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January 2006

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Volume 2, Issue 1 January 2006

NEI Bipolar One-Day Symposia (details on back cover)

NEI PRESS www.neiglobal.com

Inside This Issue-Second Messenger-

The Mystery of FibromyalgiaPart 1—Is fi bromyalgia real pain, and what causes it?Katherine J. CarpenterFibromyalgia pain is no longer considered “all in the mind” but has a true

biological basis. The fi rst of a two-part article reviews the alterations in pain

pathways that may underlie fi bromyalgia, lifting some of the mystique

and stigma surrounding this painful and destructive condition.

(Page 2)

-Essential PsychopharmaStahlogy-

Symptoms and CircuitsDeconstructing psychiatric disorders to achieve remissionStephen M. Stahl and Meghan GradyA new conceptualization of the biological basis of psychiatric disorders

has been forming—“symptoms and circuits”—which may not only

explain the biological basis of symptoms in psychiatric disorders, but may

also help clinicians select and combine treatments that are customized

to each patient’s symptom profi le.

(Page 6)

-Tips and Pearls-

MirtazapineDosing tips and prescribing pearls

An excerpt from the brand-new textbook, Essential Psychopharmacology: The Prescriber’s Guide (Stahl SM. 2005) from Cambridge University Press.

(Page 4)

-Back to Basics-

Stress-Diathesis Model (Page 4)

-Upcoming NEI Events-

NEI Global Psychopharma-cology CongressNovember 2–6, 2006

Orlando, Florida

(Back Cover)In a recent poll of 169 mental health professionals, 45% of the respondents reported that they found some controlled-release products signifi cant therapeutic advances.1,2

PsychEd Poll How valuable are the following controlled-release products in psychiatric practice? (e.g. Concerta, Effexor XR, Wellbutrin XL)

A. mostly patent extension gimmicks

B. incremental therapeutic advance over the immediate release

C. signifi cant therapeutic advances

D. some are advances, others are gimmicks

50

4030

20

10

0

1. Neuroscience Education Institute Psychopharmacology Academy; October 15-16, 2005; Phoenix, AZ.2. Stahl SM. PsychEd Up 2005;11:6,7.

2%

26%

45%

27%

A B C D

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PsychEd Up Volume2, Issue 1

NEI PRESS

- Second Messenger -

Katherine J. CarpenterNEI Staff Writer

The Mystery of FibromyalgiaPart 1—Is fi bromyalgia real pain, and what causes it?

Attitudes among clinical practitioners about fibromyalgia range from “it’s all in the mind” to “it’s all in the joints.”

That is, that fibromyalgia is a psychosomatic condition that reflects life crises and that it is an autoimmune rheumatoid condition that affects the joints and muscles. The discovery that antidepressants can reduce pain in fibromyalgia seems to suggest that the “all in the mind” theory is correct; that fibromyalgia is caused by depressed mood. In fact, fibromyalgia is not in the mind, but in the brain, caused by aberrant processing in the pain transmission pathway. The antidepressants that are effective treatments target these pain pathways and have effects independent of their antidepressant properties.

This is the first part of a two-part article that addresses some common questions about fibromyalgia. This first installment reviews experts’ current understanding of this painful and destructive condition and its possible biological basis.

Is fibromyalgia real pain?The short answer is “yes.” The longer answer includes evidence from pathological, psychophysical, and imaging studies.

Fibromyalgia has an estimated prevalence of 2% and is more common in women than men.1 It is diagnosed by a history of widespread pain in all four body segments, and pain in 11 of 18 tender point sites on digital palpation. Although pain is felt in these tender muscle and joint sites, no identifiable pathology has been found here. About one-third of patients with fibromyalgia also meet criteria for major

depressive disorder. Anxiety disorders, low self-esteem, difficult family circumstances, and poverty are not uncommon, and patients have often seen many practitioners over many years before arriving at a diagnosis of fibromyalgia. These factors, along with the absence of any identifiable pathology, led many experts to see fibromyalgia’s physical symptoms as psychosomatic manifestations of unconscious conflicts, and sufferers as difficult, malingerers, and catastrophizers.

