Pharmacologie Treatment of Depression

This article was downloaded by: [RMIT University]On: 24 August 2014, At: 03:24Publisher: RoutledgeInforma Ltd Registered in England and Wales Registered Number: 1072954 Registeredoffice: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK

Journal of Family PsychotherapyPublication details, including instructions for authors andsubscription information:http://www.tandfonline.com/loi/wjfp20

Pharmacologie Treatment of DepressionJohn Preston aa Alliant International University , Sacramento, CA, USAPublished online: 24 Sep 2008.

To cite this article: John Preston (2007) Pharmacologie Treatment of Depression, Journal of FamilyPsychotherapy, 17:3-4, 35-52, DOI: 10.1300/J085v17n03_03

To link to this article: http://dx.doi.org/10.1300/J085v17n03_03

PLEASE SCROLL DOWN FOR ARTICLE

Taylor & Francis makes every effort to ensure the accuracy of all the information (the“Content”) contained in the publications on our platform. However, Taylor & Francis,our agents, and our licensors make no representations or warranties whatsoever as tothe accuracy, completeness, or suitability for any purpose of the Content. Any opinionsand views expressed in this publication are the opinions and views of the authors,and are not the views of or endorsed by Taylor & Francis. The accuracy of the Contentshould not be relied upon and should be independently verified with primary sourcesof information. Taylor and Francis shall not be liable for any losses, actions, claims,proceedings, demands, costs, expenses, damages, and other liabilities whatsoever orhowsoever caused arising directly or indirectly in connection with, in relation to or arisingout of the use of the Content.

This article may be used for research, teaching, and private study purposes. Anysubstantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions

http://www.tandfonline.com/loi/wjfp20

http://www.tandfonline.com/action/showCitFormats?doi=10.1300/J085v17n03_03

http://dx.doi.org/10.1300/J085v17n03_03

http://www.tandfonline.com/page/terms-and-conditions

http://www.tandfonline.com/page/terms-and-conditions

Pharmacologic Treatment of Depression:New Developments and the Need

for an Integrated Approach

John Preston

ABSTRACT. Serious mood disorders affect at least 17% of the popula-tion (lifetime prevalence) exacting a significant toll on human lives. Oneimpact of severe depression is the possibility of brain damage caused bytoxic levels of stress hormones. New data suggest a role for antidepres-sants in preventing such damage to the nervous system. Psychiatricmedication treatments represent an important part of comprehensivetreatment for clinical depression. This article addresses in detail currenttreatment guidelines derived largely from large-scaled empirical studies.Also discussed are the limitations of pharmacotherapy and the need for in-tegrated treatment models. doi:10.1300/J085v17n03_03 [Article copies avail-able for a fee from The Haworth Document Delivery Service: 1-800-HAWORTH.E-mail address: <[email protected]> Website: <http://www.HaworthPress.com> © 2006 by The Haworth Press, Inc. All rights reserved.]

KEYWORDS. Psychopharmacology, depression, mood disorders, in-tegrated treatment

The World Health Organization announced findings from a multi-nation study indicating that currently for women major depression is thesecond most disabling condition (among all medical and psychiatricdisorders). And by the year 2020 it will rank as the number one overall

John Preston is affiliated with Alliant International University, Sacramento, CA.

Journal of Family Psychotherapy, Vol. 17(3/4) 2006Available online at http://jfp.haworthpress.com

© 2006 by The Haworth Press, Inc. All rights reserved.doi:10.1300/J085v17n03_03 35

Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

disabling condition, worldwide (males and females combined) (Murrayand Lopez, 1996). Each year 25 million Americans suffer from seriousdepression, it has a life-time prevalence rate of 17% (Kessler et al.,1994), and ranks as the second most commonly seen disorder in patientsseeking treatment from primary care physicians. Data suggest that theincidence of depression is increasing (Murray and Lopez, 1996). Mor-bidity and mortality associated with serious mood disorders is enor-mous. Suicide is the eighth leading cause of death in the United States,and chronic and recurrent depressions significantly increase risk forcoronary heart disease, stroke, and osteoporosis (NIMH, 2003).

Despite these grim statistics and massive efforts to educate the publicregarding depression, it is estimated that only 25%-33% of those whosuffer seek treatment. Additionally, treatment received is often very in-adequate. Most drug treatment for depression takes place in primarycare medical settings. Eighty-five percent of prescriptions written in theUnited States for antidepressants are written by physicians and nursesthat do not have specialty training in psychiatry. This is due in large partto managed care’s efforts to cut costs by having the majority of psychi-atric treatment take place in primary-care settings. Yet, only 11% ofthose treated for depression in primary care receive adequate treatment(in terms of dosing, time to response, and follow-up) (Akiskal andCassano, 1997). In addition, 76.1% of patients treated for depression inprimary-care settings are seen for two or fewer follow-up visits duringthe year following the start of treatment (Katz et al., 1998).

