CONTENTS · 2009-08-04 · logical myodesopsia or visual impairment when blood covers the macula....

Vol.45, No.1 January 2002

CONTENTS

JMAJJapan Medical Association Journal

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Visual Disorder

Guidelines for the Management of DiabeticRetinopathy for the Internist

Sadao HORI ................................................... 1

Glaucoma

Yasuyuki SUZUKI ........................................ 8

Exudative Age-related Macular Degeneration

Mitsuko YUZAWA........................................ 13

Depression

Clinical Characteristics of Depression

Arata SATO and Shin IHDA...................... 21

Drug Therapy for Depression in Japan

Makoto KAMIMURA and Anri AOBA... 28

Low Birth Society

Expectations of a Low Birth Society—From the Perspective of Historical Demography—

Hiroshi KITO ................................................. 34

JMAJ, January 2002—Vol. 45, No. 1 1

This article is a revised English version of a paper originally published inthe Journal of the Japan Medical Association (Vol. 123, No. 3, 2000, pages 365–369).

Guidelines for the Management of DiabeticRetinopathy for the InternistJMAJ 45(1): 1–7, 2002

Sadao HORI

Professor, Department of Ophthalmology, Tokyo Women’s Medical University

Abstract: Diabetic retinopathy is classified into three stages based on the stageof progression of the disease—background (simple), preproliferative and prolifera-tive. The earliest stage is called background diabetic retinopathy and is character-ized by dot or blot hemorrhages and microaneurysms associated with retinal micro-vascular lesions which are closely related to hyperglycemia. With the developmentof retinal capillary obstruction, background diabetic retinopathy progresses to thestage of preproliferative diabetic retinopathy, in which avascular zones can bedetected by fluorescein angiography. In proliferative diabetic retinopathy, whichdevelops with further progression of the disease, newly formed blood vessels,vitreous hemorrhage, and retinal detachment produce severe visual loss. Goodblood sugar control is essential for preventing the development and progression ofdiabetic retinopathy; therein lies the important role of the internist. In the stages ofpreproliferative and proliferative retinopathy, patients should be referred to theophthalmologist for laser photocoagulation and vitrectomy. Patient education isimportant to prevent blindness resulting from diabetic retinopathy. Diabetic patientsshould be aware that diabetic retinopathy may lead to blindness. It must be empha-sized that diabetic retinopathy generally causes no visual symptoms in its earlierstages and that, therefore, periodic funduscopy is necessary to detect the changesof retinopathy. In patients who are at a relatively lower risk of becoming blind,funduscopy with the use of polaroid photography could be extremely useful.

Key words: Pathology and stages; Control of blood glucose levels;Patient education for periodic ophthalmologic examination;Frequency of follow-up and stages

and the ophthalmologist. I hope that this articlewill equip the internists with sufficient basicknowledge of the important issues related tothe ophthalmologic treatment of diabetic retino-

Introduction

Medical care of patients with diabetic retino-pathy requires the collaboration of the internist

�Visual Disorder

2 JMAJ, January 2002—Vol. 45, No. 1

S. HORI

pathy to prepare them for patient education.

Disease Status and the Stage ofDisease in Diabetic Retinopathy

The pathophysiology of diabetic retinopathyis explained to facilitate the management andtreatment of the disease.

1. Stage before the development of diabeticretinopathy

Diabetic retinopathy is diagnosed when abnor-malities are observed on macroscopic examina-tion by a funduscopy. However, microstructuralor functional changes have already occurredbefore macroscopic fundus abnormalities aredetected.(1) Microstructural abnormalities

Diabetic retinopathy is essentially a retinalmicrovascular disease developing after pro-longed hyperglycemia.1) The walls of smallblood vessels are composed of endothelial cellslining the basement membrane and surround-ing pericytes.

Elevated blood glucose levels promote throm-bus on the surface of the endothelial cells andnecrosis of the pericytes, resulting in circulatorydisturbance of retinal capillary. In addition,thickening and loss of elasticity of the basementmembrane occurs, inducing circulatory obstruc-tion (Fig. 1).(2) Functional abnormalities

Among the microvascular lesions describedabove, injury to endothelial cells may lead tobreakdown of the blood-retinal barrier (BRB).BRB, which is similar to the blood-brain bar-rier, prevents leakage of high-molecular-weight

proteins or lipids into the extravascular spaceand maintains intraretinal homeostasis. Break-down of the BRB due to endothelial injurycauses extravasation of plasma proteins andlipids. While severe damage to the BRB canbe detected by funduscopy, even slight func-tional deterioration may be detected by vitre-ous fluorophotometry.2)

Neuropathy in diabetics sometimes precedesthe onset of retinopathy and often involves theretinal nerve cells. In some diabetic patients,abnormal waveforms can be observed on theelectroretinogram (ERG) even before diabeticretinopathy is detected.3)

2. Simple diabetic retinopathyChronic hyperglycemia affects the retinal

microvessels and facilitates progression of thedisease. The earliest manifestation is damageto the retinal vascular walls, which results inmicrovascular obstruction. Damage to the micro-vessels triggers the formation of microaneurysmsand rupture of the vascular walls, observed asdot or blot hemorrhages in the retina.

Breakdown of the BRB causes the retinaledema and promotes the formation of lipiddeposits, mainly consisting of cholesterol derivedfrom the plasma. These yellow-white lesions,called hard exudates, can be identified by fun-duscopy. When microvessel obstruction pro-duces focal ischemia, pallor and/or edema ofthe retina develops. These ischemic foci arereferred to as soft exudates.

3. Preproliferative diabetic retinopathyPreprolifertative retinopathy is a more severe

form of diabetic retinopathy than simple retino-

Thickened basement membrane

Endothelial lesions

Pericyte necrosis

Thrombus formation

Fig. 1 Microvascular abnormalities occurring before the development of diabetic retinopathy


MANAGEMENT OF DIABETIC RETINOPATHY

pathy, and often progresses to proliferative dia-betic retinopathy. Ischemia due to microvascu-lar occlusion or leakage of plasma constituentsstimulates the release of cytokines, particularlyvascular endothelial growth factor (VEGF),which acts as an intercellular mediator in vari-ous ways.

VEGF facilitates the proliferation of endo-thelial cells and promotes neovascularization.4)

New vessels are thus prone to form in areas ofischemia or leakage. Preproliferative changessignify the risk of progression to the stage oftissue proliferation, or proliferative diabeticretinopathy.

In the preproliferative stage, the funduscopicfindings are characterized by an increased num-ber of soft exudates in association with micro-vascular occlusions and intraretinal micro-vascular abnormalities (IRMA), consisting ofirregular segmental dilatations or abrupt reduc-tion in vessel branching around occluded ves-sels. Fluorescein angiography clearly depictsareas of microvascular occlusion as blackouts,since contrast medium does not enter infarctedregions (Fig. 2).

In fluorescein angiography, the patient isadministered 5 ml of 10% sodium fluorescein

intravenously. Immediately after the injection(in about 10 seconds or less), sequential photo-graphs are taken for up to 10 minutes. Theseprocedures cause a sensation of glare in theeyes of the patient. The dye is hepatotoxic andfluorescein angiography should not be per-formed in patients with severe hepatic insuffi-ciency. The dye should also not be administeredto patients in poor general condition, since ana-phylactic shock has been reported in a fewcases.

4. Proliferative diabetic retinopathyWith the formation of new blood vessels,

diabetic retinopathy shows markedly differentpathological features compared to previous twostages. In this stage, lesions are seen extendingfrom the retina to the vitreous. New abnormalvessels form in areas adjacent to occluded ves-sels and grow out of the retinal surface into thevitreous. These new vessels radiate throughoutthe vitreous, running along the posterior hya-loid membrane at the border of the vitreousand the retina or infiltrating into the center ofthe vitreous.

Because of their fragility, newly formed ves-sels easily rupture with increase in the blood

Fig. 3 Vitreous hemorrhage in proliferative diabeticretinopathy

Preretinal hemorrhage spread the upper half of the fundus.

Fig. 2 Fluorescein angiograph revealing occlusion ofretinal capillaries

Occluded areas are visible as blackouts surrounded bydilated or tortuous vessels (intraretinal microvascular abnor-malities, IRMA)


pressure or traction from the vitreous andbleed into the vitreous (Fig. 3), causing patho-logical myodesopsia or visual impairmentwhen blood covers the macula. New vesselsinduce gradual proliferation of connective tis-sue, mainly consisting of collagen fibers, whichproliferates along the surface of the retina as afibrous proliferative membrane. The prolifera-tive membrane is adherent to the surface of theretina. Contraction of the proliferative mem-brane causes traction on the retina, resulting inretinal detachment which may result in severevisual loss when the detachment reaches themacula.

If vitreous hemorrhage interferes with fundusexamination, echography must be performedto detect retinal detachment and examine theintraocular condition.

Treatment According to the Stages ofthe Disease

1. Stage before the development of diabeticretinopathy

Even at this stage, it is important to takemeasures to prevent the development of dia-betic retinopathy. Control of blood glucoselevels is essential and the internist plays aleading role.

Many cohort studies in the United States andEurope have shown that strict control of bloodglucose levels is of critical importance in pre-venting the development of diabetic retino-pathy and it has been recommended that theblood glucose levels be maintained within thenormal range as far as possible.5,6) In addition,diabetic patients with hypertension shouldreceive effective antihypertensive treatment,since many researchers have indicated thathypertension greatly influences the progres-sion of the disease in type 2 diabetic patients.6)

Although a number of clinical studies havebeen conducted with a view to finding a newdrug for preventing the development and pro-gression of diabetic retinopathy,7) at present,no drug effective for this purpose is available.

This suggests that many factors are involved inthe pathogenesis of diabetic retinopathy andthat no single drug can solve all the problemsrelated to the disease.

2. Simple diabetic retinopathyDamage due to aneurysms, dot/blot hemor-

rhages, hard exudates, and a small number ofsoft exudates are pathological condition of sim-ple diabetic retinopathy, and these are revers-ible under good control of blood glucose levelsby the guidance of the internist. Drugs areavailable for the symptomatic treatment ofhemorrhages or exudates, but no medicines,as mentioned before, have been shown toinfluence the disease course itself.

When retinal edema due to increased capil-lary permeability extends to the macula, severevisual loss becomes inevitable. While drug ther-apy may be somewhat useful, the ophthalmol-ogist plays an important role in preventing theprogression of macular edema and reducingits severity. At present, laser photocoagulationand vitrectomy are performed at this stage.Photocoagulation should be initiated in time,preferably before the onset of impairment ofmacular functions.8)

Vitrectomy may reduce the severity of macu-lar edema. The technique has been increasinglyapplied to the treatment of macular edemawhen the condition is too severe to performlaser surgery.9) However, even when the edemais relieved, visual loss often does not improvein patients with severe macular edema. Someinvestigators have recommended vitrectomyeven in the earlier stages of macular edema,but this is still controversial.

3. Preproliferative diabetic retinopathyIn this stage, treatment is focused on the pre-

vention of neovascularization. As new vesselsdevelop in areas of retinal vessel occlusion,laser photocoagulation on the occluded areahas been shown to be useful for the preventionof neovascularization. This is a bloodless opera-tion and can be performed on an outpatient

S. HORI


basis. The usefulness of this intervention hasbeen demonstrated in several clinical trials andits success rate in the prevention of severediabetic retinopathy and blindness has beenreported to be 70 to 90%.10)

At this stage, conservative medical treat-ment instead of laser surgery may increase therisk of blindness and impair the chances ofimprovement of the disease.

4. Proliferative diabetic retinopathyEven at this stage, if neovascularization is

mild or moderate, laser therapy may be effec-tive. However, when vitreous hemorrhage orretinal detachment is detected, vitrectomy isrecommended. Vitrectomy requires special sur-gical skill and expensive equipments.

Recently, the success rate of vitrectomy hasimproved with technical advances and the devel-opment of elaborate devices, but the operationis still challenging and the success rate isnot high enough around 80%. Several studieshave demonstrated a better outcome whenvitrectomy is performed at the stage of mildretinal dysfunction and have recommendedearly vitrectomy.

Guide to the Management of DiabeticRetinopathy for the Internist

1. Blood glucose levels control is the keyTreatment of diabetic retinopathy is based

on good control of blood glucose levels. It isessential to maintain good control of blood glu-cose levels without interruption and to neverleave hyperglycemia untreated. The first step inthe management of diabetic retinopathy by theinternist is to make the patient aware of howserious the complications could be.

2. Subjective symptoms are not reliableindicators for the detection ofdiabetic retinopathy

The patients do not complain any symptomsuntil diabetic retinopathy progresses to theadvanced stage. When vitreous hemorrhage,

retinal detachment and severe macular edemaoccur, the patient may develop visual loss.Macular edema commences even at the earlierstage of simple diabetic retinopathy, and themorbidity of macular edema becomes worseand the condition becomes more severe as theretinopathy progresses.

Vitreous hemorrhage often provokes patho-logical myodesopsia or blurred vision, whileretinal detachment may induce visual loss orvisual field defects. However, by the time thepatient develops these symptoms, the diseasehas become far advanced and the risk of blind-ness is substantially high at this stage. Diabeticpatients should thus be encouraged to undergoperiodic ophthalmologic examination, even ifthey have no visual symptoms.

3. Follow-up with polaroid photographyFundus photographs provide a permanent

record for later evaluation and can be studiedby the same ophthalmologist or other special-ists. Polaroid photography offers the additionalbenefits of instantaneous development and print-ing on the spot, and the patient does not haveto wait for the results till the next visit. For theinternist, fundus photographs obtained imme-diately are very useful for clearly explainingthe current status of the disease to the patient.However, this simple technique also has thefollowing disadvantages:

The image quality of polaroid photographs isgrainy and sometimes there are inconsistenciesin printing. Thus, tiny lesions in the earlierstages or subtle vascular changes are often notclearly detected.

The angles at which fundus photographs canbe taken are limited, and only areas of the pos-terior pole at 45 degrees can be photographed.Lesions in the earlier stages of diabetic retino-pathy are mainly noted on the nasal side of theoptic disc, and photographs limited to areas sur-rounding the macula often miss severe lesionsin other areas.

Accordingly, polaroid photography is accept-able for excluding the disease in low-risk groups



with good control of blood glucose levels inwhom no fundus abnormalities have beendetected by complete funduscopy in the previ-ous one or two years.11)

However, if any minor hemorrhage or lesionsare detected, the patient should be referredto the ophthalmologist for a thorough fundusexamination.

4. Frequency of the follow-up of funduscopyaccording to the stage of the disease

Diabetic retinopathy may progress differ-ently according to the stages. The frequency offunduscopic follow-ups should be determinedaccording to the stage of the disease in indi-vidual cases (Table 1). The internist shouldfully understand the status of the disease ineach patient and refer the patient to the oph-thalmologist when necessary, so as to offertimely intervention and prevent blindness.

Conclusion

This article describes the different stages ofprogression of diabetic retinopathy, and pro-vides guidelines to the internist for the manage-ment of the disease. I hope that these descrip-tions will equip the internist with the basicknowledge for the treatment of patients withdiabetic retinopathy.

