35: Biochemical aspects of psychiatric disorders

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Biochemical aspects of psychiatric disorders

William J. Marshall; Teifion Davies



Psychiatry is the branch of medicine that deals with the disturbance, distress and disability arising from those disorders of the nervous system that affect mental functioning. ‘Mental’ functions are those that we regard as distinguishing human beings as persons, and are usually divided into the major domains of cognition (thinking, remembering, planning); perception (awareness of self and environment); mood (feelings, emotions, ‘affect’) and behaviour (objective manifestations of subjective states). Although it is clear that each of these mental functions must be realized in the human brain (and that they may be affected by overt damage to the brain, as in head injury), they have been regarded traditionally as emergent phenomena that are only tenuously dependent upon the biological structures and processes of the brain itself.

This ‘epiphenomenal’ view of mental functions has been reinforced by two separate sets of findings. First, the psychological and neurobiological study of normal mental functions is only beginning to link them to anatomically discrete structures or pathways. Instead, they have been found to rely on distributed systems of activity in many brain areas that appear to interact in a seemingly limitless pattern of complexity. Second, the delineation of abnormal states has been constrained by a failure to identify specific causes, biological markers or even reliable pathognomonic features, with the result that psychiatry has been slow to follow most other medical disciplines away from the description of clinical syndromes (clusters of clinical symptoms and signs) towards a classification of disorders based on aetiology.

Psychiatric diagnosis remains, therefore, near one extreme of a continuum from ‘organic’ (having often localized pathology, discrete (possibly pathognomonic) signs and objective laboratory findings) to ‘non-organic’ (unclear structural pathology, overlapping signs and no confirmatory tests). Psychiatrists’ skills are largely clinical, and consist in eliciting a wide array of information directly from the patient by means of standardized interviewing and observation of behaviours and responses, supplemented by collateral information from informants such as carers, family members and others. Psychiatric decision-making begins with a comparison of this clinical information with what is known of the normal repertoire of mental states (taking into account age, sex and developmental and cultural factors), and proceeds with a systematization of the abnormal features to produce a set of recognized, but potentially overlapping, clusters. These form hypotheses to be tested by further enquiry, again usually direct questioning, so that the relative likelihood that the patient’s presentation is due to one syndrome rather than another is evaluated. The end result of this iterative process is rarely a single clear-cut diagnosis but rather a shortlist of differential diagnoses stratified according to the balance of probabilities on the evidence available. Immediate management will proceed on the basis of the most likely (or most serious in the short term) diagnosis, and will be reassessed iteratively as above and modified as new information, such as response to initial treatment, emerges.

Investigations in psychiatry

The emphasis on clinical information, that is, information gained directly from the patient in the clinic or at the bedside, should not be taken to mean that there is no role for laboratory investigations in psychiatry. Also, a general physical examination should form part of every psychiatric assessment and this or particular features of the patient’s history may lead to consideration of appropriate objective tests. What is true of psychiatry, as of all branches of medicine, is that no investigation should be regarded as ‘routine’: all investigations carry a finite risk of morbidity, and it is important to remember that this can be psychological as well as physical. Therefore, all investigations must be justified and the reasons for their selection or omission should be recorded (see below). It is also of great importance that the rationale for investigation, the intended procedures and potential unwanted effects be discussed with the patient and that his or her consent be sought before proceeding.

The reasons for selecting specific tests will be similar to other branches of medicine: screening (e.g. asymptomatic patients from high-risk population groups); baseline (to exclude or establish the extent of physical disorder, or as a preparation for certain treatments); monitoring (to monitor progression of primary physical disease or of disease secondary to the mental disorder or to monitor therapeutic drugs), and therapeutic (as part of the treatment plan, or to monitor compliance with treatment). A rational plan of investigation should be based on one or more specific purposes, as listed above, and be stratified into: primary (simpler, quicker, cheaper, more likely to gain information); secondary (more complex, expensive or specific) and tertiary (most complex, expensive or reliant on specialist operation). This stratified approach clarifies the medicolegal status of investigations, at least in psychiatric practice: primary level tests should be considered for every patient, and if not performed, the reasons for omission should be recorded; secondary and tertiary level tests should be performed only if indicated by the presentation, by other findings or on specialist advice, and the reasons for their performance recorded.