A CHANGING TREATMENT LANDSCAPE

The 1980s and 1990s saw the proliferation of HMOs and managedcare companies that attempted to streamline mental health care in orderto achieve cost containment. During this same time, psychiatry trainingprograms have increasingly emphasized psychopharmacology as themainstay of treatment for clinical depression. Finally, pharmaceuticaladvances and market-place forces have had a substantial impact onshifting patterns of practice in the mental health arena (see Table 1).

In many settings, psychopharmacology has become the primary orsole form of treatment for many suffering from serious mood disorders.Yet, the vast majority of patients treated either does not respond or onlyexperiences partial responses.

36 JOURNAL OF FAMILY PSYCHOTHERAPY

Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

TREATMENT OUTCOMES

How effective are antidepressants? All drugs must go through rigor-ous trials prior to FDA approval, and must demonstrate clear superiorityover placebos. The currently available antidepressants have all passedthe test, but the outcome data is often spurious and plagued by method-ological flaws. First and foremost in the majority of pre-FDA approvalefficacy-studies patients selected for medication trials hardly resembletypical outpatient populations. Patient selection excludes those whohave had prior suicide attempts, who have psychotic or bipolar symp-toms, and who have comorbid medical illnesses, substance abuse,or Axis II disorders. A recent paper by Zimmerman, Posternak, andChelminski (2002) looked at consecutive patients seen in an outpatientsetting who were diagnosed with unipolar, major depression. If patientselection criteria as noted above were applied to this typical group of de-pressed outpatients, 85% of them would be excluded from drug trials.Complex comorbidity is the rule, not the exception in usual clinical set-tings. Thus, it may not be appropriate to generalize results from efficacystudies to the real world of clinical practice.

Another significant flaw in the reporting of outcome data is the com-mon practice to exclude dropouts due to side effects from percentagesof responders (Gitlin, 2002). Thus, for most antidepressants studied, thepositive outcomes are inflated (see Table 2).

A more appropriate picture of outcome is derived from what aretermed Intent-To-Treat (ITT) studies. In these studies, dropouts areconsidered as failures (nonresponders).

Upon closer inspection, the picture is even less positive than theseITT data suggest. In most studies “responders” are those who achieve a50% or greater decrease in scores on the Hamilton Depression RatingScale (Ham-D) or a Ham-D score of 7 or less. In most studies, only halfof the responders reach Ham-D scores below 14, and although they aresignificantly improved, they still are not fully recovered (see Figure 1).

Integrating Psychotherapy and Pharmacotherapy 37

TABLE 1. Treatment Received by Patients Diagnosed with Major Depression*

1987 1997

Antidepressants (%) 37 75

Psychotherapy (%) 71 60

* Olfson et al., 2002, based on sample size N = 32,000.

Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

Failure to reach full remission is associated with ongoing subclinicalsymptomotology (often patients report just not feeling enthusiasticabout life) and with partial responders, there is a threefold increase inacute relapse of major depression (Paykel et al., 1995). Finally, eventhose judged to be in full remission, often continue to experience subtleresidual depressive symptoms. In one study, only 18% of “fully remit-ted” patients were truly asymptomatic (Nierenberg et al., 1999).

It must be emphasized that this critique of outcome data is not in-tended to be an indictment of antidepressants. Quite the contrary, thesemedications have been shown to be highly effective in alleviating manyserious mood-disorder symptoms (e.g., vegetative symptoms), undoubt-edly have saved many lives, and antidepressants may also be neuro-protective (see in the following sections). But they are not a panacea.Such is the case with most medications that are used to treat chronicillnesses such as diabetes, hypertension, cancer, and chronic pain. Like-


TABLE 2. Antidepressant Treatment of Major Depression Outcome Results:General Results Reported from Drug Efficacy Studies

Commonly ReportedOutcomes (%)

ITT Outcomes (%)

Side-effects drop-outs 15* 15*

Responders 60 50

Nonresponders 40 35

*Drop-out rates due to side effects vary among new generation antidepressants ranging from Wellbutrin,

SR: 9%, to Paxil: 21%.

FIGURE 1. ITT: Intent To Treat: Typical Outcomes

Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

wise, most studies of psychotherapies for depression (e.g., cognitive-behavioral therapy and interpersonal therapy, etc.) report success ratesin the 50%-55% range. It is humbling to appreciate the limits of any sin-gle treatment modality.

What has become clear is that mood disorders are tremendouslycomplex and heterogeneous disorders involving numerous interactingvariables: e.g. genetic predispositions, life stresses, interpersonal rela-tionships, hormonal, neurobiologic, intrapsychic, cultural, and existentialfeatures. It is the appreciation of such complexity that has lead to in-creased interest in integrative approaches to treatment (Preston, 2006).

