Depression: Cowen PJ

Anderson IM, Ferrier IN, Baldwin RC, Cowen PJ, Howard L, Lewis G, Matthews K, McAllister-Williams RH, Peveler RC, Scott J, Tylee A. · Senior Lecturer and Honorary Consultant Psychiatrist, Neuroscience and Psychiatry Unit, University of Manchester, UK. · J Psychopharmacol. · Pubmed #18413657 No free full text.

Abstract: A revision of the 2000 British Association for Psychopharmacology evidence-based guidelines for treating depressive disorders with antidepressants was undertaken to incorporate new evidence and to update the recommendations where appropriate. A consensus meeting involving experts in depressive disorders and their management was held in May 2006. Key areas in treating depression were reviewed, and the strength of evidence and clinical implications were considered. The guidelines were drawn up after extensive feedback from participants and interested parties. A literature review is provided, which identifies the quality of evidence to inform the recommendations, the strength of which are based on the level of evidence. These guidelines cover the nature and detection of depressive disorders, acute treatment with antidepressant drugs, choice of drug versus alternative treatment, practical issues in prescribing and management, next-step treatment, relapse prevention, treatment of relapse, and stopping treatment.

Bhagwagar Z, Cowen PJ. · No affiliation provided · Psychol Med. · Pubmed #18444278 No free full text.

Abstract: The tendency of major depression to recur is a leading problem in clinical management and is responsible for much of the illness burden. Until recently, biological studies of depression have focused on the mechanisms involved in acute illness but there are now many data to suggest that neurobiological abnormalities persist when depressed patients are clinically recovered and withdrawn from medication. These abnormalities encompass a number of neurochemical and neuropsychological mechanisms that could be relevant to recurrence, including changes in the availability of serotonin (5-hydroxytryptamine, 5-HT) receptor subtypes, decreases in cortical gamma-aminobutyric acid (GABA), increases in cortisol secretion and negative biases in the processing of emotional information. Studies of groups at high risk of depression before illness onset will help to clarify which biological abnormalities precede the development of depression and which are the product of recurrent illness. Ultimately this work should lead to a better understanding of the neurobiology of vulnerability to depression and more innovative approaches to primary and secondary prevention.

Cowen PJ. · No affiliation provided · Br J Psychiatry. · Pubmed #11823315 links to  free full text

This publication has no abstract.

Cowen PJ. · Neurosciences Building, Warneford Hospital, Old Road, Headington, Oxford OX3 7JX, UK. · Trends Pharmacol Sci. · Pubmed #18585794 No free full text.

Abstract: The notion that impaired serotonin (5-HT) function can lead to clinical depression has a long history but is still controversial. Some have argued that the 5-HT hypothesis has been misused by the pharmaceutical industry to promote a simplistic biological model of depression to market selective serotonin reuptake inhibitors (SSRIs) to medical practitioners and the public. By contrast, there is now substantial evidence that unmedicated depressed patients have abnormalities in brain 5-HT function; however, the relation of these abnormalities to the clinical syndrome is unclear. The best evidence that 5-HT contributes to the pathophysiology of depression comes from studies of tryptophan depletion, which show that lowering brain 5-HT levels can induce acute symptomatic relapse in recovered depressed patients. Clarification of the mechanism of this effect will enable an understanding of how impaired 5-HT activity contributes to the subjective experience of depression.

Cowen PJ, Ogilvie AD, Gama J. · Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK. · Curr Med Res Opin. · Pubmed #15811202 No free full text.