REFERENCES

1) Hori, S. and Okisaka, S.: Funduscopic changesand pathophysiology of diabetic retinopathy.

Table 1 Frequency of Funduscopic Follow-ups in Diabetic Patients According to the Stage of the Disease

1. No diabetic retinopathy Once a year

2. Simple diabetic retinopathy Once in 3 to 6 months

3. Preproliferative diabetic retinopathy Once in 2 months*

4. Proliferative diabetic retinopathy Once in 2 to 4 weeks*

Note) *: When the progression of the disease is stabilized by photocoagulation or vitrectomy,fundus examination once in 2 to 4 months is acceptable.

Hori, S. ed., Ophthalmology, Mook 46, Diabe-tes and Practice in Ophthalmology. Kanehara-Shuppan, 1991; pp.53–63. (in Japanese)

2) Gunha-Vaz, J.T. et al.: Early breakdown ofblood-retinal barrier in diabetes. Br J Oph-thalmol 1975; 59: 649–656.

3) Tanabe, J.: Electrophysiology in retinopathy.Tano, Y. ed., Practice in Ophthalmology 20,Practice in Diabetic Ophthalmology. Bunkodo,1995; pp.165–167. (in Japanese)

4) Funatsu, H., Hori, S., Yamashita, H. et al.:Effective mechanism of laser photocoagula-tion for neovascularization in diabetic retino-pathy. J Jap Ophthalmol Soc 1996; 100: 339–349. (in Japanese)

5) The Diabetes Control and Complications TrialResearch Group: The effect of intensive insu-lin treatment of diabetes on the developmentand progression of long-term complications ininsulin-dependent diabetes mellitus. New EnglJ Med 1993; 329: 977–986.

6) UK Prospective Diabetes Study Group: Tightblood pressure control and risk of microvascu-lar and macrovascular complications in type 2diabetes: UKPDS 38. BMJ 1998; 317: 703–712.

7) Solbinil Retinopathy Trial Research Group: Arandomized trial of Solbinil, an aldose reduc-tase inhibitor, in diabetic retinopathy. ArchOphthalmol 1990; 108: 1234–1244.

8) Early Treatment Diabetic Retinopathy StudyResearch Group: Treatment techniques andclinical guidelines for photocoagulation of dia-betic macular edema. Ophthalmology 1987; 94:761–774.

9) Tachi, N. and Ogino, N.: Vitrectomy for diffusemacular edema in cases of diabetic retino-pathy. Am J Ophthalmol 1996; 122: 258–260.(in Japanese)

10) Ando, N.: 2. Photocoagulation and cryocoagu-

S. HORI


lation. Hori, S. ed., Ophthalmology, Mook46, Diabetes and Practice in Ophthalmology.Kanehara-Shuppan, 1991; pp.134–143. (inJapanese)

11) Totani, R., Shimizu, A., Morita, C. et al.: Detec-tion of diabetic retinopathy by non-mydriatic


fundus photography in patients free of retino-pathy for more than one you. J Eye 1992; 9:1705–1708. (in Japanese)

Reference document:Hori, S. ed.: Diabetic Ophthalmology, One task aday. Medical Aoi-Shuppan, 1996. (in Japanese)


GlaucomaJMAJ 45(1): 8–12, 2002

Yasuyuki SUZUKI

Assistant Professor, Department of Ophthalmology,University of Tokyo School of Medicine

Abstract: Glaucoma is a disease characterized by “glaucomatous optic discatrophy” such as enlargement of the cupping of optic disc and retinal nerve fiberdefects, with resultant visual field defect. Visual field defect gradually progresses inan irreversible manner, ultimately leading to blindness. While a high intraocularpressure (IOP) is the greatest and most decisive risk factor in its development andprogression, glaucoma is not rare in patients with IOP within the normal range(21mmHg or lower). Therefore, high IOP is not a prerequisite for the diagnosis ofglaucoma. Glaucoma is roughly classified into open-angle glaucoma and angle-closure glaucoma, according to the size of the chamber angle that is formed by thecornea and the iris. Congenital glaucoma that develops immediately after birthor by the age of 2 or 3 years is classified separately. Since the cause, clinicalcourse, and treatment policy may vary depending on the disease type, each typeof glaucoma should be treated in a different way. Among these, the most commontype of glaucoma is open-angle glaucoma. Open-angle glaucoma should be firsttreated in a conservative manner by pharmacotherapy. When pharmacotherapyfails to prevent progression of the disease, laser therapy and invasive surgicaltherapy should be considered.

Key words: Glaucoma; Optic disc; Visual field defect;Open-angle glaucoma; Angle-closure glaucoma

Definition of Glaucoma and ItsChanges

Glaucoma is a disease in which visual infor-mation obtained by retinal neurons cannot reachthe brain due to damage of the retinal nervefiber axons at the optic disc (Fig. 1), and is char-

This article is a revised English version of a paper originally published inthe Journal of the Japan Medical Association (Vol. 124, No. 12, 2000, pages 1725–1728).The Japanese text is a transcript of a lecture originally aired on September 12, 2000, by the Nihon ShortwaveBroadcasting Co., Ltd., in its regular program “Special Course in Medicine”.

acterized by visual field defect (Fig. 2). Second-ary to axonal damage, the death of retinalganglion cells and ganglion cells in the lateralgeniculate body is induced by the mechanismof apoptosis.

One of the most well-known causes of glau-coma is elevation of the intraocular pressure


(IOP). In the past, glaucoma was regarded as acondition in which elevation of the IOP eleva-tion resulted in visual functional disorder. Theterm “glaucoma” is believed to have been firstused by Hippocrates around 400 B.C. to refer to

eyes that have turned blue-green due to highIOP and opacity of the cornea.

In recent years, however, many patients withIOP within the normal range, i.e., not higherthan 21 mmHg, have been encountered whoexhibit almost the same visual disc atrophicchanges and resultant visual field defects asthose induced by high IOP. Thus, currently,high IOP is no longer included in the definitionof glaucoma.

Prevalence of Glaucoma

According to a national epidemiological sur-vey conducted in 1988 and 1989,1) the pre-valence of glaucoma in the population agedover 40 years is 3.56%, and the actual numberof patients in Japan is estimated to be abouttwo million. Open-angle glaucoma, or so-calledchronic glaucoma accounts for three-quartersof these patients, and normal-tension glaucomawith IOP within the normal range accounts formore than two-thirds of the patients (Table 1).

After diabetic retinopathy, glaucoma is thesecond most common cause of blindness inadvanced countries, and it is predicted that itwill become the most common cause of blind-ness in the near future.2)

Causes of Glaucoma

As mentioned earlier, high IOP is the mostimportant cause of glaucoma. When the opticdisc becomes unable to resist the pressure load-

Fig. 1 Optic disc in a case of glaucomaEnlargement of the cupping is noted.

Fig. 2 Results of perimetry in a case of glaucomapresented in Fig. 1

Visual field defect (black area) corresponding to atrophy of theoptic disc is noted.

Table 1 Prevalence of Glaucoma in the Population AgedOver 40 Years1)

Disease type Prevalence (%)

Primary open angle glaucoma 0.58Normal-tension glaucoma 2.04Primary angle-closure glaucoma 0.34Secondary glaucoma 0.32Capsular glaucoma 0.16Others 0.12

GLAUCOMA


number of cases diagnosed.

Classification of Glaucoma (Table 3)

Glaucoma can be roughly classified into open-angle glaucoma and angle-closure glaucoma.In addition, glaucoma that develops immedi-ately after birth or by the age of 2 or 3 years isdistinguished as congenital glaucoma.

While primary glaucoma without specificcause accounts for the majority of the cases,glaucoma resulting from uveitis, injury or IOPelevation induced by steroid eyedrops, or othercauses is classified as secondary glaucoma.

Symptoms and Natural Course

Naturally, chronic cases and acute cases muchdiffer in the symptoms and natural course.

In the cases with sudden IOP elevation, suchas attacks of acute angle-closure glaucoma,marked ocular pain, congestion, declined visualacuity, headache, nausea, and vomiting occur.Persistent IOP elevation at such high levels forseveral days could lead to blindness. If immedi-ately treated by pharmacotherapy and surgicaltherapy, the condition could be cured with al-most no sequelae or only mild visual field im-pairment and irregularity of the pupil. However,severe IOP elevation may impair the aqueousoutflow, and the possibility of re-elevation ofIOP on a subsequent occasion should be bornein mind.

ing of increased IOP, atrophy in a characteristicshape accompanying enlargement of the opticdisc cupping develops (Fig. 1), and axonal dis-order occurs. However, glaucoma may developeven when the IOP is within the normal range.Impairment of the blood flow into the opticdisc and fragility of the optic disc due to someunknown reasons have also been suggested aspossible causes of glaucoma other than highIOP.

The occurrence of glaucoma is relativelystrongly related to genetic factors. The brothersand sisters of patients with open-angle glau-coma have a 25–35% risk of developing glau-coma, although the figures vary among reports.Primary angle-closure glaucoma is also associ-ated with a high risk of occurrence in siblings,because this disease is related to the morphol-ogy of the eye.

As a result of recent linkage analyses, numer-ous genes and loci responsible for glaucomahave been discovered. While great advances inthis area are expected in the future, cautionmust be exercised before informing the patientsabout the genetic risks of the disease as it maycause severe anxiety in the patients and theirfamilies. Appropriate systems for supportingthe patients, such as genetic counseling, need tobe established.

The genes and loci responsible for glaucomathat have been identified to date are listed inTable 2. Diagnosis by screening for geneticvariations is possible in about 3% of the total

Table 2 Genes and Loci Responsible for (Primary) Glaucoma Identified to Date

Disease type Loci Position on the chromosome Causative gene

Primary open angle glaucoma GLC1A 1q24.3-q25.2 MYOCGLC1B 2 cen-q13GLC1C 3q21-q24GLC1D 8q23GLC1E 10p15-p14GLC1F 7q35-36

Congenital glaucoma GLC3A 2p21 CYP1B1GLC3B 1p36

Y. SUZUKI


On the other hand, when the glaucoma fol-lows a chronic course without marked IOPelevation, the patients are usually unaware ofthe condition during the early stages. Impair-ment of the retinal nerve fiber axons at the opticdisc progresses gradually. It is often marked atthe top and bottom areas of the cribriformlamina of the optic disc that are structurallyweak. The visual field impairment correspondswith this disorder. Relative scotoma appearson the superior and inferior nasal sides and inBjerrum area 10 to 20° away from the point offoveal fixation, and gradually enlarges to prog-ress to absolute scotoma. Patients are not awareof the visual field defect until very late stages ofthe disease, because the central visual field ispreserved to a considerable extent until thelate stage of the disease.

The visual field defect progresses graduallyuntil only the central visual field and a smallarea of the temporal visual field is preserved. Inthe advanced stage, the central visual field isalso lost and the visual acuity declines at thisstage. Unfortunately, however, when the condi-tion is discovered at this late stage, the prog-

nosis is not good. Although some part of thetemporal visual field remains until the very latestage, the visual acuity achieved by this visualfield is 0.1 or less.

Diagnosis of Glaucoma

Glaucoma is usually diagnosed on the basisof tonometry, optic disc findings, and perimetry.High IOP is an obvious risk factor of glaucoma.When the IOP is much higher than the upperlimit of the normal, i.e., greater than 21 mmHg,for example, higher than 30 mmHg, a high like-lihood of development of glaucoma should beborne in mind even if the optic disc findingsand perimetric findings are normal, and treat-ment should be started.

Thus, tonometry is crucial for the diagnosisof glaucoma. However, tonometry alone is in-sufficient. As discussed at the beginning of thisarticle, glaucoma is defined as impairment ofthe retinal ganglion cell axons at the optic discand resultant visual field defects, and the dis-ease is not diagnosed unless both of these ab-normalities are observed. More specifically,

Table 3 Classification of Glaucoma

Primary open angle glaucoma

Normal-tension glaucomaOpen angle glaucoma

Secondary open angle glaucoma Capsular glaucomaSteroid glaucomaGlaucoma associated with uveitis, etc.

Primary angle-closure glaucoma Acute primary angle-closure glaucomaChronic primary angle-closure glaucoma

Angle closure glaucoma Plateau iris syndrome

Secondary angle-closure glaucoma Glaucoma associated with uveitisGlaucoma associated with lens subluxation, etc.

Mixed glaucoma

Primary congenital glaucoma

Congenital glaucoma Secondary congenital glaucoma Axenfeld-Rieger syndromeSturge-Weber syndromeAniridia, etc.

GLAUCOMA


abnormal findings in the optic disc, such as theenlargement of optic disc cupping, and visualfield impairment that can be explained by thesefindings should be present in order for glau-coma to be diagnosed.

Gonioscopy is also important from the pointof view of prevention of glaucoma. The cham-ber angle is the space created by the cornea andiris, and the aqueous humor circulating in theeye is excreted here. Since angle-closure glau-coma is likely to develop if the chamber angleis shallow, examination of the chamber angleby gonioscopy is very important for preventingacute attacks of angle-closure glaucoma. Need-less to say, gonioscopy is essential for the diag-nosis of angle-closure glaucoma and secondaryglaucoma.

Treatment of Glaucoma and Follow-upof the Clinical Course

At present, lowering of the IOP is almost theonly way to treat glaucoma. Calcium channelblockers for improving the blood flow at theoptic disc as well as vitamins are used occasion-ally, but their roles are only supplementary.Therefore, the main goal of treatment of glau-coma is to lower the IOP, evaluate the effectsof the treatment by perimetry, and aim at fur-ther lowering of the IOP when the effects arejudged to be insufficient.

The initial target IOP to be achieved by thetreatment is usually set at 21 mmHg, which isthe upper limit of the normal range, or 17 to18 mmHg. If the IOP is lowered to this level,but still not associated with clinical benefits,further lowering of the IOP is attempted.

The treatment of normal-tension glaucomais usually aimed at lowering the IOP by morethan 30% from the baseline. However, a morerealistic goal should be set if the baseline IOP islow, and the treatment should aim at lowering

Y. SUZUKI

the IOP further if marked visual field defectsare present and the structure of the optic discappears to be very fragile.

Specific methods of treatment shall not bediscussed here, as they are already described innumerous textbooks. As a general rule, thetreatment should be started with pharmaco-therapy using eye drops, and then argon lasertrabeculoplasty or where indicated, surgicaltherapy should be attempted if the treatmenteffects are insufficient. In the event of surgicaltherapy, trabeculectomy for draining aqueoushumor into the subconjunctival space is oftenperformed. However, as a general rule, thisprocedure should be avoided as far as possibleas it may be associated with various complica-tions, including postoperative shallow anteriorchamber, ocular hypotony, cataract develop-ment, and infection which may develop longafter the operation.

Conclusion

Glaucoma is a disease that occurs at a highprevalence (at least one in 30 people, in thepopulation aged over 40 years). Because of thepaucity of subjective symptoms, the patientsmay not notice the disease until the late stages.Therefore, early diagnosis through the effec-tive use of ophthalmological examination tech-niques, as well as health check-ups for detect-ing adult diseases is important.

