad areas: parental loss in childhood, precipitating stress, and social support. Until the aetiology of affective disorder is more fully understood, it will often be clearer if data are analysed more than once, so that several combinations of variables are systematically examined.

Hypothalamic-pituitary-adrenal regulation, neurotransmitters and affective disorders

Considerable evidence has accumulated indicating that alterations in neurotransmitters may play a role in the etiology of affective disorders on the one hand, and in the regulation of the limbic-hypothalamic-pituitary-adrenal axis (LHPA) on the other. Acetylcholine, norepinephrine, serotonin, GABA, the opioid polypeptides and dopamine have all been implicated in both phenomena. Although some contradictory evidence exists, norepinephrine, opioids, and GABA appear inhibitory, and serotonin and acetylcholine appear excitatory of the LHPA axis. In a correlative study, non-suppression of cortisol by dexamethasone correlated positively and significantly with methylphenidate-induced euphoric and antidepressant responses, and methadone induced growth hormone responses, possibly suggesting catecholamine and opioid receptor hypersensitivity. Although the overall effects of the cholinomimetic, physostigmine, did not correlate with dexamethasone non-suppression, strong positive correlations were found in a subgroup, consisting of affective disorder patients, between non-suppression of cortisol by dexamethasone and the physostigmine response, suggesting cholinergic hypersensitivity in the non-suppressing subjects.

The genetics of affective disorder: data, theory, and clinical applications.

A genetic factor in the etiology of the affective disorders has been a subject of considerable interest and investigation during the last five decades. Data from twin studies, family studies, and adoption studies strongly support three major findings: genetic factors are significant in the etiology of both bipolar and unipolar affective disorder; bipolar and unipolar affective disorder tend to breed true and are genetically distinct diseases; and both bipolar and unipolar affective disorder are genetically distinct from schizophrenia. While the mode of transmission for the affective disorders remains unclear, the genetic data already afford clinical applications pertinent to diagnosis, prognosis, treatment response, and both immediate and longitudinal clinical course. Pharmacogenetic factors unrelated to the illness are also relevant to the management of antidepressant pharmacotherapy.

Haloperidol-induced presynaptic dopamine supersensitivity is blocked by chronic lithium.

SUPERSENSITIVITY following the interruption of synaptic transmission within the dopamine (DA) system has now been established by behavioural1–3, biochemical4–6 and electrophysiological7,8 evidence. Following production of lesions which interupt DA input1, or treatment with pharmacological agents which chronically disrupt dopaminergic transmission3,9,10, an increase in the sensitivity of postsynaptic (receiving input from dopaminergic neurones) responses of cells to DA and DA agonists has been observed. However, several studies have suggested that in vivo, presynaptic DA or ‘autoreceptors’ (that is, dopaminoceptive sites on DA-containing cells) may have an important physiological role in the modulation of DA synthesis and release11–13. Thus, alterations in the sensitivity of presynaptic cells may have profound effects on the availability of the neurotransmitter. To date, only one study has attempted to investigate whether dopaminergic supersensitivity could be a presynaptic, as well as a postsynaptic, phenomenon; following long-term treatment of rats with a phenothiazine, an increase in the sensitivity of DA-containing neurones in the substantia nigra to the DA agonist, apomorphine, has been observed14. We present here electrophysiological evidence for increased presynaptic sensitivity following chronic haloperidol treatment, as measured by both the direct iontophoretic application of DA and the systemic administration of apomorphine to DA-containing cells in the zona compacta region of the substantia nigra. In addition, it has been found recently that rats treated concurrently with lithium and haloperidol fail to develop postsynaptic supersensitivity, as measured by alterations in behavioural sensitivity15,16 and DA-receptor binding16. Several groups have theorised that alterations in catecholamine receptor sensitivity may be a factor in the aetiology of affective disorders, especially manic-depressive illness17,18. As lithium therapy has been shown to be effective in preventing recurrent episodes of mania and depression in manic-depressive illness19, it is of interest to determine whether, at the level of individual DA neurones in the CNS, chronic lithium treatment could also affect the development of presynaptic supersensitivity. We provide here electrophysiological evidence for the blockade of presynaptic supersensitivity development following chronic lithium treatment.

The biochemistry of affective disorders.

The title of this review would be regarded by some psychiatrists as provocative; they would relegate the biochemical concomitants of depression and mania to a secondary position and deny that biochemical changes have any place in the aetiology of these conditions. However, in my view, the weight of evidence, although it is by no means conclusive, suggests that biochemical changes are most important in the aetiology of affective disorders. A biochemical aetiology implies that there are certain biochemical changes in the brain which need to be restored to normal before the patient's clinical condition will improve. This does not deny that psychological and environmental events may precipitate and maintain the biochemical events which in turn lead to the affective disorder. The study of these biochemical events is clearly at too early a stage for speculations about the interrelationship between environmental and endogenous elements to be fruitful; this study must wait until the biochemical aetiology is clearer than at present.