ABNORMAL NEUROBIOLOGY:A COMPELLING CASE FOR THE USE

OF ANTIDEPRESSANTS

A comprehensive review of the neurobiology of depression is be-yond the scope of this paper. However, let us consider a few importantresearch findings that have emerged during the past decade. Fifty tosixty percent of people experiencing a major depressive episode exhibita hyperactive hypothalamic-pituitary-adrenal (H-P-A) neuroendocrineaxis (see Figure 2). In mammals, when danger or adversity is perceived


FIGURE 2. Hypothalamic-Pituitary-Adrenal Neuroendocrine Axis

Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

in the environment, a number of complex events take place in the ner-vous system, launching adaptive fight-or-flight responses. One of themost important components of this biological response is the activationof the H-P-A axis, which ultimately releases glucocorticoid hormonesinto general circulation (in humans, the principal glucocorticoid iscortisol). Cortisol operates to facilitate the release of glucose into theblood stream and to increase blood pressure (both of which are essentialfor mounting an effective fight-or-flight response).

Cortisol enters circulation and is distributed throughout the body. Inthe brain, the most prominent site for cortisol response is the limbicbrain structure, the hippocampus. In adaptive fight-or-flight responsescortisol activates the hippocampus to inhibit the H-P-A axis (operatinglike a “brake”). Of course, if danger persists in the environment, theH-P-A axis is continuously reactivated. However, when stressors sub-side, the cortisol-mediated feedback loop shuts down the system, andthus plays a role in affect regulation (LeDoux, 1996).

This hyperactivity of the H-P-A axis, seen in many cases of major de-pression, results in a condition known as hypercortisolemia. Here,cortisol levels are significantly elevated and have been shown to beneurotoxic. These high, sustained, toxic levels of cortisol have a markedimpact on hippocampal nerve cells (e.g., cause dendrite retraction, celldeath, and hippocampal atrophy). Hypercortisol also may damage otherneural tissue (e.g., anterior cingulate, amygdala, cerebellum: all ofwhich have been implicated in playing a role in affect regulation). Overtime the result is progressive brain damage that likely accounts for thedeteriorating course seen in many cases of untreated or poorly treatedrecurrent and chronic depression (Sapolsky, 1996). High cortisol levelsin depressed pregnant women cross the placental-blood barrier and canadversely affect the fetus’s nervous system.

Additionally, depression reduces the gene expression of brain-de-rived neurotropic factor (BDNF), which is a neuroprotective moleculeknown to facilitate the repair of damaged nerve cells and to promoteneuron regeneration (i.e., neurogenesis) in the hippocampus.

Antidepressant medications reduce cortisol levels (Heim and Neme-roff, 2002; Nestler, Hyman, and Malenka, 2001) and reactivate the pro-duction of BDNF, which can lead not only to clinical improvement, butalso to the birth of new nerve cells in the hippocampus (Kempermannand Gage, 1999). Thus, antidepressants can play a crucial role in treat-ing symptoms of depression as well as protecting the brain from theeffects of toxic levels of stress hormones.


Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

PSYCHOPHARMACOLOGY

During recent years, large-scale empirical studies have been de-signed in order to establish guidelines for what is currently referred to as“evidence-based medicine.” These include the STAR-D (SequencedTreatment Alternatives for Relieving Depression: A multisite studysponsored by the National Institute of Mental Health), the Texas Medi-cation Algorithm Project and UCLA’s Targeted Treatment for Depres-sion Program (Metzner, 2000). Treatment guidelines in psychiatry havebeen influenced by three factors: (1) Market-place variables (e.g., phar-maceutical company advertising; decisions made by HMOs to adoptcost-effective drug formalities), (2) Consensus (i.e., invite “experts” toconvene a panel and discuss pros and cons of various medical treat-ments and agree upon best treatment strategies), and (3) Results from alarge amount of research regarding treatment outcomes. The latter ofthese offer important information, but are also inherently flawed be-cause most psychopharmacology outcome studies are sponsored bydrug companies who have a vested interest in producing good out-comes. The major drawback here is that many null studies never make itinto the journals. Thus, it is difficult to realistically evaluate the effec-tiveness of certain treatments with only positive outcome data available.

The large-scale studies mentioned above are funded by the NIMH,Texas Department of Mental Health, and a university, respectively, andthus may more accurately reflect realistic outcome data, noninfluencedby the profit motives of drug companies. Also, the studies are not onesof consensus opinions, but rather based on empirical outcomes withvery large groups of subjects.

What is summarized in the following sections are the first of whatpromises to be a growing body of evidence-based data that can suggestspecific strategies for the treatment of major depression.