Abstract: BACKGROUND: Major depressive disorders (MDD) present a significant public health problem, in terms of burden for individual sufferers, their families and society as a whole. Recently, dualacting antidepressants, which block both serotonin (5-HT) and noradrenaline (NA) reuptake, have been developed with the hope of improving depression treatment outcomes. Duloxetine is a dual reuptake inhibitor of 5-HT and NA that has recently been licensed in the USA for the treatment of MDD. OBJECTIVE: This paper summarises efficacy and tolerability data for duloxetine with particular reference to the dose recommended for clinical use -- 60 mg once daily. Papers relating to duloxetine 60 mg once daily were identified through Medline searches and the publication databases at Eli Lilly/Boehringer Ingelheim. FINDINGS: Randomised, placebo-controlled studies have demonstrated the efficacy of duloxetine 60 mg once daily for the treatment of depression in the short and long term. Thus, duloxetine 60 mg once daily was superior to placebo in reducing once daily was superior to placebo in reducing MDD symptoms according to the primary efficacy MDD symptoms according to the primary efficacy measure -- the 17-item Hamilton Depression Rating Scale (HAMD(17)). Significantly greater improvements in subfactors of HAMD(17) and quality of life measures were also seen. In addition, duloxetine has been shown significantly to reduce the general aches and pains that frequently accompany MDD. A recent placebo-controlled study demonstrated that duloxetine improved cognition and depression measures in depressed elderly patients. Duloxetine appears to have an acceptable tolerance. The most frequently observed adverse events with duloxetine were nausea, dry mouth and somnolence. Importantly, duloxetine did not appear to have a clinically significant effect on blood pressure. CONCLUSION: In summary, duloxetine 60 mg once daily is effective for the treatment of core depressive symptoms, as well as general aches and pains associated with depression.

Cowen PJ. · University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, United Kingdom. · Nucl Med Biol. · Pubmed #10962247 No free full text.

Abstract: Serotonin(1A) (5-HT(1A)) receptors are located on both 5-HT cell bodies where they act as inhibitory autoreceptors and at postsynaptic sites where they mediate the effects of 5-HT released from nerve terminals. The sensitivity of 5-HT(1A) receptors in humans can be measured using the technique of pharmacological challenge. For example, acute administration of a selective 5-HT(1A) receptor agonist, such as ipsapirone, decreases body temperature and increases plasma cortisol through activation of pre- and postsynaptic 5-HT(1A) receptors, respectively. Use of this technique has demonstrated that unmedicated patients with major depression have decreased sensitivity of both pre- and postsynaptic 5-HT(1A) receptors. Treatment with selective serotonin reuptake inhibitors further down-regulates 5-HT(1A) receptor activity. Due to the hypotheses linking decreased sensitivity of 5-HT(1A) autoreceptors with the onset of antidepressant activity, there is current interest in the therapeutic efficacy of combined treatment with selective serotonin reuptake inhibitors and 5-HT(1A) receptor antagonists.

Harmer CJ, Mackay CE, Reid CB, Cowen PJ, Goodwin GM. · Department of Experimental Psychology, Warneford Hospital, Oxford, United Kingdom. · Biol Psychiatry. · Pubmed #16460693 No free full text.

Abstract: BACKGROUND: The amygdala is believed to play a key role in processing emotionally salient, threat-relevant, events that require further online processing by cortical regions. Emotional disorders such as depression and anxiety have been associated with hyperactivity of the amygdala, but it is unknown whether antidepressant treatment directly affects amygdala responses to emotionally significant information. METHODS: The current study assessed the effects of 7 days administration of the selective serotonin reuptake inhibitor (SSRI), citalopram, on amygdala responses to masked presentations of fearful and happy facial expressions in never-depressed volunteers using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging. A double-blind, between-groups design was used with volunteers randomized to 20 mg/day citalopram versus placebo. RESULTS: Volunteers receiving citalopram showed decreased amygdala responses to masked presentations of threat compared with those receiving placebo. Citalopram also reduced responses within the hippocampus and medial prefrontal cortex (mPFC) specifically during the fear-relevant stimuli. These neural differences were accompanied by decreased recognition of fearful facial expressions assessed after the scan. By contrast, there was no effect of citalopram on the neural or behavioral response to the happy facial expressions. CONCLUSIONS: These results suggest a direct effect of serotonin potentiation on amygdala response to threat-relevant stimuli in humans. Such effects may be important in the therapeutic actions of antidepressants in depression and anxiety.

Hayward G, Goodwin GM, Cowen PJ, Harmer CJ. · University Department of Psychiatry, Warneford Hospital, Oxford OX1 3UD, UK. · Biol Psychiatry. · Pubmed #15737667 No free full text.