REFERENCES

1) Shiose, Y., Kitazawa, Y., Tsukahara, S. et al.:Epidemiology of glaucoma in Japan—a na-tionwide glaucoma survey. Jpn J Ophthalmol1991; 35: 133–155.

2) Quigley, H.A.: Number of people with glau-coma worldwide. Br J Ophthalmol 1996; 80:389–393.


Exudative Age-related Macular DegenerationJMAJ 45(1): 13–20, 2002

Mitsuko YUZAWA

Associate Professor of Nihon University School of Medicine

Abstract: In Japan, exudative age-related macular degeneration is defined asa condition in which lesions originating from choroidal neovascularization (CNV)develop in the macular area in association with aging. The symptoms include centralscotoma, metamorphopsia, and irreversible and advanced visual impairment.Serous or hemorrhagic retinal pigment epithelial detachment or retinal detachment,subretinal hemorrhage, subretinal connective tissue formation, and scar lesionsare noted in the macular area. Fluorescein and indocyanine green can be used asfluorescent dyes for fluorescein angiography, and photocoagulation is performedwhen choroidal neovascularization outside the fovea is visible on angiogramsobtained with either dye. When the CNV involves the fovea, photocoagulation of theentire subfoveal CNV, photocoagulation of the feeder vessel of the neovascular-ization, interferon � therapy, low-dose radiotherapy, submacular surgery, transloca-tion of the macula, transpapillary thermotherapy, and photodynamic therapy areattempted. Vitreous surgery is performed to remove vitreous hemorrhages originat-ing from the CNV, and procedures for transferring or eliminating subretinal hemato-mas are performed to treat large subretinal hemorrhages involving the fovea.

Key words: Age-related macular degeneration; Choroidal neovascularization;Diagnostic criterion; Treatment

Synopsis

1. Concept and definitionAge-related macular degeneration can be

divided into exudative and non-exudative types.Exudative age-related macular degeneration

is a condition characterized by choroidal neo-vascularization (CNV). It is thought to be ahereditary disease that can be affected by aging

This article is a revised English version of a paper originally published inthe Journal of the Japan Medical Association (Vol. 124, No. 12, 2000, pages 1729–1734).The Japanese text is a transcript of a lecture originally aired on September 13, 2000, by the Nihon ShortwaveBroadcasting Co., Ltd., in its regular program “Special Course in Medicine”.

and environmental factors and is characterizedby hemorrhagic and exudative retinal and reti-nal pigment epithelial detachment. Atrophicscarring occurs after absorption of the bloodand exudates, and severe persistent visual im-pairment occurs. In Europe and America, exu-dative age-related macular degeneration is alsodiagnosed if retinal pigment epithelial detach-ment is noted, even when no CNV is detected.1)


M. YUZAWA

In non-exudative macular degeneration, geo-graphic atrophic lesions consisting of atrophyof the retinal pigment epithelium and the chorio-capillaris are noted. While the incidence of thistype of macular degeneration is higher thanthat of the exudative type, progression of thevisual impairment is slower.

The prognosis of exudative age-related macu-lar degeneration is particularly poor, and it ispredicted that this may soon arise as a seriousproblem as the number of aged people increasesin Japanese society. This type of macular degen-eration is therefore discussed below in greaterdetail.

2. EpidemiologyIn 1993, the Research Committee for the

Designated Disease Retinochoroidal Degen-eration supported by the Ministry of Health,Welfare and Labour conducted a survey jointlywith Research Committee for the Epidemio-logical Study of Intractable Diseases. Accord-ing to the results of the survey, 14,400 patientswith age-related macular degeneration werediagnosed in 1993 in Japan. The overall inci-dence of age-related macular degeneration isestimated to be 11.5 subjects per 100,000 popu-lation (male: 16.2 and female: 7.0), and 7.9,33.2, 76.1, and 87.2 per 100,000 population intheir 50s, 60s, 70s, and 80s (Fig. 1).2)

3. EtiologyRetinal pigment epithelial cells play impor-

tant roles in maintaining the retinal environ-ment, including regulation of phagocytic activ-ity against the outer segment of the photore-ceptor cells, not only in the photoreceptor celllayer, but in the neurosensory retina. Age-related changes in the retinal pigment epithe-lial cells include accumulation of lipofuscin asthe catabolic digestive residue, and lipogenesis.Moreover, Bruch’s membrane beneath the reti-nal pigment epithelium thickens with aging, andthe physiological environment of the photo-receptor cells layer, retinal pigment epithelium,and Bruch’s membrane change.

Neovascularization in the choroid is thoughtto occur when such excessive age-related changesare combined with an ischemic factor or chronicinflammatory reactions, and ingrowths developthrough the damaged Bruch’s membrane andthe retinal pigment epithelium and occasion-ally emerge above the retinal pigment epithe-lium. An association with heredity3) and smok-ing4) has also been confirmed.

4. SymptomsThe symptoms include central scotoma, meta-

morphopsia, and progressive irreversible andadvanced visual impairment.

5. Objective findings(1) Since exudative age-related macular de-

generation is characterized by CNV, fluores-cein and/or indocyanine green angiographyreveals the presence of neovascularization intypical cases. Diagnosis of exudative age-relatedmacular degeneration is performed when CNVis related to aging as indicated by atrophy ofthe retinal pigment epithelium, pigmentation,and serous drusen. The following findings mayalso be noted in the presence of CNV:

(2) hemorrhage under the retina or retinalpigment epithelium (Fig. 2),

Fig. 1 Number of patients with exudative age-related macularFig. 1 degeneration under diagnosis (1993)

Age(years)

200

150

100

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7.4

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43.6

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Female

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approach, are currently being assessed. Theyinclude photocoagulation of feeder vessels, useof antiangiogenic agents, such as interferon,low-dose radiotherapy, surgical extraction ofthe CNV region, implantation of the pigmentepithelium after extraction of the CNV, andtranslocation of the fovea.

Diagnostic Criteria

1. Subjective manifestations(1) Visual impairment(2) Central scotoma(3) Metamorphopsia(4) Micropsia

2. Objective findings(1) Findings in the ocular fundus

1) Subretinal hemorrhage and hemorrhageunder the retinal pigment epithelium inthe macular area and its vicinity

2) Serous retinal pigment epithelialdetachment

3) Serous retinal detachment4) Disciform lesions (growth of subretinal

connective tissue)5) Cicatricial lesions

(2) Findings on fluorescein fundus angiography

(3) serous retinal pigment epithelial detach-ment, and

(4) serous retinal detachment.Careful examination for the presence of CNV

is necessary, particularly when serous retinal orretinal pigment epithelial detachment is presentin patients over 50.

Even when the presence of CNV describedabove in (1) cannot be identified on angio-grams, patients over 50 years of age who ex-hibit any of the symptoms described in (2) to(4) are likely to have exudative age-relatedmacular degeneration.

6. TreatmentThe only method of treatment whose efficacy

has been established to date is photocoagu-lation of CNV that possesses a clear marginand does not involve the fovea. However, theindications for this method are limited, andtreatment is difficult when the margin of theCNV is unclear. It is not an ideal method, be-cause the treatment itself significantly impairsvision if the neovascularization involves thefovea.

Faced with this situation, various approachesto the treatment of neovascularization in thefovea, where photocoagulation is not a suitable

EXUDATIVE AMD

Fig. 2 Hemorrhage under the retinal pigment epithelium(arrow) and subretinal hemorrhage (arrowhead)

Fig. 3 Classic CNV involving the fovea detected byfluorescein angiography (left: middle phase ofangiography, right: late phase of angiography)


1) Findings on fluorescein angiographyChoroidal neovascularization may be visu-

alized as described below.(a) Classic CNV (Fig. 3): Hyperfluorescence

indicating choroidal neovascularization(CNV) is clearly visualized, and a vascu-lar meshwork structure is seen in the veryearly phases of fluorescein angiography.In the later phase, marked extravascularleakage can be demonstrated.

(b) Occult CNV (Fig. 4 top): The fluoresceinangiographic image of CNV is unclear.Angiographic images obtained in theearly phase are ambiguous due to block-age of the CNV by hemorrhage and reti-nal pigment epithelial detachment.Subretinal pigment epithelial accumula-tion of dye is noted only in the late-phases. Punctate hyperfluorescence isobserved in the middle- and late-phasesin some eyes.

2) Indocyanine green angiographyThere are no established standard views on

the interpretation of hyperfluorescence andhypofluorescence on indocyanine green angio-grams. However, it is highly likely that occultCNV, which is difficult to detect on fluoresceinangiograms because of the presence of hemor-rhage or retinal pigment epithelial detachment,is detected by this approach as an area ofhyperfluorescence (Fig. 4 middle and bottom).Moreover, since the inflow of dye from the cho-roidal vessels into the CNV can be observed atan early phase, it is used to detect the vesselsfeeding the CNV (Fig. 5).

3) Optical coherence tomographyWhen CNV is present above the retinal pig-

ment epithelium, it is visualized as a bright le-sion above the red reflecting layer that repre-sents the retinal pigment epithelium. When thelesion is present beneath the retinal pigmentepithelium, differentiation is often difficult.

3. Staging of age-related macular3. degeneration(1) Early lesions

1) Serous retinal detachmentRetinal detachment localized to the macular

area is noted. A small amount of subretinal hem-orrhage, retinal edema (cystoid macular edema),

M. YUZAWA

Fig. 4 Top: Occult CNV on fluorescein angiogramHyperfluorescence (arrow) representing reti-nal pigment epithelial detachment is noted,but no hyperfluorescence representing CNVis observed.

Middle: Indocyanine green angiogramHyperfluorescence (arrowhead) representingchoroidal neovascularization is observed.

Bottom: A fluorescein angiogram obtained after laserphotocoagulation of CNV detected by indo-cyanine green angiography. The hyperfluo-rescence representing retinal pigment epithe-lial detachment has disappeared.


and hard exudate are occasionally present.2) Serous and hemorrhagic retinal pigment

epithelial detachmentCNV may develop beneath large retinal pig-

ment epithelial detachment, or retinal pigmentepithelial detachment may result from choroi-dal neovascularization. In cases with retinalpigment epithelial detachment and accompa-nying CNV, a condition in which the margin ofthe retinal pigment epithelial detachment isdepressed, the so-called “notch sign”, is oftennoted, or the retinal pigment detachment con-tains a hemorrhage.(2) Lesions in the exudative stage

Retinal pigment epithelial detachment andserous retinal detachment are induced by largehemorrhages and exudation from the CNV.Retinal detachment (including cystoid macularedema) is often present. The subretinal growthof new vessels and connective tissues is marked,and so-called “disciform lesions” are noted.(3) Lesions in the scar stage

The CNV regresses, and yellow-white fibrousvascular scar tissue remains under the retinaand/or the atrophic retinal pigment epithelium

EXUDATIVE AMD

remains. The retinal-choroidal anastomosis andserous detachment may persist. CNV may recurin the area surrounding the scar tissue.

Treatment Approach

The standard approach to the treatment ofthis condition is photocoagulation. However,it is associated with risks, such as visual impair-ment induced by the photocoagulation itself,enlargement of the laser scar, and recurrenceof CNV after treatment. Therefore, detailedexamination by fluorescein angiography isessential.

Moreover, informed consent should be care-fully obtained from patients, because the mainaim of treatment is prevention of progression,rather than improvement of symptoms. Earlydetection and early treatment are important,because the lesions enlarge and visual impair-ment progresses and becomes severe.

1. PhotocoagulationThe results of large-sample randomized

double-blind clinical studies to clarify the effi-

Fig. 5 An indocyanine green angiogram showed hyperfluorescence beforephotocoagulation, showing feeder vessel (arrowhead) of subfovealCNV (arrow) and recurrent CNV surrounding hypofluorescence sug-gesting old laser scar.Right: After photocoagulation of the feeder vessel and recurrent CNVtemporal to the fovea. Hyperfluorescence suggesting foveal CNV hasdisappeared.


M. YUZAWA

cacy of photocoagulation have been reportedin the United States, and they have shown thathigh intensity photocoagulation after identify-ing the entire CNV on fluorescence angiogramsis effective for extrafoveal, and juxtafovealCNV, except subfoveal CNV.5) This approachis also commonly employed in Japan for thetreatment of CNV, except subfoveal CNV (Fig.4, bottom). It promotes scarring of the neo-vascularization in the exudative stage and ab-sorption of the subretinal fluid and exudate,but it is not indicated in many cases associatedwith occult CNV, in which the extent of theneovascularization is obscure. Moreover, ineyes with subfoveal CNV, visual impairment isinevitably induced by treatment itself immedi-ately after it is administered.6–8) Accordingly,the approaches described below are currently

employed in Japan.

2. Photocoagulation of feeding vesselsPhotocoagulation of feeder vessels has been

attempted for the treatment for subfoveal CNV.Feeder vessels extending from the choroid areidentified by indocyanine green angiography,and then selectively coagulated (Fig. 5). Sincethe area of coagulation is small, the visual im-pairment induced by treatment is minimized,the fovea is preserved, and improvement ofvision can be expected in some patients.9) Sinceexpertise is required to detect feeder vessels,this procedure is presently being performed atonly a few facilities.

3. Administration of interferon �Regression of small choroidal neovascular-

Fig. 6 Clinical course of the patient who underwent extraction of subfoveal CNVTop left: A preoperative black-and-white photograph. Hemorrhage is noted around the CNV.

Bottom left: A preoperative fluorescein angiogram. Intense leakage suggesting CNV involving thefovea is noted.

Top right: A black-and-white photograph obtained 6 months postoperatively. Part of the sclerais exposed, but the hemorrhage has disappeared. No findings suggesting CNV areobserved.

Bottom right: A fluorescein angiogram obtained 6 months postoperatively. No hyperfluorescencesuggesting CNV or hypofluorescence suggesting hemorrhage are observed. Hyper-fluorescence suggesting scleral tissue staining is noted.


EXUDATIVE AMD

izations in the fovea has been reported follow-ing administration of 6 million units of inter-feron � for 42 consecutive days.10)

4. Low-dose radiotherapyAfter the efficacy of low-dose X-ray irradia-

tion for subfoveal CNV was reported in En-gland,11) radiotherapy with 10 to 20 Gy wasattempted in Japan. This approach has beenreported to be efficacious in maintaining andimproving vision in addition to inducing regres-sion of relatively small subfoveal CNVs,12,13) butit has also been reported to be ineffective in alarge-scale study in the United States.14) A ran-domized prospective clinical trial is currentlybeing conducted under the auspices of the Min-istry of Health, Welfare and Labour in Japan.

5. Surgical therapy (vitreous surgery,5. subretinal hematoma transfer procedure,5. hematoma elimination procedure, and5. submacular surgery)

When massive subretinal hemorrhage ispresent, pneumatic displacement or surgicalremoval of the subretinal hemorrhage isattempted, and vitreous surgery may beindicated in eyes with long-standing vitreoushemorrhage.

Surgical extraction of subfoveal CNV abovethe retinal pigment epithelium (Figs. 6 and 7)and implantation of the pigment epitheliumafter extraction have also been attempted. An

operative procedure to move the fovea has alsobeen conducted.