However, there is now much evidence that pain in fibromyalgia is very real and associated with measurable changes in pain processing systems: (1) Patients with fibromyalgia perceive a painful stimulus as more painful than healthy controls do, a phenomenon known as “hyperalgesia;”2,3 (2) In healthy, pain-free controls, repeated application of a painful stimulus causes a progressive increase in the perceived pain intensity (wind-up pain or central sensitization); this increase is greater in fibromyalgia patients;2-

4 (3) Imaging studies have shown that when

the same painful stimulus is applied, there is increased activity in pain processing brain centers in patients with fibromyalgia compared with normal controls.5

These measurable alterations in pain processing support the concept that the pain of fibromyalgia is real, slowly replacing the concept that the pain is psychosomatic.

What causes it?If fibromyalgia is not a psychosomatic illness, and is not caused by damage to muscles or joints, what does cause it? The best explanation we have currently is aberrant processing in the pain pathway. A state of “central sensitization,” seems to exist in patients with fibromyalgia, where pain signals coming in from the periphery to the spinal cord are inappropriately augmented, probably as a result of deficient descending inhibitory controls.

Neurons in the pain pathway run from the periphery (skin, joints, viscera), into the spinal cord, where they synapse with projection neurons that ascend to relay centers like the thalamus, hypothalamus and brainstem nuclei, and from there to higher centers where the location and intensity of pain is deciphered (the somatosensory cortex) and emotional and motivational aspects generated (amygdala, cingulate, and prefrontal cortex). At many points in this pathway, but particularly in the spinal cord, the basic pain signal is open to modulation, both augmentation and inhibition. One important inhibitory pathway is the opioid pathway, which descends from the brainstem to the spinal cord. It is recruited in times of severe physical and physiological stress, acting as an endogenous pain killer when the body needs to function through severe pain. The other major descending inhibitory pathways are the serotonin (5-HT) and norepinephrine (NE) pathways. These seem to be active mostly in basal conditions, damping down transmission of small, everyday noxious events that arise just from normal functioning of the human body.

This “brake” is hypothesized to be lacking in patients with fi bromyalgia: reduced activity in descending 5-HT and NE pathways would reduce the inhibitory controls,

Issue Fibromyalgia is a mysterious condition that can destroy quality of life for its sufferers. Stigma and uncertainty surround the disease, often compromising its diagnosis and rational treatment.

Actions Learn the possible biological basis of fi bromyalgia.

Benefi ts Understanding the pain pathways underlying fi bromyalgia will lift some of the mystique and stigma surrounding this disease and help the prescriber improve the quality of life of patients with fi bromyalgia.

Reduced activity in descending 5-HT and NE pathways would reduce the inhibitory controls,

allowing non useful and uninformative pain signals to get through

the “gate.”

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January 2006

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References1. Clauw DJ, Crofford LJ. Best Pract Res Clin Rheumatol 2003; 17:685-701.2. Straud R et al. Pain 2003; 102:87-95.3. Julien N et al. Pain 2005; 114:295-302.

allowing nonuseful and uninformative pain signals to get through the “gate” (Figure 1). The increased incoming barrage inappropriately activates processes that are designed to augment pain signals in times of need. A state of “central sensitization” results, giving greater output (from the spinal cord to higher centers) for a given level of input. This explains the

observations of hyperalgesia and greater magnitude of wind-up in fibromyalgia patients. Accordingly, levels of 5-HT and NE metabolites in cerebrospinal fluid and serum have been shown to be reduced in fibromyalgia patients,6 lending more evidence to the theory of insufficient 5-HT and NE.