Abstract: BACKGROUND: Acute tryptophan depletion can induce a transient reappearance of depressive symptoms in recovered depressed patients. The neurochemical mechanism is thought to be impairment of brain serotonin neurotransmission, but the neuropsychologic mechanisms underlying the effect are unclear. METHODS: To assess whether low-dose tryptophan depletion can tease out the psychological mechanisms sensitive to substrate depletion in vulnerable subjects without inducing mood changes, a between-subjects randomized design was used. Recovered depressed patients (n = 24) and healthy volunteers (n = 24) were administered while fasting either a tryptophan-free or a control mixture, containing 31.2 and 33.2 g of amino acids, respectively. Objective and subjective ratings of mood were made before and 5 hours after ingestion; at the latter time point, cognitive and emotional processing were also assessed. RESULTS: Low-dose tryptophan depletion did not affect mood. Significant changes in emotional and cognitive processing occurred in the recovered depressed group, however, and to a lesser extent in the healthy volunteers. The profile of effects seen in the recovered patients suggested a return of the impairments seen in acute depression. CONCLUSIONS: Our data suggest that low-dose tryptophan depletion permits investigation of the cognitive correlates of acute reductions in brain serotonin in populations vulnerable to depression and in healthy volunteers, without causing depressive symptoms.

McTavish SF, Mannie ZN, Harmer CJ, Cowen PJ. · University Department of Psychiatry, Warneford Hospital, Oxford, UK. · Neuropsychopharmacology. · Pubmed #15702140 links to  free full text

Abstract: The role of dopamine (DA) pathways in the pathophysiology of depressive disorder is poorly understood. However, because DA plays a key role in motivational behavior, it is important to study in a disorder characterized by anhedonia, lack of energy and psychomotor retardation. A recently developed dietary manipulation ('tyrosine (TYR) depletion') offers a novel method to assess the role of DA in major depression. We studied 15 euthymic women with a past history of recurrent depression, who received a 74 g amino-acid drink lacking TYR and phenylalanine (PHE) (TYR-free) and a balanced (BAL) amino acid drink on two separate occasions in a double-blind, random-order, crossover design. Plasma prolactin levels rose following the TYR-free drink relative to the balanced mixture, while performance on a spatial recognition memory task was impaired. However, relative to the BAL drink, the TYR-free drink did not lower objective or subjective measures of mood. We conclude that as in healthy volunteers, TYR depletion in euthymic subjects, with a past history of major depression, attenuated DA function, as reflected in increased plasma prolactin levels and decreased spatial memory performance. However ratings of depression were unaffected, suggesting that disruption of dopaminergic function by this manipulation does not induce a lowering of mood in individuals vulnerable to depression.

McTavish SF, Mannie ZN, Cowen PJ. · No affiliation provided · Psychopharmacology (Berl). · Pubmed #15232675 No free full text.

This publication has no abstract.

Harmer CJ, Shelley NC, Cowen PJ, Goodwin GM. · University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK. · Am J Psychiatry. · Pubmed #15229059 links to  free full text

Abstract: OBJECTIVE: Antidepressants that inhibit the reuptake of serotonin (SSRIs) or norepinephrine (SNRIs) are effective in the treatment of disorders such as depression and anxiety. Cognitive psychological theories emphasize the importance of correcting negative biases of information processing in the nonpharmacological treatment of these disorders, but it is not known whether antidepressant drugs can directly modulate the neural processing of affective information. The present study therefore assessed the actions of repeated antidepressant administration on perception and memory for positive and negative emotional information in healthy volunteers. METHOD: Forty-two male and female volunteers were randomly assigned to 7 days of double-blind intervention with the SSRI citalopram (20 mg/day), the SNRI reboxetine (8 mg/day), or placebo. On the final day, facial expression recognition, emotion-potentiated startle response, and memory for affect-laden words were assessed. Questionnaires monitoring mood, hostility, and anxiety were given before and after treatment. RESULTS: In the facial expression recognition task, citalopram and reboxetine reduced the identification of the negative facial expressions of anger and fear. Citalopram also abolished the increased startle response found in the context of negative affective images. Both antidepressants increased the relative recall of positive (versus negative) emotional material. These changes in emotional processing occurred in the absence of significant differences in ratings of mood and anxiety. However, reboxetine decreased subjective ratings of hostility and elevated energy. CONCLUSIONS: Short-term administration of two different antidepressant types had similar effects on emotion-related tasks in healthy volunteers, reducing the processing of negative relative to positive emotional material. Such effects of antidepressants may ameliorate the negative biases in information processing that characterize mood and anxiety disorders. They also suggest a mechanism of action potentially compatible with cognitive theories of anxiety and depression.