6. Photodynamic therapyIn this approach, a photosensitizer is injected

intravenously in advance, and after it adheresto the endothelial cells of the CNV, low-powerdiode laser irradiation is conducted to inducechemical reactions that may cause thromboticocclusion of the CNV.

Since low-power laser photocoagulation isused in this approach, retinal damage andvisual impairment after treatment of theCNV are thought to be minimal. Moreover,treatment can be repeated if the CNV is notobliterated.15)

A clinical trial of photodynamic therapy isbeing conducted in Japan and is expected toshow promise as a new method for treatingsubfoveal CNV.

REFERENCES

1) The International ARM Epidemiological StudyGroup: An international classification andgrading systems for age-related maculopathyand age-related macular degeneration. SurvOphthalmol 1997; 39: 397–374.

2) Yuzawa, M., Tamakoshi, A., Kawamura, T. etal.: Report on the nationwide epidemiologicalsurvey of exudative age-related macular de-generation in Japan. Int Ophthalmol 1997; 21:1–3.

3) Tamakoshi, A., Yuzawa, M., Matsui, M. et al.:Smoking and neovascular form of age-relatedmacular degeneration in late middle agedmales: Findings from a case-control study inJapan. Br J Ophthalmol 1997; 81: 901–904.

4) Klaver, C.C.W., Wolfs, R.C.W., Assink, J.J.M.et al.: Genetic risk of age-related maculopathy.Arch Ophthalmol 1998; 116: 1646–1651.

5) Macular Photocoagulation Study Group: Laserphotocoagulation for juxtafoveal choroidalneovascularization. Five years results fromrandomized clinical trial. Arch Ophthalmol1994; 112: 500–509.

6) Macular Photocoagulation Study Group: Sub-foveal neovascular lesions in age-related

10° 10°

Vs＝（0.03）MD＝－17.1dB

Vs＝（0.1）MD＝－7.5dB

Fig. 7 Clinical course of the central visual field andvision of the patient presented in Fig. 6.

(Left: preoperatively, right: 6 months postoperatively)


macular degeneration. Guidelines for evalu-ation and treatment in the macular photo-coagulation study. Arch Ophthalmol 1991;109: 1242–1257.

7) Macular Photocoagulation Study Group: Visualoutcome after laser photocoagulation for sub-foveal choroidal neovascularization second-ary to age-related macular degeneration. ArchOphthalmol 1994; 112: 480–488.

8) Yuzawa, M., Tamakoshi, A., Ueha, M. et al.:Factors influencing visual acuity for subfovealchoroidal neovascularization of exudative age-related macular degeneration. Ophthalmology1996; 103: 2037–2041.

9) Shiraga, F., Ojima, Y., Matsuo, T. et al.: Feedervessel photocoagulation of subfoveal choroidalneovascularization secondary to age-relatedmacular degeneration. Ophthalmology 1998;105: 313–316.

10) Kyo, B., Ishihara, N., Fujita, K. and Yuzawa,M.: Interferon � therapy for age-relatedmacular degeneration. 1999 Research Commit-tee on Chorioretinal Degenerations and OpticAtrophy, The Ministry of Health and Welfareof Japan, 2000; pp.131–134. (in Japanese)

11) Chakravarthy, U., Houston, R.F., Archer, D.B.et al.: Treatment of age-related subfoveal neo-vascular membranes by teletherapy: A pilotstudy. Br J Ophthalmol 1993; 77: 265–273.

12) Mandai, M., Takahashi, M., Miyamoto, H. etal.: Long-term effects of radiation treatmentfor age-related macular degeneration. RinshoGanka (Japanese Journal of Clinical Ophthal-mology) 1998; 52: 567–571. (in Japanese)

13) Matsuhashi, H., Takahashi, D., Noda, Y. et al.:Low-dose radiation therapy for choroidal neo-vascularization in age-related macular degener-ation. Nippon Ganka Gakkai Zasshi (Journalof Japanese Ophthalmological Society) 1996;100: 803–809. (in Japanese)

14) Spaide, R.E., Guyer, D.R., MaCormik, B. et al.:External beam radiation therapy for choroidalneovascularization. Ophthalmology 1998; 105:24–30.

15) Treatment of Age-related Macular Degenera-tion with Photodynamic Therapy (TAP) StudyGroup: Photodynamic therapy of subfovealchoroidal neovascularization in age-relatedmacular degeneration with verteporfin. ArchOphthalmol 1999; 117: 1329–1345.

M. YUZAWA



Clinical Characteristics of DepressionJMAJ 45(1): 21–27, 2002

Arata SATO* and Shin IHDA**

*Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital**Former Professor, Department of Psychiatry, Niigata University School of Medicine

Abstract: The epidemiology, premorbid character, diagnosis, and symptoms wereoverviewed regarding clinical features of depression. Depression is observed in allage groups from childhood to senescence, and its lifetime prevalence exceeds10% and that among women is 1.3 to 1.7 times higher than that among men. Itsprevalence in old age so far reported is generally low. The premorbid characters ofdepression known in Japan and Germany are Kretschmer’s cycloid, Tellenbach’smelancholic and manic types, and Shimoda’s immodithymia. Recently, Ihda pro-posed the structural theory for immodithymic character. The diagnostics of depres-sive episodes (ICD-10) and the relationship between culture and depressive symp-toms are discussed. Depression in non-European cultures as reported previouslyrarely manifested self-blame or suicidal ideas, and depressive symptoms were notsevere. In Japan, there have been reports of withdrawal depression where thepatient tries to escape from his/her studies or work without much self-guilt. At leastsome of the depressive symptoms are culturally defined, and the diversified clinicalpictures of depression may reflect the cultural and social situations of the contem-porary time.

Key words: Prevalence; Premorbid character;Comparative cultural psychiatry; Mood disorder

Its symptoms show diurnal variation, leadingto alleviation toward evening. Some patientsexperience several prolonged phases of depres-sion in their life even with development of drugtherapies, and may gradually recover to thepremorbid level.

This paper discusses the clinical features ofdepression including its epidemiology, premor-bid character, diagnosis, and symptoms. Anattempt is made to view depression from the

Introduction

Depression is primarily characterized bydepressive moods and diminished ability tothink or act, accompanied by varying degreesof functional deteriorations in emotion, drive,cognition, thinking, and behavior. It is accom-panied by somatic symptoms such as insomnia,anorexia, and autonomic imbalance as well asanxiety, fretfulness, and occasional delusion.

�Depression


A. SATO and S. IHDA

viewpoint of comparative cultural psychiatry inorder to gain a deeper understanding of theclinical features of depression.

Epidemiology1)

1. PrevalenceEpidemiological surveys based on DSM-III-

R (Diagnostic and Statistical Manual of MentalDisorders, third edition, revised) that have beenconducted on the general population have re-vealed point prevalence of depression of 1–5%,one-year prevalence of 4–10%, and lifetimeprevalence of 13–17%. Epidemiological stud-ies using DSM-III that were conducted in West-ern countries and Korea in the 1980s, revealedsomewhat lower prevalence (3.3 to 12.6% forlifetime prevalence), suggesting an increasedtendency for depression in recent years.

2. GenderThe one-year prevalence of depression among

women is 1.7 to 2.5 times higher than thatamong men, and the lifetime prevalence amongwomen is 1.3 to 1.7 times higher than thatamong men. This indicates that more womenare suffering from depression than men.

3. Age at first onsetIn 1967 Akimoto et al. studied the age of first

onset of primary manic-depressive illness inJapan. According to their report, onset occursmost frequently among individuals in theirtwenties, followed by those in their 30s, andonset occurs in a considerable number of indi-viduals in their 40–50s. According to recentstudies performed in Western countries, theaverage age for the first-time episode is themid-twenties, and the first-time onset is observedin all age groups ranging from childhood to oldage. Manic-depressive illness in children andyouths begins to appear after approximately 11years of age.2)

4. Senile depressionA comparatively large number of studies on

senile depression have been conducted in Japan.As for its prevalence among those aged 65years or older reported in studies conducted onthe general population in Japan, Hasegawa et al.reported a prevalence of senile depression of0.9% in Tokyo; Naito et al. reported a preva-lence of 2.1 to 4.8% in three districts in Niigata;Ihara et al. reported a prevalence of 0.37%, andKamahashi et al. reported a prevalence of 0.4%in Tochigi Prefecture. According to studies con-ducted in Western countries since 1980, thepoint prevalence of senile depression among thepopulation aged 65 years or older is 1–4%, andthe lifetime prevalence is also approximately1–4%. Thus, the prevalence of depression re-ported in studies on senile depression is gener-ally lower than that reported in studies per-formed on populations without age limitations.

Premorbid Character

As to the premorbid characters of depression,the Kretschmer’s cycloid, Shimoda’s immodi-thymic character, and H. Tellenbach’s melan-cholic and manic types are known. Ihda et al.3)

recently summarized these characters in a paperpublished in this journal.

Shimoda’s immodithymic character4,5) is char-acterized by hard work, perfectionism, thor-oughness, honesty, orderliness, strong sensesof justice, obligation and responsibility, andinability to deceive or to be sloppy. Hirasawa6)

amended Shimoda’s emphasis on troublesome-ness and enthusiasm of immodithymic charac-ter by pointing out that patients with depres-sion have “apparent smooth and sociable atti-tude toward others with excessive sensitivenessof others’ opinion of him.” Kasahara7) reportedthat the melancholic type cannot be distin-guished from obsessionalism (anankastic char-acter) by merely observing orderliness or punc-tuality, and that one should note that a patientwith the melancholic type “takes care to main-tain a smooth relationship with others.” Bypointing out this inclination for orderliness inone’s relationship with others, Kasahara em-


CLINICAL CHARACTERISTICS OF DEPRESSION

phasized that the immodithymic character issyntonic, which is a basic characteristic of thecyclothymic personality.

According to Ihda, Shimoda’s immodithymiccharacter is not only unipolar but is also a pre-morbid character for manic-depressive illnessin general and includes both H. Tellenbach’s8)

melancholic and manic types. Ihda9,10) sche-matized the structure of immodithymic char-acter as shown in Fig. 1. According to Ihda, atthe nucleus of the premorbid character formanic-depressive illness (affective disorder) isKretschmer’s cycloid, which is surrounded bythe melancholic type and manic type, and theimmodithymic character includes both the mel-ancholic type and manic type.

In Western countries, such temperament orcharacter models were barely noted as pre-morbid characters for depression except byTitley et al. who published the theory in the1930s. Although the theory of character andtemperament consisting of seven-factor modelsproposed by Cloninger11,12) has recently attractedattention in Western countries, it is still in astage awaiting further development regardingits relationship with the premorbid character ofdepression.13,14) According to Akiskal, the per-fectionism and obsessive-compulsive traits of

Melancholic type

Immodithymia

Depressed(schwerblütig)

Cycloid

Elated(hypomanish)

Manic type

Fig. 1 Premorbid character of mood disorder(schematic drawing)

premorbid character are not recognized asmuch in the United States as in Japan or Ger-many. Akiskal et al.15) pointed out introversionas the premorbid character of unipolar depres-sion, and Angst et al.16) pointed out neuroticism.

The following case report describes a patientwho is melancholic as well as cyclothymic.

[Case report]Mr. K is a 36-year-old computer engineer and the

elder of two sons. Following graduation from univer-sity, he entered the company at which he is currentlyworking, married three years ago and has a son.Although his wife complains that he spends too littletime with his family, the family live harmoniously andhave no problems.

He is faithful, has a strong sense of responsibility,and is capable at work with many ideas. He is proudof his supervisor’s high opinion of him. Since hispromotion two years ago to the position of leaderof computer network structuring, he has been over-worked because he could not say no to numerous jobsthat were assigned to him. One year prior to the firstepisode, he was assigned to several large-scale projectsas a leader and during the three months precedingthe onset, he worked nearly every day. Looking backon those days, Mr. K mentioned that he was over-worked and dissatisfied with the results of his workpartly because he was a perfectionist, and that hismood might have been elevated just prior to the onsetof depression.

One day, a circuit breakdown paralyzed the entirecomputer network. As a leader, he felt strongly respon-sible and became depressive following the accident.Because of easy fatigue and loss of appetite, he saw aninternist thinking that something was wrong with hisstomach. Gradually, he experienced depressive moods,insomnia, diminished willingness to work, and reluc-tance to repair the broken circuit. He became increas-ingly guilt-ridden and fretful.

He visited a psychiatric clinic of a nearby generalhospital, accompanied by his wife and supervisor ofthe company. As his suicidal ideas and depressivemood were quite serious at the first interview, the phy-sician recommended hospitalization. He was fearful ofbecoming socially ostracized by abandoning his workby hospitalization, and needed to be persuaded by hiswife and supervisor to consent to hospitalization.

In the hospital, he was placed on drug therapy withan anti-depressant and was able to obtain good-qualityrest. He recovered smoothly. At two weeks followingthe date of admission, he was aware of his improvedcondition, and two months after the start of treatment,he was discharged. He returned to work under thedoctor’s instructions, and had a reduced workload.


Diagnosis and Symptoms

1. DiagnosisTable 1 shows the simplified diagnostic cri-

teria for depressive episodes according to theICD-10 (International Classification of Dis-eases, 10th revision) published by the WHO.17)

By confirming the presence of several itemsand by elimination, the diagnosis of depressiveepisode may be established.

According to the ICD-10 as shown in Table 1,depressed mood, loss of interest, and increasedfatiguability are typical symptoms of depres-sion. Even without the subjective symptom ofdepressed mood, if additional symptoms besidesthe remaining two items are manifested, it ispossible to diagnose a mild or moderate depres-sive episode. Loss of self-esteem, feeling of self-reproach and presence of suicidal ideas as wellas diminished ability to think or concentrate,agitation or retardation, sleep and dietary dis-turbances are additional symptoms. The sleepand dietary disturbances include not only insom-nia and loss of appetite, but also hypersomniaand increase in appetite.

Depressed mood, diminished ability to thinkand act, loss of confidence, and self-blame are

frequently encountered when diagnosingdepression in Japanese patients. However,some patients are in a depressive state wherethese symptoms can not be easily determined.While clinicians should naturally be careful notto overly increase the number of cases diag-nosed as depression, it is also important notto overlook depression in patients who havefew complaints but who are observed to bedepressed, and in those whose depressed moodand inhibitions are not apparent, but who arehypochondriac (masked depression18)).

2. Relationship between culture anddepressive symptoms

The symptoms of mental disorders may pre-sent different themes according to the gender,age, and social status of the patient. The charac-teristics of depressive symptoms, particularlydelusions in depression, are discussed from theviewpoint of comparative cultural psychiatry19,20)

referring mainly to Kondo’s paper.19)

Depression observed in non-European cul-tures such as in African countries used to bedescribed as lacking self-blame and suicidalideas, and was associated with not very seriousdepressive conditions. Table 2 is quoted from

A. SATO and S. IHDA

Table 1 Criteria for Diagnosis of Depressive Episodes (ICD-10)

A. Episode lasts for at least two weeksB. Typical symptoms

(1) Depressed mood(2) Loss of interest or pleasure(3) Decreased energy or increased fatiguability

C. Additional symptoms(1) Loss of confidence or self-esteem(2) Self-reproach or guilt(3) Suicidal thoughts or behaviours(4) Diminished ability to think or concentrate(5) Change in psychomotor activity, with agitation or retardation(6) Sleep disturbance(7) Change in appetite

Mild episode: At least two items of B, and at least four items of B and CModerate episode: At least two items of B, and at least six items of B and C

Severe episode: At least three items of B, and at least eight items of B and C


Prince.21) According to Prince, depression inAfrica prior to 1957 (independence of Ghana)was characterized by (1) few complaints ofdepressed mood, (2) rare instances of self-blame,(3) uncommon suicide, (4) and prevailing hypo-chondria and physical complaints.