First-Line Medication Choices:Major Depression

Major depression as defined by DSM-IV criteria (APA, 1994) repre-sents a heterogeneous group of mood disorders that vary in terms ofseverity (mild-to-severe), clinical/symptomatic presentation, and pre-sumed etiology. A large body of neuroscience research has strongly im-plicated that dysregulation of certain central neurotransmitters may beassociated with particular psychiatric symptoms. Most individuals thatexperience a decreased availability of neurotransmitters such as seroto-


Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

nin (abbreviated 5-HT), dopamine (DA) or norepinephrine (NE) do notdevelop clinical depression (Delgado et al., 1990). However, some do,which is likely due to underlying genetic or other vulnerability factors.Among depressed subjects inadequate functioning of 5-HT, DA, or NEcan contribute to certain core depressive symptoms such as a depressedmood, pessimistic and negative thinking, guilt, low self-esteem, and fa-tigue. What has emerged during the past two decades of research aregeneral but consistent findings suggesting that beyond common, coresymptoms of depression, particular neurotransmitter dysfunctions maybe accompanied by or cause specific symptoms:

• Serotonin Dysregulation: Irritability, impulsivity, suicidal impul-ses/behavior, and ruminations

• Dopamine and/or Norepinephrine Dysregulation: Apathy,anhedonia, low motivation, and psychomotor symptoms.

Closely paralleling these findings from neuroscience research aredata from empirical pharmacologic studies (e.g., Metzner, 2000; Sheltonand Tomarken, 2001), which have led to the following guidelines inwhich particular symptomatic features point toward first-line antide-pressant medication choices:

Major Depressive Disorder (MDD) Treatment Algorithm:Choosing a First-Line Antidepressant

Major Depression with agitation and/or comorbid anxiety (representsabout 50% of cases of major depression). Medications recommended:Selective Serotonin Reuptake Inhibitors (SSRI’s: Prozac, Zoloft, Paxil,Luvox, Celexa, Lexapro). Additionally, patients that present with irrita-bility, impulsivity, rumination, and/or significant suicidal ideationsmay also preferentially respond to these serotonin-specific antidepres-sants. Although these agents may prove to be effective in treating agitated/anxious depressions, a significant problem is commonly encountered astreatment begins. This is a side effect referred to as activation; which isexperienced as increased energy, anxiety, and/or agitation typicallyemerging several hours after taking the first dose. In individuals withthis version of MDD, such acute-onset side effects often result in abruptpatient-initiated discontinuation (the side effects often scare patientsand may make them very reluctant to go through another antidepressanttrial). Thus, although after 4-6 weeks of treatment SSRIs often begin to


Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

significantly reduce both depression and anxiety symptoms, the initialfew weeks of treatment can be very challenging and many patients dropout of treatment. A popular and effective way to address this problem isto initially coadminister a benzodiazepine (i.e., minor tranquilizer, e.g.,Ativan), using this drug to rapidly reduce anxiety, agitation, and drug-induced activation. In addition, since benzodiazepines begin to reduceanxiety within an hour of taking the medication, the experience formany patients is that they feel noticeably better, quickly. This is anadded benefit because it often leads to hopefulness about treatment andenhances compliance. Generally, after one month of treatment thebenzodiazepine can be phased out. This is often a very successful strat-egy, however, there is one important warning. Since benzodiazepinescan be drugs of abuse, the use of these agents is risky and not indicated ifthere is a history of alcohol or substance abuse. With an addiction history,many psychiatrists are now using the non-habit-forming anticonvulsant,Neurontin (gabapentin) to target the activation and initial anxiety. Thisapproach is often successful, but it is considered as experimental andhas not yet been subjected to rigorous research.

Major Depression with marked anhedonia, apathy, amotivation, andpsychomotor retardation (represents about 30%-35% of MDDs). Therecommended antidepressants are Wellbutrin (that targets DA and NE)and norepinephrine reuptake inhibitors (NRI’s), for example, Stratteraor Norpramin.

Atypical Depression (15%-20% of MDDs). Atypical symptoms in-clude Hypersomnia, appetite increase, carbohydrate craving and subse-quent weight gain, and severe fatigue. Other symptoms often associatedwith atypical MDD are as follows: Rejection sensitivity and anxietyattacks. Medications of choice are SSRIs, MAOIs and possibly Well-butrin (APA, 2003). It is important to exercise caution when treatingatypical MDD because many such individuals may be expressing thedepressive phase of bipolar illness, and if treated with antidepressantsalone there is a risk of switching (i.e., provoking mania or hypomania) orcycle acceleration (the tendency to cause increasingly severe or morefrequent mood episodes).

Very Severe and/or Highly Recurrent Cases (symptoms can be anx-ious, anergic, or atypical). These more severe and recurrent disordersappear to respond best to dual-action antidepressants such as Effexor(NE and 5-HT), Cymbalta (NE and 5-HT), Remeron (NE and 5-HT), orthe combination of an SSRI and Wellbutrin (this combination actuallybecomes triple action, that is, targeting NE, DA, and 5-HT).


Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

Metzner (2000) has demonstrated that targeted treatment for depres-sion (i.e., TTD) where the choice of a first-line antidepressant is basedon the presenting clinical picture (as outlined above) yields superioroutcomes compared with standard (STD) treatment as usual. Positiveresponses to antidepressants: STD = 65%, TTD = 96%.

PARTIAL AND NONRESPONDER STRATEGIES

Fifty-five to sixty-five percent of patients treated with antidepres-sants only experience a partial response or no response at all (Paykelet al., 1995; Doraiswamy et al., 2001). And as noted earlier, those whodo not reach full remission incur an increased risk of relapse (Paykelet al., 1995). Empirical studies are beginning to provide data-basedtreatment guidelines for partial or nonresponders (see Texas Depart-ment of Mental Health, 2003; NIMH: STAR-D Program, 2003).

It must first be recognized that a number of factors may account forless than adequate antidepressant responses, including the following:

• Poor compliance• Unreported substance abuse (in particular, alcohol use/abuse, which

may both exacerbate depressive symptoms and interfere with themetabolism of antidepressant medications).

• Unsuspected medical illnesses (e.g., sleep apnea or thyroid dis-ease).

• Failure to address key psychological conflicts and/or family basedpsychopathology

• Choice of wrong class of antidepressant medication (e.g., pharma-cologically targeting the serotonin system when in fact a particularpatient’s depression is associated with dysregulation of norepine-phrine)

• Chronic, residual brain impairment sustained in previous untreatedor inadequately treated depressive episodes.

PARTIAL RESPONDER STRATEGIES

The highest yield next step strategy is to progressively increase themedication dose. Some patients who are hyper-or rapid metabolizers re-quire higher doses to achieve adequate blood levels. The doses can beprogressively increased if tolerated. If this strategy is ineffective or im-possible owing to emergent side effects, step two is to augment (i.e., to


Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

add an additional medication to the current drug). Augmentation strate-gies often yield good responses in 35%-65% of those treated. The fol-lowing are common augmentation strategies that often are successful:

• SSRI plus Wellbutrin• SSRI plus BuSpar• SSRI plus stimulant (e.g., Ritalin) for anergic depressions• Antidepressant plus Lithium (generally Lithium levels of 0.4-0.6

mEq/l)• Combining Effexor and Remeron (Stahl, 2000) SSRI plus atypical

antipsychotic (e.g., Zypexa) (Shelton et al., 2001). Note: Thisstrategy is often successful in treating partial responders (Trivediand Klieber, 2001) who have major depression without psychoticfeatures. Several of the new-generation, atypical antipsychoticsappear to have mood stabilizing and antidepressant properties(e.g., Zyprexa, Risperdal, Geodon, Abilify)

• Antidepressant plus T3 (triiodothyronine), 25-50 micrograms perday.

NONRESPONDER STRATEGIES

Once again, one must evaluate issues involving compliance and pos-sible substance abuse. Should these issues be ruled out, then the highestyield next step strategy (Trivedi and Klieber, 2001) is to optimize thedose (dosage increases, if tolerated). Should a high dose be reached andthere is still little or no response, then the next step strategy is to changeclasses of medications (e.g., switch from a serotonin active drug (SSRI),for example, Zoloft, to an antidepressant that targets norepinephrine, forexample, Strattera, or dopamine, for example, Wellbutrin).

PHASES OF TREATMENT

There is general agreement among research groups that the treatmentof major depression involves three phases (American Psychiatric Asso-ciation, 2003; Texas Department of Mental Health, 2003).

Acute Phase. Starts with the first dose and extends until the patient isasymptomatic. Since symptoms have abated, many clients will natu-rally think that they no longer need medications and will discontinue(against medical advice). At this point in treatment should patients dis-continue, more than one-half will experience an acute relapse within a


Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

few weeks (Stahl, 2000). Ongoing antidepressant treatment, however,decreases the likelihood of acute relapse, necessitating the next phase.

Continuation Phase. Continue treatment at the same dose for a mini-mum of six months. If during this time period there are no breakthroughdepressive symptoms, then discontinuation can be considered (gradualdiscontinuation, for example, over a period of six weeks is strongly rec-ommended to avoid discontinuation withdrawal symptoms).

Maintenance Treatment. Lifelong treatment is strongly indicated forpatients with highly recurrent major depressions (e.g., those in theirthird or subsequent episodes). Chronic treatment attempts to preventrecurrence.

TREATMENT OF DEPRESSIVE SUBTYPES

Minor Depression. Patients suffering from dysthymia have shown avery positive response to antidepressant medication treatments (33%Good response, 33% Very good response) (Akiskal and Cassano, 1997).