Psychological aspects are still important in fibromyalgia, and depression and anxiety occur in many patients. These may arise as direct consequences of the ongoing pain, or may even result from the same 5-HT and NE deficiency that could underlie the pain. Physical consequences of unrelenting pain can include muscle wasting and deconditioning; physiological consequences include changes in the hypothalamic–pituitary–adrenal (HPA) axis and reduced immune function; vegetative consequences include poor, unrestorative sleep and insomnia; and the emotional anguish of pain (as well as the long journey to an accurate diagnosis) is

Figure 1

likely to have psychological ramifications, leading to depression and anxiety.

Reciprocal interactions likely occur between these circuits, which all use 5-HT and NE as important transmitters. It must not be forgotten that 95% of fibromyalgia sufferers are women, suggesting the existence of a sex difference that predisposes to fibromyalgia.

The bottom line—Fibromyalgia is a real and painful condition that is probably caused by inappropriate augmentation of pain transmission at a central site, likely the spinal cord. This may be due to reduced activity of descending serotonin and norepinephrine pathways. Complicated overlap exists between these pain pathways and other important monoaminergic pathways, possibly underlying problems fibromyalgia patients have with sleep, mood, and anxiety.

(a) Normally, basal pain signals arrive in the spinal cord from the body. (b) Descending serotonin (5-HT) and norepinephrine (NE) pathways inhibit the pain signal, preventing these every day inputs from being detected. (c) In fi bromyalgia, the descending 5-HT and NE inhibitions may be lost, allowing every day pain impulses to ascend the spinal cord and be perceived as widespread pain.

The emotional anguish of pain (as

well as the long journey to an accurate diagnosis) is likely to have psychological

ramifi cations.

4. Price DD et al. Pain 2002; 99:49-59.5. Gracely RH et al. Arthritis Rheum 2002; 46:1333-43. 6. Legangneux E et al. Rheumatology 2001; 40:290-296.

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PsychEd Up Volume2, Issue 1

NEI PRESS

- Tips and Pearls -

Brands RemeronGeneric? Yes

Class Alpha 2 antagonist; noradrenaline and specifi c serotonergic agent (NaSSA); dual serotonin and norepinephrine agent; antidepressant

MirtazapineDosing tips and prescribing pearls

Adding mirtazapine’s 5-HT3 antagonism to venlafaxine or SSRIs may reverse drug-induced nausea, diarrhea, stomach cramps, and gastrointestinal side effects

Phentermine, bupropion, venlafaxine, SSRIs, or stimulants may mitigate mirtazapine-induced weight gain

It is less likely that weight gain will occur if it has not occurred by the sixth week of treatment

Has been demonstrated to have earlier onset of action than SSRIs

May be preferable in patients requiring concomitant medications because it does not affect the CYP450 system

Preliminary evidence suggests effi cacy as an augmenting agent to haloperidol in treating negative symptoms of schizophrenia

Anecdotal reports of effi cacy in recurrent brief depression

Mirtazapine-induced weight gain is more likely in women than in men and before menopause rather than after

May cause sexual dysfunction only infrequently

Patients can have carryover sedation and intoxicated-like feeling if particularly sensitive to sedative side effects when initiating dosing

Patients may rarely complain of visual “trails” or after-images on mirtazapine

Dosing TipsSedation may not worsen as dose increases

Breaking a 15 mg tablet in half and administering a 7.5 mg dose may actually increase sedation

Some patients require more than 45 mg daily, including up to 90 mg in diffi cult patients who tolerate these doses

If intolerable insomnia, activation, anxiety, agitation, or akathisia occur either upon dosing initiation or discontinuation, consider the possibility of activated bipolar disorder and switch to a mood stabilizer or an atypical antipsychotic

Prescribing PearlsAdding alpha 2 antagonism to agents that block serotonin and/or norepinephrine reuptake may be synergistic for severe depression

Adding mirtazapine to venlafaxine or SSRIs may reverse drug-induced anxiety and insomnia

Adapted from Stahl SM. Essential Psychopharmacology: The Prescriber’s Guide. Cambridge: Cambridge University Press; 2005. Reproduced by permission of Cambridge University Press. To order, go to: http://us.cambridge.org/titles/catalogue.asp?isbn=0521011698

Stress-Diathesis Model

The infl uence of genetic and environmental interactions upon neurocircuitry and disease is modeled here. The bridge represents the genetic makeup of an individual, with each vertical suspension strut symbolizing a single gene, while the traffi c represents environmental infl uences. If the bridge is intact, then it functions normally and allows various environmental inputs to pass without diffi culty.