Three major themes of delusion that depres-sive patients often complain about are hypo-chondria, sense of guilt, and fear of poverty.The hypochondriacal delusions of depressionare considered to be affected by the medicalknowledge shared by the society in which thepatient resides. As shown by the concept ofmasked depression,18) the fact that depressivepatients are hypochondriac and not delusive,may be a cross-cultural phenomenon. The themeof guilt delusions may be affected by the religionand social systems defining the individual’ssense of responsibility. In Japan, patients oftenblame themselves in view of the interests of thecompany they work, colleagues and their rela-tionship with family system rather than havinga religious sense of guilt. The delusion of pov-erty is also strongly affected by culture. Themanifestation of delusion of poverty is basedon the existence of a widely accepted idea inthe society that each individual is responsiblefor his/her future financial conditions, and onemight suggest that in a society lacking such anidea, delusion of poverty would barely appear.

In a world where people equally aim at eco-

nomic development on the global scale, dis-cussing the cultural characteristics of depres-sion per se seems to be quite difficult. However,we should point out that the characteristics ofthe contemporary social system (or psychologi-cal introjection, projection and formed super-ego when expressed in terms of psychodyna-mics) that drive depressive patients to despair-ing self-guilt and suicidal ideation should notbe disregarded. The physician’s instruction forrest and guarantee of security to depressivepatients may be meaningful in that they areissued by a person who is recognized as carry-ing out a prescribed role in that social system.

3. Changes in the clinical features ofdepression in Japan

Ihda described the following22): After the mid-Edo period, the so-called popular morals ofdiligence (or hard work), frugality, and submis-sion became the motives for modern Japanesecapitalism and the historical background forimmodithymic character,23–25) but they declinedafter World War II, particularly among youngergenerations. The new generation who are char-acterized by dependence and “apathy” andwho grew up under overprotection and a let-alone policy, emerged. The changes in theclinical features of depression are classifiedinto two types; the dependent type and narcis-sistic type. The former includes neurotic depres-


Table 2 Depressions in Past Day Africa

1895 Greenlees TD Rare examples of melancholia

1936 Gordon HL Remarkable absence of affective disturbance except for elated type

1937 Laubscher BJF Severe depressions and depressions with agitation are hardly ever seen, suicide is extremely rare

1947 Carothers JC Manic-depressive insanity is relatively uncommon, ideas of guilt are consistently absent

1950 Tooth G Rarity of depressive reactions, suicide and self-reproach

1953 Lamont AM and Rarity of depressive psychoses, not a single case with delusions of guiltBlignault WJ

1955 Moffson A Manics are observed but depression is very rare

Source: Prince (1968)21)


sion or somatized depression where physicalsymptoms are predominant, while the latterincludes withdrawal depression and apatheticsyndrome.3,26,27)

According to Hirose,28) melancholic-typepatients fall into a depressive state as theystruggle with changes in situations, whereaswithdrawal- and apathetic-type patients simplyabandon efforts for a solution once they realizethe difficulty of overcoming the changes byconventional methods, and jump into a depres-sive state where they are free from uneasinessand pain. Very few patients in the latter groupbecome self-blaming and very few manifeststrong suicidal ideas or attempts.

The premorbid character and clinical fea-tures of depression change as the contempo-rary system of society changes.10,25) Alterna-tively, the clinical features of depression maystand on various psychological defense mecha-nisms. When chronic depression in Japan andGermany are compared, dependence, whichdevelops to a neurotic tendency, becomes moreapparent in Japan, while development to anautistic tendency is more evident in Germany.Clinicians should attend to patients by beingaware that there are diversified types ofdepressed state depending on the individual’spersonality and the situation in which he/sheis placed.

Conclusion

The epidemiology, premorbid character, diag-nosis, and symptoms of depression were re-viewed with regard to its clinical features.Depression is observed in all ages from child-hood to senescence at high prevalence, and isobserved at a higher frequency among womenthan among men. The premorbid characters ofdepression include cycloid, immodithymic char-acter, melancholic, and manic types. We men-tioned the structural theory of immodithymiccharacter (Ihda), summarized the ICD-10 cri-teria for diagnosis of depression, and discussedthe relationship between culture and depres-

sive symptoms. Based on previous reports ondepression in Africa and on withdrawal depres-sion in Japan, one may assume that the emer-gence of a symptom such as self-reproach islargely prescribed by the cultural situation.Clinicians should be aware of the diversifiedand varied clinical features of depression,which reflect changes in the social system.

REFERENCES

1) Maeda, M. and Sato, A.: Epidemiology ofmood disorders. Hirose, T. and Higuchi, T. ed.,Encyclopedia of Clinical Psychiatry Vol.4,Mood Disorders. Nakayama Shoten, Tokyo,1998; pp.21–41. (in Japanese)

2) Shimizu, M.: Manic-depressive illness in child-hood and adolescence. Okuma, T. ed., ClinicalPractice and Theory of Manic-depressive Ill-ness. Igaku Shoin, Tokyo, 1990; pp.239–253.(in Japanese)

3) Ihda, S. and Kato, Y.: Premorbid character ofdepression. J JMA 1983; 100: 1016–1020. (inJapanese)

4) Naka, S.: Presenile depression. PsychiatriaNeurologia Japonica 1932; 34: 655–680. (inJapanese)

5) Shimoda, K.: Premorbid character of manic-depressive illness. Psychiatria NeurologiaJaponica 1941; 45: 101–102. (in Japanese)(translated by Shinfuku, N. and Ihda, S., Überden prämorbiden Charakter der endogenenDepression—Immodithymie von Shimoda,Fortschr Neurol Psychiatr 1969; 37: 545–552.)

6) Hirasawa, H.: Study of “immodithymic char-acter” in depression. Clin Psychiatry 1962; 4:229–237. (in Japanese)

7) Kasahara, Y.: Premorbid character of depres-sion. Kasahara, Y. ed., Psychopathology ofManic-depressive Illness I. Kobundo, Tokyo,1976; pp.1–29. (in Japanese)

8) Tellenbach, H.: Melancholie—Problemges-chichte, Endogenität, Typologie, Pathogenese,Klinik. Springer, Berlin, 1961.

9) Ihda, S.: Study of twins and psychopathology.Jap J Clinical Psychopathology 1994; 23: 13–21. (in Japanese)

10) Sato, A., Yokoyama, T. and Ihda, S.: Pre-morbid personality of manic-depressive ill-ness in Japan—Change of concept and struc-

A. SATO and S. IHDA


ture of immodithymic personality—. Jap JClin Psychiatry 1994; 23: 13–21. (in Japanese)

11) Cloninger, C.R., Svrakic, D.M. and Przybeck,T.R.: A psychobiological model of tempera-ment and character. Arch Gen Psychiatry1993; 50: 975–990.

12) Svrakic, D.M., Whitehead, C., Przybeck, T.R.and Cloninger, C.R.: Differential diagnosis ofpersonality disorders by the seven-factor modelof temperament and character. Arch Gen Psy-chiatry 1993; 50: 991–999.

13) Nakajima, T.: Psychobiological model andneurobiology of pathological personality. Brainand Nerve 1999; 10: 355–363. (in Japanese)

14) Sakamoto, K.: Depression and premorbid char-acter. Jap J Clin Psychiatry 1998; 27: 259–266.(in Japanese)

15) Akiskal, H.S., Hirschfeld, R.M. and Yerevanian,B.I.: The relationship of personality to affec-tive disorders. Arch Gen Psychiatry 1983; 40:801–810.

16) Clayton, P.J., Ernst, C. and Angst, J.: Premor-bid personality traits of men who develop uni-polar or bipolar disorders. Eur Arch Psychia-try Clin Neurosci 1994; 243: 340–346.

17) WHO: Pocket Guide to the ICD-10 Classifica-tion of Mental and Behavioural Disorders withGlossary and Diagnostic Criteria for Research.Churchill Livingstone, Edinburgh, 1991.

18) Shinfuku, N.: Profile of problems of maskeddepression. Ihda, S. ed., Manic-depressive Ill-ness (Esprit of Modern Times 88). Shibundo,Tokyo, 1974; pp.139–145. (in Japanese)

19) Kondo, K.: Depression as viewed in terms ofcomparative cultural psychiatry. Miyamoto,T., ed., Psychopathology of Manic-depressiveIllness II. Kobundo, Tokyo, 1977; pp.225–248.(in Japanese)

20) Ogino, K.: Comparative cultural psychiatry.Ihda, S. ed., Manic-depressive Illness. KokusaiIsho Shuppan, Tokyo, 1983; pp.572–580. (in


Japanese)21) Prince, R.: The changing picture of depressive

syndromes in Africa; Is it fact or diagnosticfashion? Can J African Studies 1968; 1:177–192.

22) Ihda, S.: Premorbid character of manic-depressive illness. Annals Niigata Pref MedicalAssoc 1983; 6: 1–8. (in Japanese)

23) Kawashima, T.: Family Structure of JapaneseSociety. Nippon Hyoronsha, Tokyo, 1950. (inJapanese)

24) Nakai, H.: Diligence and contrivances as theethics for reconstruction—trial discussion ofhistorical background of immodithymic char-acter. Kasahara, Y. ed., Psychopathology ofManic-depressive Illness I. Kobundo, Tokyo,1976; pp.117–146. (in Japanese)

25) Ohashi, M. and Ihda, S.: Changes in clinicalfeatures of depression and social pathology.Iwai, K. and Fukushima, A. ed., ModernClinical Sociopathology. Iwasaki GakujutsuShuppansha, Tokyo, 1980; pp.87–110. (inJapanese)

26) Ihda, S.: Development of melancholic type—from analysis of discordant twins of depres-sion. Ihda, S. ed., Psychopathology of Manic-depressive Illness III. Kobundo, Tokyo, 1979;pp.1–19. (in Japanese)

27) Sato, T.: Psychopathology and life history ofthe withdrawal depression and the apatheticsyndrome—comparison with the endogenousunipolar depression. Clin Psychopathology1986; 7: 147–160. (in Japanese)

28) Hirose, T.: On “withdrawal depression.”Miyamoto, T. ed., Psychopathology of Manic-depressive Illness II. Kobundo, Tokyo, 1977;pp.61–86. (in Japanese)

29) Ihda, S., Yokoyama, T. and Ueki, H.: Anlageund Familie. hrsg.v. Folkerts, H., Schonauer,K. and Tölle, R. Dimensionen der Psychiatrie.Thieme, Stuttgart, 1999; pp.33–41.



Drug Therapy for Depression in JapanJMAJ 45(1): 28–33, 2002

Makoto KAMIMURA* and Anri AOBA**

Assistant Professor*, Professor**, Department of Neuropsychiatry,St. Marianna University School of Medicine

Abstract: Drug therapy for depression fails in more than half of the patientsreceiving it because inadequate doses are given. It must be explained beforestarting drug therapy that its effects only appear after 2–4 weeks, but side-effectsdevelop immediately and then begin to subside after 1 week. As a rule, a singleantidepressant is administered. SSRIs are as effective as tricyclic antidepressants,but their adverse effects are far weaker than those of the older drugs. This is anadvantage of SSRIs over tricyclic antidepressants. According to the Americanversion of the therapeutic algorithm for depression (1995), the first-line drugs formoderate depression are SSRIs. For servere depression, however, tricyclic anti-depressants are more effective than SSRIs. To prevent the relapse of acute depres-sion, drug therapy should be continued for 4–6 months at the same dose. When thepatients have had two or more depressive episodes in the last 5 years, drugtherapy must be continued without changing the dose for 2–3 years, or for 5 yearsif possible, to prevent recurrence.

Key words: Depression; Drug therapy; Evidence-based medicine (EBM);Selective serotonin reuptake inhibitor (SSRI)

use in Japan in 1999. Subsequently, anotherSSRI (paroxetin) and the first serotonin nor-adrenaline reuptake inhibitor (SNRI, milnaci-pran) have been successively released in Japan.Thus, all the types of new-generation antide-pressants have now become clinically availablein Japan, as in many other countries. Thesechanges have propelled drug therapy for depres-sion in Japan to a new level.

The prevalence of depression in the generalpopulation is 2–7%, with a lifetime prevalenceof 4–19%, indicating that it is a very common

Introduction

In recent years, drug therapy for depressionhas been undergoing the transition from expe-rience-based medicine to evidence-based medi-cine (EBM) utilizing the findings of random-ized controlled trials. To cope with the transi-tion, the investigation of algorithms for EBM-oriented drug therapy is underway. Although itwas far later than in many other countries,fluvoxamin was introduced as the first selectiveserotonin reuptake inhibitor (SSRI) for clinical


disease. Among all patients, about one third seekattention at psychiatric clinics, with anotherone third being seen at other types of clinics.The remaining one third do not seek any medi-cal assistance. Even at psychiatric clinics, depres-sion is often overlooked. In addition, drugtherapy fails to control depression in more thanhalf of the patients receiving it because of inad-equate doses. In the end, only one tenth of allpatients with depression receive appropriatedrug therapy.1,2)

This article provides an outline of drug ther-apy for depression following the introductionof the first SSRI in Japan, with the factorsdescribed above being taken into consideration.

Pharmacology of Antidepressants(Tables 1–3)

Antidepressants can be divided into two majorclasses: one is drugs that selectively inhibit the

reuptake of monoamines such as serotonin andnoradrenaline at the synapses and the other istricyclic and tetracyclic antidepressants, whichnot only inhibit the reuptake of monoaminesbut also block various neurotransmitter recep-tors such as adrenergic �1 and �2, muscarinic(cholinergic), histamine H1 and dopamine D2

receptors. Antidepressants of the former classcan be further divided into two subclasses,which are selective serotonin reuptake inhibi-tors that have a much stronger inhibitory effecton the reuptake of serotonin than that of nor-adrenaline (SSRIs) and drugs that inhibit thereuptake of both serotonin and noradrenaline(SNRIs).