Psychiatric illnesses are usually referred to as ‘disorders’ rather than ‘diseases’, in part because of the overlap in clinical features between individual conditions and, indeed, with what may be regarded as an extreme of normal behaviour.

There are two principal systems for classifying psychiatric disorders. One is provided by the Diagnostic and Statistical Manual (DSM) of the American Psychiatric Association. The current edition (DSM-5), published in 2013, includes 18 groups of disorders, including personality disorders, together with a group of conditions that are deemed to require further research before they can be accepted for clinical use.

The World Health Organization’s (WHO) International Classification of Diseases (10th edition) (ICD-10) is more widely used outside the USA. The ICD-10 classification of mental and behavioural disorders is shown in Table 35.1. The number of psychiatric disorders that are recognized is continuing to increase as new conditions are described and others are subdivided and reclassified. The number of psychiatric diagnoses listed in DSM-II in 1968 was 182, and this had slightly more than doubled to 365 in DSM-IV (1994). Although the number appears not to have been significantly increased in DSM-5, several conditions have been sub-divided and others unified and there is an effective overall increase.

Psychiatric disorders have traditionally been divided into neuroses (in which the symptoms, principally anxiety, vary only in severity from those of normal behaviour) and psychoses, with features such as delusions (an abnormal belief, e.g. of persecution) or hallucinations (perceptions lacking an objective stimulus) and typically with little insight. However, this is not to suggest that neuroses are less harmful in their effect. There are also conditions that have features that overlap these definitions (e.g. anorexia nervosa). The classification of some mental disorders as neuroses therefore has little practical value.

Psychiatric disorders are common: the overall prevalence in the general population is estimated to exceed 20%, comprising mainly depression, anxiety and adjustment disorders (e.g. grief reactions) and contribute to about 30% of consultations with family doctors; in hospitals, organic disorders (e.g. delirium, particularly in the elderly) are more common. The major psychoses (by any definition) (e.g. schizophrenia) are less common (< 5% in total), but form a major part of the work of many psychiatrists.

There are several subspecialties within psychiatry. These include child psychiatry, old age psychiatry, substance misuse and forensic psychiatry.

This chapter primarily concerns the clinical biochemical aspects of psychiatric disorders and those general medical disorders that have psychiatric manifestations.


The causation of most psychiatric disorders is multifactorial. Biological (e.g. genetic, organic), psychological and behavioural (e.g. abuse in childhood, emotional trauma), and social and environmental factors (e.g. social isolation) are all involved.

Alterations in neurotransmission are undoubtedly a key mechanism in schizophrenia and affective disorders, although the cause of this remains uncertain. In schizophrenia, for example, there is considerable evidence to implicate dopaminergic pathways, with increased activity in the subcortical and limbic regions of the brain and reduced activity in the prefrontal cortical regions. The drugs that are used in the treatment of schizophrenia all have effects on dopaminergic neurotransmission. Decreased monoamine activity has long been considered to be an important mechanism in depression, a notion that is supported by the efficacy of monoamine oxidase inhibitors in its management. Many addictive drugs have effects on neurotransmission: for example, cocaine blocks the reuptake of dopamine in the brain and benzodiazepines bind to receptors for γ-aminobutyric acid, an important inhibitory neurotransmitter.

Until recently, it has been difficult to study biochemical activity in the brain. Measurements of neurotransmitters and their metabolites made in peripheral blood, blood in veins draining the brain and in cerebrospinal fluid provide only indirect information about brain activity and none on localization. However, the techniques of positron emission tomography (PET) and single-proton emission tomography (SPET) are beginning to shed light on the molecular basis of psychiatric disorders. Functional MRI measures cerebral blood flow, which is related to neuronal activity. And there can be little doubt that studies on the molecular genetics of receptors and enzymes involved in neurotransmission will contribute to a greater understanding of the biochemical disturbances that underlie psychiatric disorders.