Rabiner EA, Bhagwagar Z, Gunn RN, Cowen PJ, Grasby PM. · PET Psychiatry, Translational Medicine and Technologies, GlaxoSmithKline, Cambridge, UK. · Neuropsychopharmacology. · Pubmed #15127080 links to  free full text

Abstract: Using positron emission tomography and the selective 5-HT1A receptor radioligand [11C]WAY100635, we previously demonstrated a preferential occupancy of 5-HT1A autoreceptors, compared to postsynaptic receptors by pindolol in healthy volunteers. We have speculated that preferential occupancy may be clinically important for the purported actions of pindolol in accelerating the antidepressant effects of selective serotonin re-uptake inhibitors (SSRIs). In this study, we have examined the preferential occupancy by pindolol of 5-HT1A autoreceptors, following three different pindolol regimes (10 mg single dose, 2.5 mg t.i.d., and 5 mg t.i.d., in 15 depressed patients on SSRIs. In addition, seven healthy volunteers were examined following a single 10 mg dose of pindolol. We found a preferential occupancy of 22.6+/-7.7% following a single dose of 10 mg of pindolol, in the healthy volunteers, which was attenuated in depressed patients on the same dose of pindolol to 2.9+/-10.8% (Student's t=3.94, df=12, p=0.002). In addition, we found a significant negative correlation between the degree of preferential occupancy and the severity of depression as assessed by the Hamilton depression rating score (HAM-D), Spearman's rho=-0.728, N=14, p=0.003, in the depressed sample. A possible mechanism underlying preferential occupancy and the attenuation of this phenomenon in depressed patients on SSRIs may include changes in the proportion of high affinity 5-HT1A sites in the autoreceptor region of the midbrain raphe. Speculatively, the degree of preferential occupancy may serve as a surrogate marker for depression, or the pharmacological effects of antidepressants.

Bhagwagar Z, Rabiner EA, Sargent PA, Grasby PM, Cowen PJ. · University Department of Psychiatry, Warneford Hospital, Oxford, UK. · Mol Psychiatry. · Pubmed #15042104 No free full text.

Abstract: Positron emission tomography (PET) studies with the selective 5-HT(1A) receptor ligand, [(11)C]WAY-100635, have indicated that the binding potential (BP) of brain 5-HT(1A) receptors is lowered in unmedicated subjects with acute major depression. However, it is unclear if these changes persist after recovery from depression. To resolve this issue, we used [(11)C]WAY-100635 in conjunction with PET imaging to compare 5-HT(1A) BP in 18 healthy controls and 14 male subjects with recurrent major depression who were clinically recovered and free of antidepressant medication. BP values, derived from a reference tissue model, were analysed by region of interest and statistical parametric mapping. Both analyses showed a widespread and substantial (17%) decrease in 5-HT(1A) receptor BP in cortical areas in the recovered depressed subjects. In contrast, 5-HT(1A) BP in the raphe nuclei did not distinguish depressed subjects from controls. Our results suggest a persistent dysfunction in cortical 5-HT(1A) BP as measured by [(11)C]WAY-100635 in recovered depressed men. Lowered 5-HT(1A) receptor binding availability could represent a trait abnormality that confers vulnerability to recurrent major depression.