Gene/Environment Interactions Gene/Environment Interactions Gene/Environment Interactions

If a few vertical suspension struts are compromised due to alterations in genetic expression or regulation, the functionality of the bridge declines. The degree of decline is dependent upon the weight of the load it is bearing as well as the percentage of struts that have been compromised.

If too many of the struts, or genetic underpinnings, are damaged so too is the functionality of the bridge. The compromised integrity combined with environmental stress may ultimately end in the collapse of the bridge, or, metaphorically, the overtaking by disease.

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January 2006

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PsychEd Up Volume2, Issue 1

NEI PRESS

A new conceptualization of the biological basis of psychiatric disorders has been forming—namely, the idea of “symptoms and circuits.”1-3 Rather than diagnose and treat a psychiatric syndrome, clinicians can deconstruct these disorders into symptoms and then match those individual symptoms to hypothetically malfunctioning neuronal circuits.

Our current understanding of the association between certain

Table 1: “Emotional” Brain Centers1

- Essential PsychopharmaStahlogy -

Symptoms and CircuitsDeconstructing psychiatric disorders to achieve remission

Stephen M. Stahl Meghan Grady Adjunct Professor of Psychiatry, UCSD NEI Staff WriterEditor-in-Chief

Associated Symptom(s)

Depressed mood, guilt, feeling worthless, suicidality

Depressed mood, guilt, feeling worthless, suicidality

Depressed mood, guilt, feeling worthless, suicidality

Guilt, feeling worthless, suicidality

Loss of pleasure, feeling worthless, guilt, suicidality

Loss of pleasure

Figure 1. Projections to “Emotional” Brain Centers

Brain Area

Medial prefrontal cortex

Anterior cingulate cortex

Orbital prefrontal cortex

Amygdala

Nucleus accumbens

Hypothalamus

Noradrenergic projection from the locus coeruleus to the hypothalamus

Serotonergic projections from the midbrain raphe to the hypothalamus

Noradrenergic projections from the locus coeruleus to the amygdala and prefrontal cortex

Serotonergic projections from the midbrain raphe to the amygdala and prefrontal cortex

Dopaminergic projections from the ventral tegmentum to the nucleus accumbens

Figure 2. Projections to “Somatic” Brain/CNS CentersNoradrenergic projection from the locus coeruleus to the hypothalamus

Noradrenergic projection from the locus coeruleus to the cerebellum

psychiatric symptoms and brain regions is demonstrated in Tables 1 through 5. In addition, key neurotransmitter projections for brain regions associated with emotionality are shown in Figure 1, while key neurotransmitter projections for brain regions associated with somatic symptoms are shown in Figure 2, those associated with cognition are shown in Figure 3, and those associated with sleep are shown in Figure 4.

Figure 3: Projections to “Cognitive” Brain Centers

Serotonergic projections from the midbrain raphe to the hypothalamus

Noradrenergic projection from the locus coeruleus to the dorsolateral prefrontal cortex

Histaminergic projections from the hypothalamus to the dorsolateral prefrontal cortex

Dopaminergic projections from the ventral tegmentum to the dorsolateral prefrontal cortex

Figure 4: Projections to “Sleep” Brain Centers

Nigrostriatal dopaminergic projections

Serotonergic projections from the midbrain raphe to the striatum

Serotonergic projections from the midbrain raphe to the spinal cord

Noradrenergic projections from the locus coeruleus

Histaminergic projections from the TMN of the hypothalamus to the VLPO of the hypothalamus