Seasonal Depression. Often responds to high-intensity light therapy,generally provided by the use of a commercially available light box.The typical “dose” of light therapy is 10-30 minutes of exposure to alight source that emits a minimum of 2500 lux. The light has an impactby striking the retina, which activates a specific nerve pathway (the reti-nal-hypothalamic nerve). In most cases, high-intensity light therapymust be accompanied by the use of antidepressant medications (Bleharand Rosenthal, 1989; Terman, Terman, and Ross, 1998).

PreMenstrual Dysphoric Disorder (PMDD). If mood symptoms areonly seen for discrete periods of time prior to menstruation and absentthe rest of the month, acute treatment with SSRIs is often successful(while all other mood disorders require two-six weeks of treatment priorto the first signs of clinical improvement, many of those suffering fromPMDD realize symptomatic relief a few hours after taking the first doseof an SSRI). Often this strategy allows the PMDD patient to avoidchronic medication use (i.e., needing to take the medication only duringthose days each month when mood symptoms are present) (Nutt, 2002).

TREATMENT OF PSYCHOTIC DEPRESSIONS

Success rates for treating psychotic disorders with single agents aregenerally poor (American Psychiatric Association, 2003). Thus, thecombined use of antidepressants and antipsychotics are required.


Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

Phases of treatment for psychotic depression recommend a period ofone-year continuation treatment with both antidepressants and anti-psychotics before a trial discontinuation. Premature discontinuation isassociated with a high risk of acute relapse. And poorly treated psy-chotic depressions carry a higher risk of suicide than do other forms ofMDD. Should pharmacologic treatment fail, ECT (electroconvulsive/shock therapy) is often highly effective.

HIGHLY TREATMENT-RESISTANT CASES

If despite standard treatments or augmentation strategies, there is stilllittle or no response, be sure to reassess for the presence of:

• Unreported substance abuse• Undiagnosed sleep apnea (often causes depressions that fail to re-

spond to standard antidepressant treatments)• Unsuspected occult illnesses (e.g., endocrine disease, cancer)• Undiagnosed bipolar disorder (bipolar depressions are often espe-

cially difficult to treat and treatment with antidepressants at timescan aggravate the disorder causing switching and/or cycle acceler-ation)

Other possible factors are as follows:

1. Secondary gain2. Unaddressed psychological issues (e.g., internal conflicts or un-

mourned loses)3. Psychologically toxic family environment that has not been ad-

dressed (e.g., no intimacy, domestic violence).

EXPERIMENTAL TREATMENTS

A number of promising new treatments have emerged during the pastfive years, including: Vagus nerve stimulation, repetitive transcranialmagnetic stimulation (George, 2003), omega-3 fatty acid supplementa-tion (Peet and Horrobin, 2002), and exercise therapy (Lawlor andHopker, 2002). Each of these approaches has been found to be effectivein treating a number of otherwise treatment-resistant cases of MDD.


Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

PSYCHOTHERAPY FOR DEPRESSION

A large body of research supports the role of psychotherapy as a pri-mary treatment for depression. Five types of psychological treatmenthave empirical support of efficacy in treating major depression: Cogni-tive-behavioral therapy, interpersonal psychotherapy for depression,cognitive-behavioral analysis system of psychotherapy, brief psycho-dynamic therapy for depression and behavioral marital therapy. A re-view of this literature is beyond the scope of this article, however a briefreview of those psychotherapies that relate to marital and family therapyis addressed briefly.

The research on depression suggests a strong association betweendepression and marital distress. For an overview, see Yager (1992)and Coyne (1988). Whisman (2001) in a meta-analysis, found that mar-ital quality was negatively correlated with a diagnosis of depression(r = .66), and that the average depressed person scored in the distressedrange of Spanier’s (1976) Dyadic Adjustment Scale. Whisman andBruce (1999) found that individuals in discordant marriages were atover double the risk for onset of a new episode of depression a yearlater. A number of authors have also suggested that the onset and courseof depression may be influenced by the presence of maladaptive pat-terns of family interaction (Beach, 2001; Yapko, 1999). These findingssuggest that marital and family therapy may have advantages as a treat-ment for depression.

The effectiveness of marital and family treatments for depression hasrecently been reviewed by Beach (2003) and earlier by Prince and Ja-cobson (1995). Beach (2003) found that there is solid research supportfor the effectiveness of a number of couple treatment approaches. Inthree studies comparing Beach, Sandeen, and O’Leary’s (1990) Behav-ioral Marital Therapy (BMT) with individual therapy, BMT performedcomparably to individual therapy when the outcome variable was reduc-tion in depression, and performed better than individual therapy whenthe outcome variable was marital functioning.