Bhagwagar Z, Cowen PJ, Goodwin GM, Harmer CJ. · University Department of Psychiatry, Warneford Hospital, Oxford. · Am J Psychiatry. · Pubmed #14702268 links to  free full text

Abstract: OBJECTIVE: The present study aimed to 1) assess facial expression recognition in subjects with a previous history of major depressive disorder relative to subjects with no history of depression and 2) characterize the effects of acute citalopram infusion on recognition performance for both groups. METHOD: Unmedicated euthymic women with a history of major depression and matched comparison subjects with no history of depression were given a facial expression recognition task following intravenous infusion of saline or citalopram (10 mg) in a double-blind, between-group design. RESULTS: Following saline infusion, subjects with a previous history of depression showed a selectively greater recognition of fear relative to the subjects with no history of depression. The abnormal fear processing observed in the subjects with a previous history of depression was normalized following citalopram infusion, an effect that was opposite to that seen with the subjects with no history of depression. CONCLUSIONS: These results suggest that increased recognition of fear is a trait vulnerability marker for depression and that this is normalized following a single dose of citalopram.

Bhagwagar Z, Montgomery AJ, Grasby PM, Cowen PJ. · Clinical Sciences Centre Medical Research Council, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom. · Biol Psychiatry. · Pubmed #14573316 No free full text.

Abstract: BACKGROUND: Elevated cortisol levels might account for the reduction in central serotonin 1A (5-hydroxytryptamine [5-HT](1A)) receptor binding and function observed in patients with major depression. We tested this hypothesis by studying the effect of acute administration of hydrocortisone on 5-HT(1A) receptor binding potential (BP) in subjects recovered from depression. METHODS: We studied 14 subjects (8 male, 6 female) who had recovered from at least two episodes of major depression and had been euthymic and drug free for at least 6 months. Serotonin 1A receptor BP was measured by [(11)C]WAY-100635 in conjunction with positron emission tomography. Subjects were tested on two occasions in a double-blind, random-order, crossover design after administration of either hydrocortisone (100 mg orally) or placebo 12 hours previously. Positron emission tomography scans were analyzed with a region of interest analysis. RESULTS: Hydrocortisone treatment did not decrease 5-HT(1A) receptor BP either in the hippocampus, which was our a priori hypothesis, or in other cortical 5-HT(1A) regions; however, female subjects had a higher 5-HT(1A) receptor BP in certain brain areas compared with male subjects. CONCLUSIONS: These data are consistent with an earlier study in healthy volunteers and do not support the proposal that decreased 5-HT(1A) receptor BP in patients with acute major depression is a consequence of cortisol hypersecretion.

Harmer CJ, Hill SA, Taylor MJ, Cowen PJ, Goodwin GM. · Department of Psychiatry, Oxford University, Warneford Hospital, Oxford OX3 7JX, USA. · Am J Psychiatry. · Pubmed #12727705 links to  free full text

Abstract: OBJECTIVE: Antidepressants that increase serotonin or norepinephrine in the brain are effective in treating depression, but there is no neuropsychological account of how these changes relieve depressive states. Cognitive theories suggest that biases in information processing lead depressed patients to make unrealistically negative judgments about themselves and the world. METHOD: A single dose of the noradrenergic antidepressant reboxetine or placebo was administered to 24 healthy volunteers. Effects on emotional processing were assessed through facial expression recognition, emotional categorization, and emotional memory. RESULTS: On the three measures, reboxetine biased perception toward positive, rather than negative, information in the absence of changes in nonemotional performance or mood. CONCLUSIONS: These results suggest that a single dose of an antidepressant can increase the processing of positively valenced material in nondepressed volunteers. Antidepressants may therefore work in a manner similar to that of psychological treatments that aim to redress negative biases in information processing.

Harmer CJ, Bhagwagar Z, Perrett DI, Völlm BA, Cowen PJ, Goodwin GM. · University Department of Psychiatry, Warneord Hospital, Oxford, UK. · Neuropsychopharmacology. · Pubmed #12496951 links to  free full text