Although laboratory investigations do not have a specific role in the diagnosis of the majority of psychiatric disorders, they are important for several reasons. First, because many physical diseases can give rise to symptoms that occur in psychiatric disorders (e.g. psychosis and delirium in systemic lupus erythematosus), it is frequently important to exclude an organic cause in a patient presenting with an apparent psychiatric disorder (albeit the results of such investigations are usually negative). Features suggesting an organic cause for an apparent psychiatric disorder include late age of onset, with no previous history or family history of psychiatric disorder, and no psychological or social precipitating factor. Second, organic illnesses may be complicated by psychiatric disorders. For example, panic disorder, generalized anxiety, social phobia and depression, occur more frequently in patients with irritable bowel syndrome (IBS) than in the general population, and antidepressant and anxiolytic medication has been shown to benefit significant numbers of patients with refractory IBS. Another connection between organic illness and psychiatric disorders is that the latter may cause both metabolic and endocrine disturbances (e.g. amenorrhoea in anorexia nervosa).

Third, psychotropic medication can cause metabolic abnormalities, and particularly given the high prevalence of psychiatric disorders, and hence the use of psychotropic drugs, clinical biochemists must be cognizant of these, so that, for example, the finding of a high serum prolactin concentration in a patient being treated with an antipsychotic drug should not lead automatically to a search for a pituitary tumour. Fourth, substance abuse may involve the clinical biochemist both analytically and in relation to the metabolic disturbances that may ensue. While it is beyond the scope of this book to discuss the role of the laboratory in the detection of substance abuse, the metabolic complications associated with some of the more frequently encountered substances are discussed in Chapter 40.

Table 35.2 summarizes the biochemical and other laboratory investigations that may be of value in excluding an organic cause for an apparent ‘psychiatric presentation’; the ensuing sections of this chapter describe the major psychiatric manifestations of organic diseases and the metabolic changes that can occur in psychiatric disorders and as a result of their treatment.

TABLE 35.2

Laboratory investigations to exclude organic disease in patients with psychiatric symptoms

Investigation Rationale
Full blood count Anaemia can lead to cerebral hypoxia, causing confusion; macrocytosis may be due to vitamin B12 deficiency, a cause of dementia, and to a high alcohol intake; chronic anaemia may contribute to depression
Acute phase proteins High erythrocyte sedimentation rate (ESR) suggests systemic illness, e.g. infection, malignancy, that may cause delirium; C-reactive protein (CRP) elevation may indicate abrupt onset of inflammation
Creatinine, ‘electrolytes’, estimated glomerular filtration rate (eGFR), calcium, liver function tests Electrolyte disorders and renal and hepatic failure can cause delirium; they may result from behavioural disturbance secondary to psychiatric disorder
Blood gases Hypocapnia can mimic anxiety (but note that, more frequently, hyperventilation secondary to anxiety or a panic attack can cause hypocapnia); hypercapnia in respiratory failure can cause delirium
Glucose Hypoglycaemia can mimic anxiety (and, when chronic, may lead to behavioural disturbance and trigger referral to a psychiatrist); hyperglycaemia can cause delirium
Thyroid function tests See text
Syphilis serology General paresis (a late manifestation of neurosyphilis), presenting with dementia, tremor and upper motor neuron signs, can develop 5–15 years after primary infection, if this is not treated
Blood cultures To detect occult sepsis
Blood alcohol A frequent cause of and exacerbating feature in psychiatric presentations

Other laboratory investigations that may be valuable (though are less frequently required) include measurement of heavy metals, carboxyhaemoglobin (for carbon monoxide poisoning), antinuclear factor (for cerebral lupus erythematosus) etc.


Acute confusional state (delirium)

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