Serotonergic projections from the midbrain raphe to the brainstem

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

TMN: tuberomammillary nucleusLPO: ventrolateral preoptic area

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

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References1. Stahl SM. J Clin Psychiatry 2003;64(11):1282-3.2. Stahl SM. J Clin Psychiatry 2003;64(12):1408-9.3. Stahl SM. J Clin Psychiatry 2004;65(1):8-9.4. Brewin et al. Behav Res Ther 2001;39(4): 373-393.5. Sala et al. Eur Neuropsychopharmacol 2004;14(5): 393-405

Contact Information

5857 Owens Avenue, Suite 102Carlsbad, CA 92008Tel: (760) 931-8857Fax: (760) 931-8713E-mail: psychedup@neiglobal.comURL: www.neiglobal.com

Publication InformationPsychEd Up—ISSN:1553-8907 (print), 1553-8915 (online)—is published monthly by NEI Press. Copyright © 2005, NEI Press. All rights reserved. No part of this publication may be reproduced or transmitted, in any form, by any means, without the prior written permission of NEI Press.

The opinions expressed in this publication are those of contributing authors and do not necessarily refl ect the views of NEI Press. NEI Press will not assume responsibility for damages, losses, or claims of any kind, including direct or consequential damages, arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Doctors recommending and patients using drugs based on information in this publication are strongly advised to pay careful attention to and consult information provided by the manufacturer of any drugs they plan to recommend and/or use.

Additionally, every effort has been made in preparing this publication to provide accurate and up-to-date information in accord with accepted standards and practice at the time of publication. Nevertheless, the psychopharmacology fi eld is evolving rapidly. The authors, editors, and NEI Press therefore (i) make no warranties that the information contained herein is totally free from error, not least of which because clinical standards are constantly changing through research and regulation, and (ii) disclaim any responsibility for the continued currency of this information.

PsychEd Up Staff

Editor-in-Chief Stephen M. Stahl

Managing EditorGerardeen Santiago

Publication EditorAuriana Albert

NEI Staff WritersKatherine J. CarpenterMeghan GradyEleanor RobertsJennifer Stahl

Arbor Scientia Staff WriterDarius Shayegan

Design ArtistsDonny CarpioElizabeth Kim

IllustratorsNancy Muntner

The Bottom Line—The concept of symptoms and circuits may have implications beyond helping to explain the biological basis of symptoms in psychiatric disorders. It may also allow clinicians to base treatment on the specifi c symptom profi le of each patient, rather than select the same treatment for every patient with a particular disorder, since symptoms are associated with divergent parts of the brain and different neurotransmitters project to each of those brain regions. Ultimately, this may optimize the chances of achieving remission of all symptoms and improve patient outcomes.

Table 3: “Cognitive” Brain Centers1,2,4,5

Table 4: “Somatic” Brain/CNS Centers1-2

Table 5: “Sleep” Brain Centers1-2

Brain Area

Dorsolateral prefrontal cortex

Hippocampus

Amygdala

Cerebellum

Motor cortex

Associated Symptom(s)

Problems concentrating, mental fatigue, executive dysfunction

Problems with declarative memory

Problems with procedural memory

Problems with procedural memory

Problems with procedural memory

Brain Area

Hypothalamus

Striatum

Cerebellum

Spinal cord

Associated Symptom(s)

Weight change

Physical fatigue, psychomotor agitation/retardation

Physical fatigue, psychomotor agitation/retardation

Physical fatigue, pain

Brain Area

Hypothalamus

Brainstem sleep centers

Associated Symptom(s)

Sleep disturbance

Sleep disturbance

Table 2: “Anxious” Brain Centers2

Brain Area

Medial and orbital prefrontal cortex

Amygdala

Striatum

Thalamus

Hippocampus

Brainstem areas

Associated Symptom(s)

Panic, phobia, anxious misery, apprehension, obsessions

Panic, phobia, re-experiencing

Anxious misery, apprehension, obsessions

Anxious misery, apprehension, obsessions

Re-experiencing

Autonomic responses

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PsychEd Up Volume2, Issue 1

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