Abstract: Enhancement of serotonin neurotransmission plays an important role in the antidepressant response to agents presently available to treat depression. This response forms the major evidence for the role of serotonin in affective and social behaviour in humans. The present study investigated the effects of acute administration of the selective serotonin reuptake inhibitor (SSR1), citalopram (10 mg, i.v.) upon a measure of emotional processing in healthy female volunteers. Subjects completed a facial expression recognition task following infusion of citalopram or saline (between-subjects design, double-blind). Facial expressions associated with five basic emotions--happiness, sadness, fearfulness, anger and disgust--were displayed. Each face had been 'morphed' between neutral (0%) and each emotional standard (100%) in 10% steps, leading to a range of emotional intensities. Mood and subjective experience were also monitored throughout the testing session. Volunteers receiving citalopram detected a higher number of facial expressions of fear and happiness, with reduced response times, relative to those given the placebo. By contrast, changes in the recognition of other basic emotions were not observed following citalopram. Notable differences in mood were also not apparent in these volunteers. These results suggest that acute administration of antidepressant drugs may affect neural processes involved in the processing of social information. This effect may represent an early acute effect of SSRIs on social and emotional processing that is relevant to their therapeutic actions.

Bhagwagar Z, Hafizi S, Cowen PJ. · University Department of Psychiatry, Warneford Hospital, OX3 7JX, Oxford, UK. · J Affect Disord. · Pubmed #12450642 No free full text.

Abstract: BACKGROUND: Recent formulations of the pathophysiology of major depression suggest that stress-induced cortisol secretion may lower brain serotonin (5-HT) function, thereby precipitating depressive symptomatology. This implies that people who develop depression after stressful life events may be particularly vulnerable to the effect of cortisol on brain 5-HT activity. We therefore assessed the effect of a single dose of hydrocortisone on 5-HT-mediated growth hormone (GH) release in healthy volunteers and euthymic subjects recovered from at least two episodes of major depression. METHODS: Eleven recovered depressed patients and 20 healthy controls received intravenous tryptophan (TRP) 10.5 h after placebo and hydrocortisone (50 mg orally) in a double-blind, cross-over design. Plasma GH levels were sampled for 90 min after TRP infusion. RESULTS: The GH response to TRP was significantly lower in the recovered depressed patients than controls after hydrocortisone. LIMITATIONS: The number of recovered depressed subjects studied was small and the effect of hydrocortisone on TRP-induced GH release was different to that observed in a previous study. CONCLUSIONS: These findings are consistent with other evidence suggesting abnormal regulation of 5-HT neurotransmission in people vulnerable to recurrent depression.

Harmer CJ, Bhagwagar Z, Cowen PJ, Goodwin GM. · Neurosciences Building, University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK. · Psychopharmacology (Berl). · Pubmed #12185407 No free full text.

Abstract: OBJECTIVES: Decreasing serotonergic neurotransmission in humans has been found to impair memory consolidation. Such effects may be relevant to the memory deficits seen in major depression and the cognitive actions of antidepressant drugs used to treat them. However, the improvement in cognitive function often found following successful pharmacological treatment in depression may be confounded by symptom improvement. RATIONALE: The present study assessed the effects of an acute challenge with the selective serotonergic re-uptake inhibitor citalopram in healthy (non-depressed) females. METHODS: Immediate and delayed recall/recognition was assessed using the auditory verbal learning test following 10 mg (intravenous) citalopram or placebo in a double-blind between groups design. RESULTS: Immediate recall on the verbal memory test was unaffected by citalopram administration. However, volunteers receiving citalopram showed enhanced long-term memory performance in terms of delayed recall and recognition relative to those receiving placebo. Sustained attention performance was also comparable in the two groups of subjects suggesting that non-specific increases in information processing are not responsible for this effect. CONCLUSIONS: These results indicate that augmentation of serotonergic neurotransmission is associated with increased memory consolidation, which may be relevant to its therapeutic and cognitive actions in acutely depressed patients.

Murphy FC, Smith KA, Cowen PJ, Robbins TW, Sahakian BJ. · MRC Cognition and Brain Sciences Unit, 15 Chaucer Road, Cambridge CB2 2EF, UK. · Psychopharmacology (Berl). · Pubmed #12185399 No free full text.

