CASE REPORT Serotonin Responsive and Nonresponsive Diurnal Depressive Mood Disorders and Pathological Affect in Thalamic Infarct Associated with Myoclonus and Blepharospasm Edward C. Lauterbach, Spencer T. Price, T. Elisabeth Spears, Joseph G. Jackson, and Alan D. Kirsh Key Words: Depression, pathological affect, thalamus, serotonin (5HT2), fluoxetine, anxiety Introduction A patient with a central thalamic infarct developed several affectire and anxiety disorders that responded differentially to serotoninergic and nonserotoninergic antidepressants. This case, compatible with recent positron emission tomography (PET) data, offers a clinical window to the pathophysiology of mood dysregalation. Case Report A 62-year-old Caucasian woman developed acute poststmke delirium with visual hallucinations, resolving within ! week. Magnetic resonance imaging (MRI) disclosed a l-cm right thalamic lacunar infarct (Figure 1). Major depression and generalized anxiety disorder symptoms evolved 1 year later. Past psychiatric history revealed only lifelong claustrophobia. Depressive phenomena included diurnally varying morning depression, fully remitting by mid-afternoon. Although morning depression did not worsen, depressive symptoms gradually progressed over the next 6 months (18 months post infarct) to involve late afternoons and evenings, with evening depressive severity From the Department of Psychiatry & Behavioral Sciences (ECL, STP. TIES) and Department of Radiology (JGJ, ADK) of Mercer University School of Medicine and the Medical Center of Central Georgia (JGJ, ADK). Macon, GA. Address reprint requests to Edward (2. Lauterbach. MD, Associate Professor of Psychiatry (Neumpsychial~). Deparlment of Psychiatry & Behavioral Sciences. Mercer University School of Medicine. 1500 College Street, Macon. GA 31207. Received July 15,1993; revised October 18.1993. © 1994 Society of Biological Psychia~ equal to moming severity. Static depressive symptoms included loss of interest, insomnia, worthlessness, death wish, and low mood. Hamilton Depression Rating Scale was 18, Beck Depression Inventory (BDI) 16, and Mayeux-modified minimental state exam 52/57 (Mayeux et al 1981). Superimposed on this stable background were labile episodes of much more severe depressed mood, appetite surge, anhedonia, amotivation, and anergia developing acutely (within 24 hr) and continuing several weeks with sudden offset, unrelated to medication or psychosocial stressors. Also present after, but not before, infarction were pathological affect, word-finding, nonperiodic myoclonns (20 jerks over 30 rain when drowsy), blepharospasm, left-sided motor impersistence, dysdiadocbokinesia and dyscoordination. Treatment commenced with fluoxetine 20 mg/day. In 6 weeks the patient experienced full recovery from anxiety, pathological affect, word-finding, insomnia, and all morning and early afternoon depressive symptoms (BDI = 1). Labile depressive episodes ceased entirely. Evening depressive symptoms of low mood, anergia, amotivation, loss of interest, and anhedonia persisted without any improvement (evening BDI = 15). Increasing fluoxetine to 40 mg/d for 30 days produced no improvement and led to nausea and headache. The addition of a 2-week trial of lithium carbonate 300 tug each day led to a several hour prolongation of the morning response within 5 days. The evening syndrome now presented at 6 or 7 PM instead of 3 or 4 PM. A trial of 600 rag of lithium led only to tremor, increased dyscoordination, and sedation necessitating discontinuation after 10 days, with no further prolongation of response on this higher dose. Lithium was discontinued. Triiodothyronine 100 tzg each morning for 2 weeks 0006-3223/94/$07.00 Case Report Figure 1. T2-weighted magnetic resonance imaging (SE 2000/70) depicting right central thalamic infarct. produced no improvement. Triiodothyronine was discontinued and bupropion 100 mg at 3 PM each afternoon was started for a 4-week trial, in combination with the fluoxetine. Within 4 weeks, the patient noticed partial ("70%") remission of the evening syndrome, along with short-lived side effects of drowsiness and "jitteriness" without evident tremor. Bupropion was increased to 100 p,g twice daily with fluoxetine 20 mg each morning for 2 more weeks with remission of the evening syndrome, excepting anergia and amotivation, which were only "80%" remitted (BDI = 3). Fluoxetine was discontinued and the patient was maintained on bupropion 100 mg tid alone for 4 weeks. The morning syndrome quickly relapsed within 2 weeks, remedied by fluoxetine reinstatement, whereas the evening syndrome gradually remitted fully. Bupropion was discontinued and the evening syndrome gradually relapsed within 3 months. Discussion At issue are thalamic lesion anatomy, pathophysiology, and the differential pharmacologic responses. We inferred specific thalamic nuclei involvement by comparison of the MRI with a brain atlas section in a similar plane (Miller and Burack 1982). The lesion probably involved centromedian, anterolateral pulvinar, internal medullary lamina, posterior lateral, inferoposterolateral dorsomedial, medial intermediate ventral, and medial posterolateral ventral thalamic nuclei. Clinically, blepaharospasm, myoclonus, and cerebellar features suggest centromedian (Alexander and Crutcher 1990), puivinar and posterior association (Avanzini et al 1977), and ventral lateral posterior (Jones 1985; Eiras and Garcia Cosamalon 1980) nuclei pathology. Assuming reliable anatomical and clinical correlation, thalamocortical pathways