Selective monoamine reuptake inhibitors haveas strong an antidepressant action as tricyclic ortetracyclic antidepressants, but cause much lesssevere side-effects. This is an advantage overthe older antidepressants, particularly duringlong-term treatment to prevent relapse or recur-

Table 1 List of Antidepressants Clinically Available in Japan and Their Daily Doses

Nonproprietary name Daily dose (mg)

Tricyclic antidepressantsImipramine 25–300Amitriptyline 30–300Trimipramine 50–300Nortriptyline 20–150Clomipramine 50–225Amoxapine 25–300Lofepramine 20–150Dosulepin 75–150

Tetracyclic antidepressantsMaprotiline 30–150Mianserin 30–60Setiptiline 3–6

OthersTrazodone 75–200Sulpiride 150–600

Selective serotonin reuptake inhibitors (SSRIs)Fluvoxamine 50–150Paroxetine (2001�) 20–40

Serotonine noradrenaline reuptake inhibitors (SNRIs)Milnacipran (2001�) 50–100

DRUG THERAPY FOR DEPRESSION IN JAPAN


rence, because poor compliance can be avoided.In addition, because of adverse effects on thecentral nervous system and cardiovascular sys-tem, these drugs are relatively safe even forelderly and/or debilitated patients. Unlike tri-cyclic antidepressants, these drugs are rarelylethal even when an overdose is taken forattempted suicide.

Fluvoxamine may cause side-effects suchas gastrointestinal disorders (including nauseaand decreased appetite), anxiety and irritation,tremor, impaired ejaculation, and the seroto-nin syndrome. Therefore, this drug should beused with careful consideration of such side-

effects. The co-administration of drugs to poten-tiate gastric defensive factors may be effectivein preventing the gastrointestinal side-effectsof fluvoxamine, although the value of such com-binations is largely unproven. Care must betaken when fluvoxamine is used because it is apotent inhibitor of cytochrome P-450(CYP)1A2and thus blocks the metabolism of propranolol,theophylline, and warfarin. It also causes mod-erate inhibition of CYP3A4, and hence blocksthe metabolism of antiallergic drugs (such asterfenadine or astemizole) and cisapride (agastrointestinal prokinetic drug). Fluvoxamineshould not be used in combination with any of

Table 2 In vitro Short-term Biochemical Activities of Selected Older and Newer Antidepressants. Adapted from Potter et al.(1991) and Pirmohamed et al. (1992), plus data from Richelson & Nelson (1984) and Lancaster & Gonzalez (1989a,b)

DrugReuptake inhibition Receptor affinity

NA 5-HT D �1 �2 H1 MUSC D2

Older drugsa

Amitriptyline � ? 0 ÷ � ¿ ¿ 0Clomipramine � ÷ 0 ? 0 / ? ?

Desipramine ÷ 0 0 / 0 � / 0Dothiepin � � 0 � 0 ÷ ÷ 0Doxepin ? / 0 ÷ 0 ¿ ? 0Imipramine / / 0 ? 0 / ? 0Nortriptyline ? � 0 ? 0 / ? 0Trimipramine / 0 0 ÷ � ¿ ? ?

Newer drugsAmfebutamone (bupropion) � 0 ? 0 0 0 0 0Amoxapine ? 0 0 ? 0 / 0 ?

Citalopram 0 ÷ 0 0 0 0 0 0Fluoxetineb 0 ÷ 0 0 0 0 0 0Fluvoxamine 0 ÷ 0 0 0 0 0 0Lofepramine ÷ 0 0 / 0 / ?

Maprotiline ? 0 0 ? 0 ÷ / /

Mianserin 0 0 0 ÷ ? ¿ 0 0Paroxetineb 0 ¿ 0 0 0 0 � 0Sertralineb 0 ÷ 0 0 0 0 0 0Trazodone 0 / 0 ÷ � � 0 0

a: Tricyclic antidepressants.b: Selective serotonin reuptake inhibitors.Abbreviations and symbols: NA�noradrenaline (norepinephrine); 5-HT�5-hydroxytryptamine (serotonin);D�dopamine; �1��1-adrenergic receptor; �2��2-adrenergic receptor; H1 = H1 histamine receptor;MUSC�muscarinic (cholinergic) receptor; D2�D2 dopamine receptor; 0�no effect; ��equivocal effect;/�small effect; ?�moderate effect; ÷�large effect; ¿�maximal effect.

Source: Rudorfer, M.V. et al.: Comparative tolerability profiles of the newer versus older antidepressants.Source: Drug Saf 1994; 10(1): 18–46.

M. KAMIMURA and A. AOBA


after about 1 week. In order to assess the effec-tiveness of drug therapy, a single antidepres-sant is usually administered. In the case ofantidepressants, combined drug therapy hasrarely evidenced an increase in efficacy.

When the treatment of moderate depressionis tried from the perspective of EBM, there isno evidence that one antidepressant is superiorto another in effectiveness. On the basis of anti-depressant activity, consequently, drug therapycan be started with any antidepressant, but it isbetter for one having minimal side-effects beselected. According to the American version ofthe therapeutic algorithm (1995), the first-linedrugs for initiating therapy are SSRIs.3) Basedon this policy, fluvoxamine and paroxetine be-come the drug of choice in Japan. According tothe Japanese algorithm (1998) produced beforethe introduction of fluvoxamine, sulpiride and

these drugs because the inhibition of metabo-lism may result in QT prolongation and ven-tricular arrhythmia.

Acute Therapy

As a rule, acute therapy of depression istreated at outpatient clinics. When anxiety, irri-tation, or suicidal ideation is severe or thepatient is unable to eat, hospitalization is nec-essary. Before starting drug therapy, it shouldbe carefully explained to the patient and thefamily that: 1) depression is a brain disease thatcan be cured by drug therapy and rest, 2) thefamily should make allowance for the diseaseand should not encourage the patient to do toomuch, 3) drug therapy begins to have an effectafter 2 to 4 weeks, and 4) side-effects developimmediately, but begin to subside gradually

Table 3 Antidepressants Side-effects and Possible Clinical Consequences of NeurotransmitterReceptor Blockade by Antidepressants

Antihistamine H1

Potentiation of central depressant drugsSedation, drowsinessWeight gainHypotension

AntimuscarinicBlurred visionDry mouthSinus tachycardiaConstipationUrinary retentionMemory dysfunction

Anti-�1-AdrenergicPotentiation of the antihypertensive effect of prazosin (Minipress)Postural hypotension, dizzinessReflex tachycardia

Anti-�2-AdrenergicBlockade of the antihypertensive effects of clonidine (Catapress) and �-methyldopa (Aldomet)

Anti-dopaminergicAntipsychotic effectsExtrapyramidal movement disorders: dystonia, parkinsonism, akathisia, tardive dyskinesiaEndocrine effects: increase of prolactin (galactorrhea, gynecomastia, and menstrual changes)

Source: Kanba, S. and Richelson, E.: Antidepressant interactions with neurotransmitter receptorsin vitro; Prediction of potential side effects. Ed. O’Brien, R.A. In Receptor Binding inDrug Research. Mircel Dekker Inc., New York, Basel, 1986; pp.429–477



the tricyclic or tetracyclic antidepressants are allregarded as first-line drugs.4)

Fluvoxamine is initially administered at adose of 25–50 mg/day, which is increased to75–100 mg/day after 1–2 weeks, if necessary.If the condition shows a tendency to improveafter 2–3 weeks, treatment is continued withouta further increase of the dose. If not, the dosecan be increased to 150 mg. If the drug is inef-fective despite administration at a higher dosefor 4–6 weeks, fluvoxamine should be replacedwith another antidepressant. If the alternativedrug is one of the tricyclic antidepressants, theinitial dose should be 75–100 mg/day. The doseis increased gradually once every two weeks ifthere is no response and an absence of side-effects or tolerable side-effects. It is desirablefor the drug to be administered for 4–6 weeksor longer at an adequately high dose exceeding150 mg or around 250 mg, if possible (see Table1). Because antidepressants can lower the thresh-old for tremor at high doses, the patients shouldundergo electrocardiography and electroenceph-alography. When an antidepressant is given atsuch a high dose and fails to elicit any effect, itcan be regarded as having failed and an alter-native antidepressant should be used.

For severe depression, tricyclic antidepres-sants are more effective than SSRIs.3) Ami-triptyline and clomipramine are the drugs ofchoice. Intravenous infusion of clomipramineand electroconvulsive therapy are used in somecases.

When depression is refractory to antidepres-sant monotherapy, the drugs are administeredin combination with lithium, thyroid hormone,or bromocriptine (an antiparkinson agent) forpotentiation of efficacy. The effectiveness ofsuch combinations has been documented.3,4)

Remission is achieved with first-line drugs in38% of patients. This rate increases to 61% andthen 77% when therapy is continued by replac-ing the first-line drug with a second-line andthen third-line drug, respectively. If fourth-linedrugs and alternatives are given subsequently,remission is only achieved in another 9% in

total. Depression resolves completely within6 months after the start of drug therapy in79% of all patients treated. During the sub-sequent 12 months, remission is only achievedin 2%.5) If depression is associated with psy-chotic features, the remission rate is even lower.For depression of this category, a combinationof antidepressants and antipsychotic drugs iseffective.

When depression is associated with insomnia,anxiety, and irritation, the combination of anantidepressant with a benzodiazepine is effec-tive, particularly soon after the introduction ofantidepressant therapy. When the response isinadequate, however, treatment should not becontinued for more than 2–4 weeks. Generally,drug therapy is discontinued step-wise whenthe symptoms have been stabilized.4)

Continuation Therapy andMaintenance Therapy

1. Continuation therapy: To prevent relapsebefore the termination of a depressiveepisode

Drug therapy for a first episode is continuedfor 4–6 months without changing the dose. Forsecond and subsequent episodes of depression,treatment is continued the same period as forthe previous episode.6-9)

2. Maintenance therapy: Prevention ofrecurrence and new depressive episodes

After a first depressive episode, depressionwill recur within one, five, and ten years in28%, 68%, and 75% of patients, respectively.10)

Among patients receiving long-term drug ther-apy with fluvoxamine at an average dose of100 mg/day for 2 years, the recurrence rate was20%.11) The rate for patients receiving imipra-mine at a dose of 200 mg/day for three and fiveyears was 21%12) and 9%,13) respectively. If apatient has had two or more depressive epi-sodes in the previous five years, it is desirablefor prophylactic therapy to be continued for 2–3 years at the same dose as that used during

M. KAMIMURA and A. AOBA


acute treatment and for 5 years, if possible.11,13)

Conclusion

Drug therapy for depression fails to work inmore than half of the patients receiving it. Inparticular, tricyclic antidepressants are verylikely to cause adverse events, and have failedto elicit a sufficient clinical response in patientsreceiving these drugs at inadequate doses be-cause of such adverse effects. This has beenpartly responsible for the frequent occurrenceof therapeutic failure. Because two SSRI drugs(fluvoxamin and paroxetine) and an SNRI(milnacipran) have now become clinicallyavailable in Japan, more patients with depres-sion can receive adequate doses of antidepres-sants at present. With the advent of this newstage in the treatment of depression, it is hopedthat psychiatrists will not overlook depressionand depressive states that can easily be im-proved by drug therapy, even if the response isnot perfect. In other words, it is important toidentify patients with the indications for ag-gressive drug therapy as completely as possible.

REFERENCES

1) Shapiro, S., Skinner, E.A., Kessler, L.G. et al.:Utilization of health and mental health ser-vices. Three epidemiologic catchment areasites. Archi Gen Psychiatry 1984; 41(10): 971–978.

2) Katon, W., von Korff, M., Lin, E. et al.:Adequacy and duration of antidepressanttreatment in primary care. Med Care 1992;30(1): 67–76.

3) Nelson, J.C., Docherty, J.P., Henschen, G.M.et al.: Algorithms for the treatment of sub-types of unipolar major depression. Psycho-pharmacol Bull 1995; 31(3): 475–482.

4) Shioe, K., Kubota, M., Shinohara, M. et al.:Therapeutic algorithms for major depression.

Edited by Sato, K., Higuchi, T. and Yamawaki,N.: Therapeutic Procedures for Schizophreniaand Mood Disorders. Seiwa Shoten, Tokyo,1998; pp.63–74. (in Japanese)

5) Naganuma, H.: Outcomes of drug therapy foracute phase mood disorders. No to Seishin noIgaku (Brain and Mind Medicine) 1999; 10: 1–8.(in Japanese)

6) Frank, E., Kupfer, D.J., Perel, J.M., Cornes, C.et al.: Comparison of full-dose versus half-dosepharmacotherapy in the maintenance treat-ment of recurrent depression. J Affect Disord1993; 27(3): 139–145.

7) Furukawa, J.: Drug therapy for major depres-sion. Edited by Otsuka, T., Kazamatsuri, H.,Kitamura, T. et al.: Evidence-Based PsychiatricTherapy, Nippon Hyoron Sha, Tokyo, 1998;pp.17–29. (in Japanese)

8) American Psychiatric Association: Practiceguideline for major depressive disorder inadults. Am J Psychiatry 1993; 150 (4 Suppl):1–26.

9) Task Force of the Collegium InternationaleNeuro-Psychopharmacologicum (CINP): Im-pact of neuropharmacology in the 1990—Strat-egies for the therapy of depressive illness. EurNeuropsychopharmacol 1993; 3(2): 153–156.

10) Lavori, P.W., Keller, M.B., Scheftner, W.A. et al.:Recurrence after recovery in unipolar MDD:An observation follow-up study of clinicalpredictors in somatic treatment as a mediatingfactor. Int J Methods in Psychiatr Res 1994; 4:211–229.

11) Franchini, L., Gasperini, M., Perez, J. et al.:A double-blind study of long-term treatmentwith sertraline or fluvoxamine for preventionof highly recurrent unipolar depression. J ClinPsychiatry 1997; 58(3): 104–107.

12) Frank, E., Kupfer, D.J., Perel, J.M. et al.: Three-year outcomes for maintenance therapies inrecurrent depression. Arch Gen Psychiatry1990; 47(12): 1093–1099.

13) Kupfer, D.J., Frank, E., Perel, J.M. et al.: Five-year outcome for maintenance therapies inrecurrent depression. Arch Gen Psychiatry1992; 49(10): 769–773.



This article is a revised English version of a paper originally published inthe Journal of the Japan Medical Association (Vol. 122, No. 2, 1999, pages 213–221).The paper is a transcription of a lecture in the Health Policy Symposium onA Low Birth Society—A View of the 21st Century—held at the JMA office in Tokyo on February 6, 1999.

Expectations of a Low Birth Society—From the Perspective of Historical Demography—JMAJ 45(1): 34–44, 2002

Hiroshi KITO

Professor, Faculty of Economics, Sophia University

Abstract: Fertility in Japan has fallen under the population reproductive standardfor the past quarter century and it continues to decline. The low birth rate hasprecipitated the demographic aging of Japanese society which has produced pro-jections of a population decrease. Studies on the merits and demerits of a low birthrate vary, but the general concern is that a low birth rate is debilitating to bothsociety and the economy and will lead to the eventual ruin of the country. Thisunprecedented transition is very alarming, but it is not necessarily an abnormalphenomenon in terms of historical demography. The objective of this presentationis to evaluate Japan’s low birth rate from a historical demographic perspective.Firstly, the long-term population wave over the past 10,000 year period, which isclosely linked to systematic changes in Japanese civilization, will be discussed.Secondly, the trend toward late marriages and low child births that occurred duringthe latter half of the pre-modern Tokugawa period will be discussed. Lastly, if Japanachieves the status of a prosperous, aging nation with a low birth rate, its accom-plishment will contribute greatly to resolving the global population, environmental,and resource issues.