Abstract: RATIONALE: Cognitive impairment is a common feature of depressive illness. While accumulating evidence suggests that brain serotonin (5-HT) pathways play an important role in the neurobiology of depression, the extent to which altered 5-HT function is responsible for the associated changes in cognition and emotion remains unclear. OBJECTIVE: The present study examined the effects of acute dietary depletion of tryptophan (TRP) on cognitive and affective processing in healthy volunteers and explored the putative role of 5-HT in the neuropsychology of depression. METHODS: We administered computerised cognitive tests to healthy control participants following ingestion of TRP-free and nutritionally balanced amino acid drinks in a double-blind, placebo-controlled, crossover design. RESULTS: The TRP-free amino acid mixture significantly lowered plasma total and free TRP concentrations relative to baseline values and produced selective deficits similar to those observed previously in cases of clinical depression. In particular, TRP depletion increased response times for happy but not sad targets in an affective go/no-go task and slowed responding in a visual discrimination and reversal learning task. These deficits were not due to a global sedative effect, as planning ability was unimpaired. CONCLUSIONS: The present data indicate that serotonergic factors may be more involved in the disrupted inhibitory and emotional processing characteristic of depression than in other aspects of executive function, such as planning ability. These findings support the recent proposal that serotonergic manipulation may have greater effects on tasks mediated by frontal circuitry that includes the orbitofrontal cortex than by dorsolateral prefrontal cortex circuitry.

Bhagwagar Z, Whale R, Cowen PJ. · University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK. · Br J Psychiatry. · Pubmed #11772847 links to  free full text

Abstract: BACKGROUND: Neuroendocrine studies of brain serotonin (5-HT) function in depression generally show evidence of impaired 5-HT function but it is disputed whether or not this impairment resolves with clinical recovery. AIMS: To use the endocrine response to the selective 5-HT reuptake inhibitor, citalopram, to study brain 5-HT function in acute and recovered depressed subjects relative to healthy controls. METHOD: We used a double-blind, placebo-controlled design to measure the prolactin and cortisol responses to citalopram (10 mg intravenously) in patients with major depression, in unmedicated subjects recovered from depression and in healthy controls. RESULTS: The prolactin responses to citalopram were blunted similarly in both acutely depressed and recovered subjects. The cortisol responses were blunted in the acutely depressed patients but not in the recovered subjects. CONCLUSIONS: Our data support the proposal that some aspects of impaired 5-HT neurotransmission may be trait markers of vulnerability to depression. The recovery of the cortisol response to citalopram may indicate resolution of hypothalamic-pituitary-adrenal axis dysfunction.

Harmer CJ, McTavish SF, Clark L, Goodwin GM, Cowen PJ. · University Department of Psychiatry, Warneford Hospital, Oxford, UK. · Psychopharmacology (Berl). · Pubmed #11291999 No free full text.

Abstract: RATIONALE: Tyrosine depletion has been shown to reduce dopamine over activity in animal and human investigations. However, the effects on basal dopamine function have not been explored. Such information could establish tyrosine depletion as an effective probe of dopamine function in healthy volunteers and would also have relevance for future therapeutic applications of this manipulation. OBJECTIVE: The present study investigated the effect of acute tyrosine depletion on dopamine function in healthy volunteers using a combination of neuroendocrine, neuropsychological and subjective measures. METHODS: On one occasion, volunteers received an amino acid drink selectively lacking tyrosine and phenylalanine (TYR-free), whilst on the other they received a balanced (BAL) amino acid drink. Plasma prolactin, amino acid levels and subjective state were monitored over 6 h following the two drinks, and volunteers also completed a battery of tests from the CANTAB, including measures of spatial memory previously found to be sensitive to changes in dopamine function. RESULTS: Plasma prolactin levels rose following the TYR-free drink relative to the balanced mixture, indicative of decreased dopamine neurotransmission within the hypothalamus. Following the TYR-free drink, volunteers were impaired at spatial recognition memory and spatial working memory. Volunteers also tended to report that they felt less good following the TYR-free than the BAL mixture. CONCLUSION: Tyrosine depletion in healthy volunteers affected baseline dopamine function on the different measures employed in this study. Tyrosine depletion would thereby seem valuable as a probe of dopamine function in human volunteers. Ratings of depression and other aspects of cognitive function were unaffected, suggesting that this manipulation may be free of significant side effects when used as a treatment for conditions characterised by dopamine over activity, such as acute mania and schizophrenia.

Whale R, Bhagwagar Z, Cowen PJ. · University Department of Psychiatry, Warneford Hospital, Oxford, UK. · Psychopharmacology (Berl). · Pubmed #10463324 No free full text.