There are also indications from a recent study by Dessaulles, John-son, and Denton (2003) that Emotion-Focused Therapy (EFT) forcouples may be an effective treatment for depression. InterpersonalPsychotherapy (IPT) originally developed by Klerman, Weissman,Rounsaville, and Chevron (1984) recognizes marital distress as a majorstressor contributing to the development of depression. This is espe-cially likely in chronically unhappy and dysfunctional relationshipswhere there is an ongoing sense of helplessness. Many such couples


Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

have unsuccessfully tried to resolve problems, but with time, begin tofeel increasingly powerless to overcome their difficulties. There are twofoci of IPT: Improving relationship skills (e.g., communication andproblem-solving skills) and helping couples to collaboratively face andgrieve losses (see Reynolds et al., 1999).

COMBINED PSYCHOTHERAPYAND PHARMACOTHERAPY

Aside from its role as a primary treatment for some types of depres-sion, a number of studies have demonstrated that psychotherapy can en-hance treatment outcomes when combined with drug treatment (e.g.,McCollough, 2000) and may contribute significantly to aiding in relapseprevention (Reynolds et al., 1999; Evans et al., 1992; Thase et al., 1997).Several authors including MacFarlane (2003) and Whisman and Uebe-lacker (1999) advocate treatment models that combine couple therapywith individual and pharmacological interventions for a more integratedtreatment approach. Additionally, the psychotherapist is in the best posi-tion for closely monitoring compliance, side effect problems, and clinicalresponse to medication treatment. This is especially important if the clientis being treated in a primary-care setting where the therapist can collabo-rate with the physician in order to optimize treatment outcomes.

CONCLUDING REMARKS

Clearly, pharmacotherapy is an important component of comprehen-sive treatment for major depression. However, as a solo treatment it isoften inadequate in the treatment of depression, especially if the goal istrue remission. It has become clear that human psychological function-ing is extremely complex and etiological factors are numerous andvaried from one client to another. This calls for an integrated and multi-disciplinary approach.

REFERENCES

Akiskal, H.S. & Cassano, G.B., (Editors). (1997). Dysthymia and the Spectrum ofChronic Depression. Guilford Press, New York.

American Psychiatric Association. (1994). Diagnostic and Statistical Manual: IV.Washington, D.C.: American Psychiatric Press.


Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

American Psychiatric Association. (2003). Treatment recommendations for patientswith major depressive disorder. http://www.psych.org/clin_res/Depression2e.book-7.cfm

Beach, S.R.H., Sandeen, E.E., & O’Leary, K.D. (1990). Depression in marriage. NewYork: Guilford Press.

Beach, S.R. (Editor). (2001). Marital and Family Processes in Depression: A ScientificFoundation for Clinical Practice. Washington, D.C.: American PsychologicalAssociation.

Beach, S. (2003). Affective disorders. Journal of Marital and Family Therapy. 29 (2):247-261.

Blehar, M.C., & Rosenthal, N.E. (1989). Seasonal affective disorders and photo-therapy. Archives of General Psychiatry. 46(5): 469-474.

Coyne, J.C. (1988) Strategic Therapy. In: Affective Disorders and the Family. Editedby: Clarkin, J.F., Haas, G.L., and Glick, J.D. New York: Guilford Press.

Delgado, P.L., Charney, D.S., Price, L.H., Aghajanian, G.K., Landis, H., & Heninger,G.R. (1990). Serotonin function and the mechanism of antidepressant action: Re-versal of antidepressant induced remission by rapid depletion of plasma tryptophan.Archives of General Psychiatry. 47: 411-418.

Dessaulles, A., Johnson, S.M., & Denton, W.H. (2003). Emotion-focused therapy forcouples in the treatment of depression: A pilot study. American Journal of FamilyTherapy. 31: 345-353.

Doraiswamy, P.M., Kahn, Z.M., Donahue, R.M., & Richard, N.E. (2001). Quality oflife in geriatric depression: A comparison of remitters, partial responders, andnonresponders. American Journal of Geriatric Psychiatry. 9: 4223-4428.

Evans, M.D., Hollan, S.D., DeRubelis, R.J., Paisecki, J.M., Grove, W.M., Garvey,M.J., & Tuason, V.B. (1992). Differential relapse following cognitive therapy andpharmacotherapy for depression. Archives of General Psychiatry. 49: 802-808.

Foley, S.H., Rounsaville, B.J., Weissman, M.M., Sholomskas, D., & Chevron, E.(1989). Individual versus conjoint interpersonal psychotherapy for depressed pa-tients with marital disputes. International Journal of Family Psychiatry. 10: 29-42.

George, M.S. (2003). Stimulating the brain. Scientific American, 289(3): 66-73.Gitlin, M. (2002). Recognize and resolve: Treatment resistant depression. Las Vegas:

U.S. Psychiatric Congress.Heim, C., & Nemeroff, C.P. (2002). Neurobiology of early life stress. Seminars in

Clinical Neuropsychiatry. 7(2): 147-159.Katz, S.J., Kessler, R.C., Lin, E., & Wells, K.B. (1998) Medication management of de-

pression in the U.S. and Ontario. Journal of General Internal Medicine. 13: 77-85.Kempermann, G., & Gage, F.H. (1999) New nerve cells for the adult brain. Scientific

American. 280(5): 48-53.Kessler, R.C., McGonagle, K.A., Zhao, S., Nelson, C.B., Hughes, M., Eshleman, S.,

Wittchen, H.U., & Kendler, K.S. (1994). Lifetime and 12-month prevalence ofDSM-IV-R psychiatric disorders in the United States. Results from the NationalComorbidity Survey. Archives of General Psychiatry. 151(1): 8-19.