to SlOLPSYCHIATRY 1994~35:488-.490 489 cingulate, medial frontal, laterofmntal, motor and sensory cortex (Jones 1985) may be affected in this patient. Some of these pathways may be important in affcctive regulation, as discussed below. Pathophysiologically, lesions of these thalamic nuclei would diminish thalamocortical activity (Alexander and Crutcher 1990), compatible with cortical hypometabolism in depression (Baxter et al 1989) and, presumably, in pathological affect (Lauterbach and Schweri 1991). Both pathological affect (Seliger and Hornstein 1989; Lauterbach and Schweri 1991) and depression are reversible with serotonin reuptake inhibitors, perhaps improving this state (Mayberg et al 1988). In support, postthalamotomy depression occurs with pulvinar lesions (Angelini et al 1982). In further support, resulting pallidal disinhibition leading to excessive inhibition of these thalamic nuclei (Alexander and Crntcher 1990) could result in depression following caudate lesions (Starkstein et al 1988). As an alternative hypothesis, however, loss of inhibition on certain intact thalamocortical pathways remote to the infarct (possibly orbitofrontal thalamocortical neurons) might also lead to depression (Lanterbach et al 1992). The greater frequency of depression following left-sided caudate lesions than following thalamic lesions (Starkstein et al 1988) may rely on these intact thalamocortical pathways to mediate depressive pathophysiology. Ablation of these pathways might explain the lower prevalence of depression after thalamic lesions than after caudate lesions. In summary, although a lesion of pulvinar, centromedian, or other thalamic nuclei is a likely basis for depression in this patient, disinhibition of orbitofrontal thalamoconical pathways remote to the infarction might also be explanatory. Differential pharmacological responses of the affective disorders argue against a single slowly evolving depressive disorder. The patient developed two different diurnally varying mood disorders, one presenting soon after the stroke affecting daytime functioning, which was fluoxetine responsive and another presenting months later affecting evening functioning which was fluoxetine nonresponsive. Serotonin 5HT2 receptor binding increases after right hemispheric infarcts, although 5HT2 binding did not correlate with depression in those cases (Mayberg et al 1988). It is possible in our patient, however, that the early-onset daytime depressive syndrome and pathological affect, both responding to fluoxetine, do relate to serotonin insaffciency after right thalamic infarct (compatible with 5HT2 upregnlation), whereas the later-onset evening depression may have a differing (non.5HT2.1inked) pathophysiology, also suggested by Mayberg and colleagues. The response of the evening syndrome to bupropion but not to fluoxetine or lithium might suggest possible dopaminergic insufficiency. Neither myoclonns nor blepharospasm were altered by treatment although anxiety and depression occur in cranial dystonia (including blepharospasm) and may reflect the proximity of motor and affective circuits (Alexander et al 1986; Lauterbach et al 1992). This case suggests differential pharmacological, neuronal, and phenomenological subtypes of' mood disorders and affective dysregnlation following a central thalamic infarct. It suggests that the study of thalamic lesions may yield a better understanding of depressive pathophysiology. Thisresearchwassupportedin partbyGrant# 16-12!-50fromtheMedCen FoundationClinicalResearchCenter,Macon,Georgia. The authorsalsowishto thankFayeFrazierforpreparationof Figure1. 490 toOLPsYcmATeY 1994;35:488--490 Case Report References Alexander GE, Crutcher btD (1990): Functional architecture of basal ganglia circuits: Neural substmtes of parallel processing. Trends Neurosci 13:266-271. Alexander GE, DeLong MR, Snick PL (1986): Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9:357-381. Angelini L, Nardocci N, Bono R, Broggi G (1982): Depression after stereotactic thalamotomy in patients with abnormal movements. Itai 3 Neuroi Sci 3:301-310. Avanzini G, Broggi G, Caraceni T (1977): Intention and action myoclonus from tbalamic angioma. Fur Neuro115:194-202, Baxter LR Jr, Schwartz JM, Phelps ME, et al (1989): Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry 46:243-250. Eiras J, Oarcia Cosamalon J (1980): Post-traumatic myoclonic syndrome, Arch Neurobio14 3:17-28. Jones EG (1985): The Thalamus. New York: Plenum Press. Lauterbach EC, Schweri MM (1991): Amelioration of pseudobulbar affect by fluoxetine: Possible alteration of dopamine- related pathophysiology by a selective serotonin uptake blocker. Y Clin Psychopharmacol 11:392-393. Lauterbach EC, Spears TE, Price ST (1992): Bipolar disorder in idiopathic dystonia: Clinical features and possible neurobiology. J Neuropsychiatry Clin Neurosci 4:435-439. Mayberg HS, Robinson RG, Wong DF, et al (1988): PET imaging of cortical $2 serotonin receptors after stroke: Lateralized changes and relationship to depression. Am J Psychiatry 145:937-943. Mayeux R, Stem Y, Rosen J, Leventhal J (1981): Depression, intellectual impairment, and Parkinson disease. Neurology (NY) 31:645-650. Miller RA, Burack E (1982): Atlas of the Central Nervous System in Man. 3rd ed. Baltimore: Williams & Wilkins. Seliger GM, Homstein A (1989): Semtonin, fluoxetine, and pseudobolbar affect. Neurology 39:1400. Starkstein SE, Robinson RG, Berthier ML, Parikh RM, Price TR (1988): Differential mood changes following basal ganglia vs thalamic lesions. Arch Neuro145:725-730.