Abstract: RATIONALE: Effective neuroendocrine probes of 5-HT1B and 5-HT1D receptor function may facilitate investigation of the role of these receptor subtypes in the pathophysiology of depression and the mode of action of antidepressant medication. OBJECTIVE: To investigate the neuroendocrine profile of the 5-HT1B/1D receptor agonist, zolmitriptan, in healthy volunteers. METHODS: Twelve subjects entered a double-blind, placebo-controlled, cross-over design study of zolmitriptan (5 mg orally). Blood samples were taken at 15-min intervals for assay of prolactin and growth hormone. A further six healthy men were recruited to an equivalent study to examine the effect of ketanserin (a 5-HT receptor antagonist with some preference for 5-HT1D over 5-HT1B receptors) on the growth hormone response to zolmitriptan. RESULTS: Zolmitriptan significantly increased plasma growth hormone but had no effect on plasma prolactin or oral temperature. The increase in growth hormone produced by zolmitriptan was significantly attenuated by ketanserin. CONCLUSIONS: We suggest that the ability of triptans such as zolmitriptan, sumatriptan and rizatriptan to increase plasma growth hormone is mediated by their common agonist activity at postsynaptic 5-HT1D receptors.

Smith KA, Fairburn CG, Cowen PJ. · University Department of Psychiatry, Warneford Hospital, Oxford, England. · Arch Gen Psychiatry. · Pubmed #10025442 links to  free full text

Abstract: BACKGROUND: Preclinical and clinical studies suggest that lowered brain serotonin neurotransmission may contribute to the pathophysiology of bulimia nervosa (BN). The aim of our study was to test this hypothesis by examining the psychological effects of a dietary-induced impairment in serotonin activity in subjects known to be at risk for manifestation of the clinical syndrome of BN. METHODS: An 85.8 g amino acid mixture lacking the serotonin precursor tryptophan and a balanced mixture were administered to 10 clinically recovered, medication-free female subjects with a history of BN in a double-blind, crossover design. Twelve healthy female subjects with no history of psychiatric disorder were studied as a comparison group. Observer and self-rated measures of mood and eating disorder cognitions were made for the 7 hours following administration of each amino acid mixture. RESULTS: Compared with healthy controls, subjects with a history of BN had significant lowering of mood, increases in ratings of body image concern, and subjective loss of control of eating following the tryptophan-free mixture. CONCLUSIONS: Our results suggest that diminished serotonin activity may trigger some of the cognitive and mood disturbances associated with BN. Our findings support suggestions that chronic depletion of plasma tryptophan may be one of the mechanisms whereby persistent dieting can lead to the development of eating disorders in vulnerable individuals.

Horder J, Cowen PJ, Di Simplicio M, Browning M, Harmer CJ. · University Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK. · Psychopharmacology (Berl). · Pubmed #19337726 No free full text.

Abstract: BACKGROUND: Emotional processing measures are sensitive to acute administration of clinically useful antidepressant drugs. We wished to test the hypothesis that these models would also be able to detect agents likely to cause depression as an adverse effect. The anti-obesity drug and cannabinoid type 1 receptor antagonist, rimonabant, is associated with significant rates of depression and anxiety in clinical use. MATERIALS AND METHODS: Thirty healthy adult volunteers were randomly assigned to receive a single dose of rimonabant (20 mg) or lactose placebo in a double-blind, between-groups design. Three hours after medication administration, subjects undertook an emotional processing test battery including facial emotion recognition, emotional word attentional dot probe, self-relevant word classification, emotional and declarative memory and the emotion-potentiated acoustic startle response. Subjective state was assessed via self-report measures. RESULTS: A single dose of rimonabant did not alter subjective mood. However, rimonabant selectively reduced incidental recall of positive self-relevant adjectives, an effect contrary to that seen following the administration of antidepressants. There were no effects of rimonabant on the other measures of emotional processing. CONCLUSIONS: These results suggest that a single dose of rimonabant decreases positive emotional memory in the absence of changes in subjective state. Further studies are required to examine whether rimonabant might produce a wider range of negative emotional biases with repeated treatment.