Key words: Low birth society; Population decline; Demographic transitions;Civilization system; Historical demography

the paper I am presenting and I hope that mypresentation will serve as a useful source ofreference.

The first major underlying reason for my con-cern is that I am not a population analyst or anexpert on economic issues. My field is historicaldemography, which is centered on researchpertaining to the populations in pre-modern

Presentation of the Issues

It is an honor to be present at this prestigioussymposium and I am grateful for the opportu-nity to address the many academically renowncolleagues assembled here today. However,despite this fact, I am slightly apprehensive thatI may not be an appropriate speaker in terms of

�Low Birth Society


society that predates the establishment ofpopulation dynamics or the population censusthat is characteristic of the study of moderndemography. As one who is constantly viewingthe history of populations from the standpointof past societies, I am concerned as to whatsuggestions about the present and the futurecan be proposed.

Secondly, I view the low birth rate and theapproaching population decline in a positivelight. It is my understanding that I was invitedto speak at this symposium because one of thetrustees happened to read an article of minethat was published in a journal. The followingquotation from that article largely summarizesmy standpoint. “The national and the localgovernments are desperately trying to forciblyraise the number of births, but they do not havethe time, revenue, nor the ideas to squander ...the time has come to seriously endeavor to for-mulate a plan on land usage and to create asocial framework suited to the needs of a soci-ety with a declining population, in order to allo-cate production facilities and social capital pru-dently within limited financial resources. As oneof the foremost nations faced with a low birthrate and aging population, establishing a pros-perous society characterized by a declining pop-ulation will be Japan’s contribution to the inter-national community.” Therefore, I am afraidthat by proposing that the low birth rate is awelcome phenomenon before my distinguishedcolleagues, whose energies are dedicated entirelyto resolving the issue of Japan’s low birth rate,I do so at the risk of being tarred and feathered.

Japan’s fertility rate has continued to drop,which has driven the country’s low birth rateand aging population. Moreover, it has been pre-dicted that a decreased population will becomea reality within the next ten-year period. Oneof the series of transitions, which is anticipatedto occur, is the debilitation of Japanese societyand the ensuing ruin of the country. This unprec-edented transition is most certainly very fore-boding and studies on the merits and demeritsof a low birth rate vary. But the overall con-

sensus has been an emphasis on the negativeaspects produced by this phenomenon; and thissymposium is one means of addressing thesefears and apprehensions for the future. How-ever, this is not a phenomenon which requiresour acknowledgment, denial, or our attemptsto raise the birth rate.

Although the current low birth rate anddecreased population is an unprecedented occur-rence in recent Japanese history, it is not anabnormal phenomenon from the standpoint ofhistorical demography. There has been a stag-nation in population growth throughout differ-ent periods of human history. Additionally, theissue of population decline is a problem that isnot restricted to Japan alone, but it is an issuethat confronts most of the European nationsas well.

The objective of my presentation is to assessthe issue of a low birth rate from the perspectiveof historical demography and the study of civi-lizations. The report is divided into the follow-ing three sections. In section one, demographictransitions that occurred in the Japanese archi-pelago 10,000 years ago will be discussed. Theclose link between the wave of populations thathave occurred over an extended period of timeand the shift to a civilization system will beexplained. The second section of the report willdiscuss the trend toward late marriages and alow birth rate that occurred during the Edoperiod. It is a well-known fact that populationgrowth stagnated during the 18th century whichproceeded an era of high population growth inthe 17th century. The characteristics that distin-guish this period will be described from the his-torical perspective of civilizations. Lastly, thelow birth rate that characterizes contemporaryJapan will be discussed from the context of his-torical demography.

A History of the Demographic Transi-tions in the Japanese Archipelago

The demographic transitions that occurred inthe Japanese archipelago during the last 10,000

EXPECTATIONS OF A LOW BIRTH SOCIETY


years are characterized by continuous growthfollowed by a period of population decline orstagnation. As shown in Fig. 1, population growthis seen in large waves. The first growth waveoccurred during the Jomon period. The popula-tion grew from 20,000 people in the early Jomonperiod to 260,000 by the middle Jomon periodand declined from a population of 160,000 inthe latter Jomon period to 80,000 people in thelate Jomon period.

The second population growth wave occurredduring the Yayoi period (population 590,000) tothe Nara period (7th century, population 5 mil-lion) and stagnated or declined from the Heianperiod (10th century, population 6 million) tothe Kamakura period.

The third growth wave began in the period ofthe Northern and Southern Courts (14th cen-tury). Although clear population statistics fromthis period are nonexistent, it is hypothesizedthat it is linked to the population explosion thatoccurred during the early Edo period (17th cen-tury) when the population, estimated at about12 million in 1600, grew to 31 million by 1721.However, as can be seen from the statisticsobtained from a nationwide population surveytaken by the Tokugawa government, the nationalpopulation was only 32 million in 1846, which isindicative of a stagnant population growth whichlasted for over 100 years from the mid-Edo era.

The fourth wave began during the early 19thcentury. From the final days of the Tokugawagovernment-Meiji Restoration period to presentday Japan, the population has greatly increased.However, this large population growth rate,which occurred in tandem with modernization,was not permanent and was predicted to leveloff at the beginning of the 21st century. Theunderlying causes of this population growth waveare firstly, environmental changes, and secondly,contact with other civilizations which in turn,triggered the shift to a civilization system.

1. Environmental changesThe environmental changes which contrib-

uted to the fourth population growth wave willbe explained very briefly. The large populationdecrease or devastation which occurred in thelatter half of the Jomon period is attributed toclimatic changes. In the aftermath of the glacialperiod, the early Jomon period was distinguishedby a warm climate which reverted back to acolder climate by the middle Jomon period. Themarked decrease in population occurred mainlyin the Tohoku, Kanto, and Chubu mountainousregions. According to one theory, the popula-tion is surmised to have been drastically reduceddue to contact with ethnic groups from Chinaand Korea that contributed to the onset of newdiseases.

The underlying cause for the static growth inpopulation during the Heian and Kamakuraperiods is not known. It is said that the studyof medieval Japanese history is presently invogue and the prevailing concept promulgates“an illuminated medieval age” supported by anactive populace. Unfortunately, from the stand-point of population history, the Japanese medi-eval period is categorized as the Dark Age. Thestatic population growth rate of this period isnot due to the advent of a cold climate, but awarm climate accompanied by dry weather,which is believed to have led to unstable condi-tions in rice cultivation. National managementof the rice fields based on an ancient legal sys-tem was destroyed and the establishment of the

105

104

103

102

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1BC4000 BC2000

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Pop

ulat

ion

(10,

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Fig. 1 Long-term Trends of the Japanese Population(Early Jomon period�2100)

H. KITO


manor system may have also affected popula-tion growth. These climatic changes may havealso indirectly caused the fall of the Taira gov-ernment centered in western Japan and the vic-tory of the succeeding Genji clan which movedthe seat of government to eastern Japan.

Stationary population growth in the latterhalf of the Edo era may also have been affectedby climatic changes. The period from the 18thto the 19th centuries is also known as the littleice age due global cooling. The three great fam-ines which occurred from the 1730s to the 1830sstemmed from long, rainy spells in the summer,the lack of sunlight, lowered temperatures, andfloods which devastated the rice crop. The situ-ation was further compounded by the onset ofdisease. The atmospheric conditions that pre-vailed during the crop failure of 1993 were simi-lar to the conditions that occurred 200 years ago.

Then why is the growth in population becom-ing static despite the continued onset of globalwarming? Because the static population growthin the past and the decline in population arenot due solely to climatic changes.

The French historian, Braudel, who greatlyinfluenced the study of history, claimed that thechanges in population were the progressive out-come of a materialistic civilization and the fore-most index that reflected progress. This defini-tion aptly describes the long-term populationgrowth wave seen in the Japanese archipelago.Japanese civilization is based on a cumulative10,000 year history. It is comprised of at leastfour segments when analyzed in terms of thelong-term population growth wave.

2. Transition to a civilization systemThe civilization system refers to the human

collective or community lifestyle and the termis used to signify culture or a living system. Wedevise tools, machines, buildings, customs, insti-tutions, laws, and a variety of other componentsto help us create a life of comfort and conve-nience. These components have become thesecond environment for human beings. Just aswe refer to an ecosystem to describe the rela-

tionship of an individual or groups of livingorganisms with the external environment, therelationship of human beings with all of thecomponents that have been created by and sur-round human beings is called the civilizationsystem.

The characteristics of the four civilizationsystems that developed in the Japanese archi-pelago in conjunction with the population growthwave are shown in Table 1. Various factors suchas the largest population, population density,stage of civilization, the major energy resourcesthat supported the society, and the predominanteconomic system that comprised each civilizationsystem have been listed. Additionally, energyusage, the type of social community, and thepredominant staple foods have also been given.Although there are many more factors whichneed to be reviewed, these are the factors thathave been included in this paper.

The first population growth wave, known asthe Jomon civilization system, was based on thenatural environment and the basic activities werehunting, collecting, and fishing. The lives of theJomon people were deeply linked to and greatlyaffected by the natural environment.

The second population growth wave spansthe Yayoi, Nara, and Heian periods. Triggeredby the development of the rice field farmingsystem, it represents the transition to an agri-cultural society. A national legal governmentstructure also developed in conjunction withthe spread of rice field farming and a legalsystem, construction of capital(s), the familyregister, a government system of land distribu-tion, a written language system based on Chi-nese characters, Buddhism, Taoism, Confucian-ism, and other institutions were introducedfrom China (T’ang dynasty).

The third population growth wave is believedto have occurred during the Northern and South-ern Courts period. The period from the 14th tothe 17th centuries was a major transitional periodin the history of Japan comparable in signifi-cance to contemporary times. The advent of asocioeconomy was the underlying cause of this



transition in the civilization. A market economy,which grew within the framework of an agrar-ian society, accelerated productivity and trig-gered economic growth. This socioeconomicchain of events is called the making of an eco-nomic society. The impact of the market econ-omy on the rural community created narrowareas of cultivated land, and established smallfarm management centered on family labor,which was an integration of labor intensivefarming technology and diligent labor. Someresearchers have called this phenomenon anindustrious revolution.

Wrigley has referred to pre-industrial Englandas an advanced organic energy-based economyand Japan with its advanced socioeconomy fitsthis description as well. Although it was an

agrarian society that was dependent on the land(natural environment), it was a society withhigh productivity and an advanced system ofland usage. Japan’s mode of behavior, sense ofvalues, and social structure underwent a majortransition. The country was influenced by theChinese, Portuguese, and Dutch civilizations.Japan’s traditional culture and many familiaraspects of the Japanese lifestyle evolved anddeveloped at this time.

The fourth population growth wave occurredin tandem with the establishment of the indus-trialized system. In the 19th century, the popu-lation growth rate in Japan, which had remainedstatic for about one century, gradually began toaccelerate. During the final days of the Toku-gawa government, the energy supply was nearly

Table 1 A Comparison of Civilization Systems

1 2 3 4

Jomon System Paddy Cultivation Socioeconomic IndustrializationSystem System System

Population 0.91) 241) 1121) 350density [1/km2] (26/middle(pop/10,000) Jomon period)

(700/10th century) (3,258/year 1828) (13,044/year 2011)

Naturalenvironment Agrarian society Agrarian society

Civilization (hunting, (direct (Indirect Industrializedstage fishing, consumption of consumption of society

collecting food) farm products2)) farm products2))

Plants and animals� Plants and animals� Plants and animals� MineralMajor energy manual labor manual labor manual labor Natural energyresources Natural energy Natural energy Natural energy �electricity

MineralWrigley’s Organic Organic Advanced energy-basedcategorization3) economy economy organic economy economy

TraditionalTraditional economy�Major economic Traditional economy� command Market economysystems4) economy command economy�

economy market

Social Stem family Industrializedcommunity5) Band society Clan society

society community

Rice, minor grains,Staple foods6) Nuts, fish, shellfish Rice Rice and minor sweet potato�grains diversification

1)Excluding the Ainu, Ryukyu (Okinawa), 2)Van Bart, 1980, 3)Wrigley, 1991, 4)Heilbroner, 1972,5)Murakami, Sato, Kumon, 6)Koyama, Goto, 1985

H. KITO


at a bottleneck in conjunction with a rise inliving standards. The European and Americansystem was introduced following the openingof Japan to the West and its entrance into theprevailing global system of that time. The Japa-nese economy which incorporated the frame-work needed for modernization began to indus-trialize at the end of the 19th century. However,like the three preceding population growth waves,the current growth in population is anticipatedto become stationary in the future and industri-alization is nearing maturity.

3. A static population growth society anda mature society

Let us assume that the population approachesthe maximum carrying capacity of a society orcivilization following a long-term growth inpopulation. It gradually becomes difficult forproductivity and the population to quantita-tively increase based on the current system andtechnology. This type of society is defined as amature society. When society reaches this stageof maturity, tension develops between civiliza-tion (living standards), the environment, and thepopulation and it becomes vulnerable to climaticchanges. A mature society at first glance is astatic society. Certainly, development is difficultin a mature society since it represents the after-math of an expanded population, cultivated land,residential areas, and productivity. It is also aperiod of prosperity and thriving culture.

In studying the Jomon culture of the SannaiMaruyama ruins, it has been deduced that theculture was based on a fairly advanced socialstructure and technology for a society rootedin the natural environment. The Nara period,which introduced the ancient legal codes, litera-ture (Chinese characters), religion (Buddhism,Taoism, Confucianism), and various other pro-ductivity related technology from China, has astrong foreign cast. In contrast, Japanese cul-ture flourished during the Heian period whenthe legal system was more relaxed and lessstringent. The kana writing system evolved and“The Tale of Genji”, the famous literary work,

was written in this period; and in the area ofreligion, all Buddhist sects which developedafter the Tendai sect were Japanized. This wastruly an ancient mature era.

Japanese society in the Edo period around1700 had become a stationary. This became aconfirmed reality during the 1720s and popu-lation growth for the next 100 years or moreremained static. Although the people were notmaterialistically blessed as today, the cultureflourished — it was a time when artists exhibitedtheir talents, the populace enjoyed the theaterand hobbies, pleasure-seeking activities, trips,and other aspects of an active culture. Scholarsand other intellectuals were earnestly engagedin absorbing knowledge from the West. The edu-cational facility for the populace, the templeschools, increased from the 1780s and experi-enced an explosive boom during the final daysof the Tokugawa government. In tandem withthe rise in the literacy rate, there was an increasein the number of published books. The res-taurant industry flourished in the urban areasof Edo, Osaka, and Kyoto and the populaceenjoyed an abundant food culture. These socialconditions are far removed from the image ofa populace eking out a destitute living.

The Population in the Latter Half ofthe Edo Period

I would like to discuss in detail the latter halfof the Edo period as exemplar of a mature civi-lization with a static population. There is anaccumulation of historical demographic researchfindings on the population phenomenon of thisperiod, based on the religious investigationsthat were conducted to contain the spread ofChristianity, the death registry of Buddhist tem-ples, and other sources of information.

The contradictions within the Tokugawa gov-ernment are said to have erupted during thelatter half of the Edo period, which is betterdescribed as the collision between the develop-ing market economy and the prevailing economybased on feudal directive. The feudal lords who



were levied a land tax and faced with financialdifficulties were drawn into the commodity econ-omy. The situation was further compounded bybad harvests which caused a large number offarmers to starve to death, in addition to mis-carriages and the practice of killing unwantedchildren which cumulatively contributed to thestatic population growth. The commonly heldopinion is that static population growth wascaused by a rising mortality rate and the func-tioning of what Malthus referred to as the posi-tive check.

1. Analysis of the Malthus population theoryThe year 1998 was the 200th anniversary of

the publication of “An Essay on the Principle ofPopulation” by Malthus. In this paper, Malthusadvocates that the population is constantly striv-ing to increase, but the limited production ofliving resources inevitably produces social con-fusion such as famine and war which leads to arise in the mortality rate and static populationgrowth. In view of the life ethics and techno-logical limitations of that time, the solution wasto restrict population growth through restric-tive measures such as marrying late or remain-ing single throughout one’s life, in order to pre-vent the occurrence of war, famine, and othertragic events. It is self-evident that if popula-tion growth was disregarded, living standardswould fall to survival levels.

When Malthus’s essay was published inEurope, Japan was recovering from the after-math of the volcanic explosion of Mt. Asamaand the great famine of the 1780s. Farmlandwas devastated and population growth was atrock bottom levels. The conditions matched thecriteria described by Malthus. In addition, cli-matic cooling began in the 17th century. How-ever, the impact of bad harvests ended within arelatively short period of time and populationgrowth continued to be sustained. In contrast,when the population surpassed 30 million inthe 18th century, the carrying capacity withinthe Japanese archipelago had reached its limits,thus producing static population growth. Exces-

sive development caused by economic growthhad debilitated the capacity to absorb unex-pected traumas. The cooling climate raised thepopulation carrying capacity which triggeredthe occurrence of tragic events.

The agrarian society of the Edo period wasdependent on agricultural products. Due to thenonexistence of modern scientific technologyto prevent disasters, disease and insect damage,Japanese society was strongly affected by thenatural environment. It was not a society thathad an adequate system of information, trans-port means, and policies to cope with famineand other disasters. Subsequently, some regionsin Japan were case examples of the gloomyprognoses made Malthus. In cities where thepopulation density was high and the socialcapital was inadequate, the mortality rate washigh in contrast to a low birth rate. As a result,population growth could not be sustained andthere was a constant need for a populationinflow from the rural areas. This is known as thegrave-yard theory in Europe and the UnitedStates and the ant lion theory among Japaneseresearchers.

2. Late marriages and a low birth rateContrary to common opinion, the compara-

tively high living standards that prevailed dur-ing the latter half of the Edo period are attri-buted to what Malthus called the preventivecheck, namely the existence of a population con-trol factor that lowered fertility. In contrastto general supposition, the mortality rate wasdeclining and the average life expectancy hadrisen. Improved nutritional intake, easy accessto physicians and medicine, a higher publicawareness of child care, and other factors re-flected a higher living standard. One underly-ing cause of the drop in the fertility rate in con-junction with a lower mortality rate was thetrend toward late marriages. This became espe-cially pronounced when women became engagedin sericulture, weaving, domestic help, and othernon-farming activities, thus raising their impor-tance as income earners. As a result, women

H. KITO


were prolonging their marriages by three yearsthroughout the nation. Another underlying causewas a lower marital fertility rate— women werehaving fewer children. The number of childrenthat a woman had throughout her lifespan aver-aged six to seven children throughout the 17thcentury when the annual population growth ratewas near 1 percent. But this figure dropped tofive or less in the middle of the 18th centurywith the advent of a lower infant mortality rate,since there was less need to have added chil-dren to replace the male heir in the event ofdeath. The increased population in the 17thcentury also reduced the area of cultivated landper household, thereby curtailing the fertilityrate of branch families with lowered economicprospects. Nonetheless, both in the East and inthe West, the practice of fertility control wasessential. Unfortunately, in addition to long-termbreast-feeding and abstinence, miscarriages,abortions, and infanticide were also practiced.However, this situation can also be assessedfrom a different perspective. Thomas Smith, whoconducted his research on a village in Nobi Plain,and others have raised the high possibility thatabortions and infanticide were conducted sys-tematically based on such factors as the balancebetween the genders and the scope of availableresources.

Susan Hanley has called the high qualitativeliving standard that prevailed during this timeas “the Tokugawa legacy”, namely the rich cul-ture, effective utilization of resources in theform of recycling, adequate nutritional intakerelative to the Japanese physical constitutionat the time, and a respectable life expectancyfor a preindustrialized society. This high quali-tative living standard was realized through plan-ned fertility control, which was a vital precon-dition to Japan’s modernization. By the early19th century the components of popular society,specifically mass production, mass consumption,and mass advertising, were already evolving.The energy crisis that would inevitably resultfrom the pursuit of national wealth by the clansand the populace’s aspirations for wealth was

narrowly avoided through recovery of the for-ests due to a warmer and more humid climate,population control, recycling, and economiza-tion. The decision to open the country to theinternational community and pave the way to afree economic system was timely and occurredjust before the ecosystem’s equilibrium wasdestroyed by the economic growth of the Toku-gawa period. The immediate start of Japan’sindustrialization saved the country from therestrictive civilization system of the Tokugawaperiod.

Expectations of a Low Birth Society

1. Conditions in JapanIn the aftermath of the oil shock, the Japa-

nese government published the white paper,Japanese Population Trends, in June 1974. Thesubtitle, “Aiming for a Stationary Population”left an indelible impression. The term, station-ary population, refers to a population that nei-ther increases nor decreases and maintains aconsistent size and a zero population growthrate. During this time the fertility rate, whichwas rapidly dropping, showed slight signs ofincreasing. It also coincided with the periodwhen the baby boomer generation was marry-ing and entering parenthood. The developingcountries were in the midst of a populationexplosion. Under the consignment of the RomeClub, the Massachusetts Institute of Technol-ogy had just published the “Limits to Growth”in 1972 which propounded the theory that coun-tries would face shortages in food and resourcesstemming from increased populations and eco-nomic growth; and warned of the potential dev-astation of civilization. The oil supply was pro-pitiously decreased at this time as part of thetactics related to the Fourth Mideast War thatoccurred in the fall of 1973. Oil prices skyrock-eted and the global community was forced toconfront the reality of limited growth. The totalfertility rate (TFR) was barely able to sustainthe population size at this time and the net re-productive ratio was near 1.0. However, just as



it is difficult to instantaneously stop the speedof an ongoing giant oil tanker, it is estimatedthat it takes approximately 40 years for popula-tion growth to actually cease. Meanwhile, themass media was propounding in unison a zeropopulation growth rate. Although I do not knowwhether this was an effective factor, the fertil-ity rate began to fall from that year and contin-ued its downward slide. The 1.57 fertility rate,that shocked the nation, occurred in 1990 andJapan’s TFR has recorded new lows annuallyfrom that year.

The decline in fertility is an issue that isshared by the advanced industrialized nations.European nations have fallen under the popu-lation reproductive line since the 1970s. Thefertility rate has also fallen under 2 in NorthAmerica as well. The fact that the fertility rate,which indicates the number of children onewomen is expected to have throughout her life,continues to fall under 2 for an extended periodof time signifies that population growth is declin-ing. Perhaps this phenomenon represents thefirst step toward the realization of a societywith a static population that was touted duringthe oil shock. The fact that this goal is about tobe realized 25 years later has been a source ofnational apprehension.

2. Global conditionsIn contrast, the fertility rate in developing

countries remains high. In particular the TFRin Africa continues to be over 5. However, incontrast to the fertility rate which exceeded 6 inthe latter half of the 50s in Southeast Asia andother developing countries, the rate is steadilydeclining. This is due to successful economicgrowth and the spread of education. Anotherimportant factor is the active national policyadopted by many developing countries to con-trol the fertility rate.

In view of these conditions, the United Nationshas adopted lower figures in their revision offuture population statistics recently. For example,the average estimate of the world population in2050 in 1992 was 10 billion, but the revised sta-

tistic projected in 1998 for 2050 was lowered to8.9 billion.

However, the situation is not optimistic. Theaverage statistics are in anticipation of the grad-ual decline of the fertility rate to below the popu-lation reproductive line (2.05). If the fertilityrate does not change (high statistics), the popu-lation is estimated to reach 10.7 billion. If theworld population increases according to the aver-age statistics projected by the United Nations,the population will have nearly doubled to 10billion by the end of the 21st century.

3. Global population capacityWill the earth be able to support a world popu-

lation of 10 billion people? American demog-rapher, Joel Cohen, addresses this question in hisbook, “How Many People Can the Earth Sup-port?”, published in 1995. He introduces andevaluates more than 65 theories regarding thepotential population capacity which the earthcan support. The methodology used to supportthese theories are very diverse and include un-founded theories to system models. The major-ity of the theories support a maximum figureof 8 billion to 16 billion, the minimum figureswere concentrated in the 4 billion to 8 billionrange; and the maximum average estimate was12 billion and the minimum estimate was 7.7billion people, which was similar to the highestimations of the world population for 2050given by the U.N. in 1992.

But this does not mean that the population willcontinue to be sustained without undue prob-lems. Firstly, there is no guarantee that the worldpopulation will remain at 12 billion people. Thehigh estimations given by the U.N. signify thatthe world population will exceed this figure.

Secondly, there is no guarantee that the esti-mated global population capacity will remainpermanently at sustainable levels. The Medows,et al., system model which includes population,food, industrialization, nonrenewable energyresources, and the environmental pollution vari-able, postulates that a global population of 7.7billion people can be sustained. However, even

H. KITO


the most elaborate statistic guarantees sustain-ability only until the year 2100. According tothe supplementary studies of other researchers,the population and economy will be destroyedbefore 2300.

Thirdly, an universally accepted, standardizedconcept regarding the global population capac-ity does not exist. When oil imports ceased fol-lowing the 1974 oil shock in Japan, the popula-tion capacity of the Japanese archipelago wasdebated. According to one calculation, if alllevel land was converted to rice fields and cul-tivated without pesticides, fertilizers, or farm-ing machinery, the land would be capable ofsustaining a maximum population of only 40million people. This is comparable to the popu-lation of the latter half of the Edo period. Willwe be able to tolerate a situation where themajority of the population had to be engaged infood production activities? If we want to enjoyan urban lifestyle with an abundant supply ofmeat and fruits and to enjoy sports and nature,an immense amount of land is needed. Accord-ing to this definition, many countries, includingJapan, clearly support an excess population atpresent and it would not be inaccurate to statethat the global population will shortly exceedthe limit.

Establishing an Prosperous Societywith a Reduced Population

Recently, the burden of a low birth rate andaging population on the Japanese economy andsociety has been accentuated and debates cen-tered on raising the fertility rate have been prom-inent. It is indeed a fact that an increased popu-lation in the developing countries has contrib-uted to food shortages, poverty, populationmovement across international borders, andenvironmental destruction. Additionally, massproduction, mass consumption, and mass dis-posal that occurs in advanced countries withhigh living standards can not be ignored as well.Stopping the population growth in developingcountries and decreasing the population growth

in advanced countries can be likened to the heroKandata who sought his salvation from a spi-der’s thread.

Simon Kuznitz has defined modern economicgrowth as the simultaneous, sustained increaseof per capita income and population growth.However, when the economy and populationgrowth become stationary, it does not automat-ically mean that per capita income and livingstandards become static. Advanced countrieswith an industrial civilization that has entered amaturation stage must abandon the idea of aneconomy where growth is expected and takenfor granted. Post modern economics must em-brace the concept of a stationary political econ-omy aimed at establishing a high living stan-dard within a decreased population.

Since the end of the Tokugawa period, Japanhas taken economic and population growth forgranted. However, the country is entering anage when a population decline will be a com-monplace reality. Both the national and localgovernments are desperately and forcibly try-ing to increase the birth rate, but do they reallyhave the time, budget, and ideas to dedicate tothis endeavor? In conjunction with a decreasedpopulation, the population distribution will alsogreatly change. In a breakdown of the popula-tion statistics according to the urban and ruralprefectures and metropolis (May 1997), a popu-lation decline is predicted in 33 urban and ruralprefectures from 1995 to 2025. In order to allo-cate production facilities and social capital fromlimited financial resources, it is now the time toseriously build a social organization and to uti-lize the land in ways that are suited to a societywith a declining population. As the front run-ner nation in terms of a low birth rate and agingpopulation, Japan’s contribution to the interna-tional community is to establish a prosperoussociety with a declining population.

Conclusion

Stationary population growth is another char-acteristic of a mature society. A society with a



static population growth rate is not necessarilya poor society. The issues which we must addressis how to guide the population toward a certainliving standard and to determine what kind ofmature society should be built. The foremostissue is not the fact that the population willdecrease. The average life expectancy duringthe latter half of the Edo period was 36 or 37years of age, but the average life expectancy ofcontemporary Japanese has doubled. A nation-wide life expectancy of 50 years was realizedonly after WWII in 1947. The majority of Japa-nese children born after WWII live to see their61st birthday and become senior citizens. TheJapanese of today live very different lifestylesfrom their counterparts 50 years ago and itwould not be erroneous to state that they haveevolved into a different species of people. Thereare many problems that must be resolved andbuilding a new social system and fostering newperspectives and values will take time. But weshould remember that in every era, changes inthe civilization system were realized after muchpainstaking effort. We should strive to be pru-dent, while optimistic and remain modest andconfident in our endeavor to achieve simpleprosperity.

Former Prime Minister Obuchi advocated theneed to make the change in our perspectives byfiguratively referring to a glass of water in his

inaugural speech in January 1999. Fortunately,economists have begun to advocate the viewthat if measures are taken to build a society thatqualitatively adapts an aging, declining popu-lation and a low birth rate, regaining balancedeconomic growth is not an impossibility. Whentadpoles evolve into frogs, their gills and tailsdisappear. Similarly, in order to change an exist-ing system, apoptosis, a resorption of unneces-sary organs, is also required for human societyto undergo a transformation in civilization. Weshould not emphasis the pessimistic negativeaspects of a low birth society, but look to thepositive aspects as well; and confront the real-ity that was forecasted 25 years ago with strongconvictions.

REFERENCES

1) Cohen, J.E.: How Many People Can the EarthSupport? 1995, (J. translation by Shigesada,N.: Shin Jinkouron Seitaigakuteki Apurochi.Noubunkyo, 1998.)

2) Ito, S., Yasuda, Y. Ed.: Civilization and Environ-ment, Part 2. The Epoch of the Earth and Civi-lization. Asakura Shoten, 1996. (in Japanese)

3) Kito, H.: A History of Japanese Population.Kodansha, 2000. (in Japanese)

4) Otsuka, R. and Kito, H.: The Century with aGlobal Population of Ten Billion People—How will Humanity Cope? Wedge, 1999.

H. KITO

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CONTENTS · 2009-08-04 · logical myodesopsia or visual impairment when blood covers the macula....

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