Klerman, G.L., Weissman, M.M., Rounsaville, B.J., & Chevron, E.S. (1984) Interper-sonal Psychotherapy of Depression. New York: Basic Books.


Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

Lawlor, D.A., & Hopker, S.W. (2001) The effectiveness of exercise on an interventionin the management of depression: A systematic review and meta-regression analy-sis of randomized controlled trials. British Medical Journal. 322 (7289): 263-767.

LeDoux, J. (1996) The Emotional Brain. Simon and Schuster, New York.MacFarlane, M.M. (2003). Systemic treatment of depression: An integrative approach.

Journal of Family Psychotherapy. 14(1): 43-61.McCullough, J.P. (2000). Treatment for Chronic Depression. The Guilford Press, New

York.Metzner, R.J. (2000). Neurotransmitters and depression: New possibilities. Annual

Meeting: American Psychiatric Association.Murray, C.J.L., & Lopez, A.D., (Editors) (1996). Global burden of disease, Vol. 1

Geneva: Harvard School of Public Health on Behalf of the World Health Organiza-tion and the World Bank.

Nestler, E.J., Hyman, S.E., & Malenka, R.C. (2001). Molecular Neuropharmacology.McGraw-Hill, New York.

Nierenberg, A.A., Keefe, B.R., Leslie, V.C., Alpert, J.E., Pava, J.A., & Worthington, J.J.3rd. Rosenbaum, J.F., and Fava, M. (1999). Residual symptoms in depressedpatients who respond acutely to fluoxetine. Journal of Clinical Psychiatry. 60(4):221-225.

NIMH (2003). http://www.nimh.nih.gov. National Institute of Mental Health, Bethesda,Maryland.

Nutt, D.J. (2002). The neuropharmacology of serotonin and noradrenaline in depres-sion. International Clinical Psychopharmacology. 17(Suppl 1): 51-512.

Olfson, M., Marcus, S.C., Druss, B., Elinson, L., Tanielian, T., & Pincus, H.A. (2002).National trends in the outpatient treatment of depression. JAMA. 28(2): 203-209.

Paykel, E.S., Ramana, R., Cooper, Z., Hayhurst, H., Kerr, J., & Barocka, A. (1995). Re-sidual symptoms after partial remission: An important outcome in depression. Psy-chological Medicine. 25: 1171-1180.

Peet, M., & Horrobin, D.F. (2002). A dose ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequatetreatment with standard drugs. Archives of General Psychiatry. 59: 913-919.

Preston, J.D. (2006). Integrative Brief Therapy (2nd edition). Impact Publishers,Atascadero, CA.

Prince, S.E., & Jacobson, N.S. (1995). A review and evaluation of marital and familytherapies for affective disorders. Journal of Marital and Family Therapy. 21 (4):377-401.

Reynolds, C.F., Frank, E., Perel, J.M., Imber, S.D., Cornes, C., Miller, M.D.,Mazumdar, S., Houck, P.R., Dew, M.A., Stack, J.A., Pollack, B.G., & Kupfer, D.J.(1999). Nortriptyline and interpersonal psychotherapy as maintenance therapies forrecurrent major depression: A randomized controlled trial in patients older than 59years. JAMA. 281: 39-45.

Sapolsky, R.M. (1996). Glucocorticoids and atrophy of the human hippocampus. Sci-ence. 273: 749-775.

Shelton, R.C., & Tomarken, A.J. (2001). Can recovery from depression be achieved?Psychiatric Services. 52(11): 1469-1478.


Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

Shelton, R.C., Tollefson, G.D., Tohen, M., Stahl, S., Gannon, K.S., Jacobs, T.G.,Bruas, W.R., Bymaster, F.P., Zhang, W., Spencer, K.A., Feldman, P.D., & Meltzer,H.Y. (2001). A novel augmentation strategy for treating resistant major depression.American Journal of Psychiatry. 158: 131-134.

Spanier, G.B. (1976). Measuring dyadic adjustment: New scales for assessing the qual-ity of marriage and similar dyads. Journal of Marriage and the Family. 38: 15-28.

Stahl, S. (2000). Essential Psychopharmacology. (Second edition). Cambridge Uni-versity Press, Cambridge.

Terman, M., Terman, J.S., & Ross, D.C. (1998). A controlled trial of timed bright lightand negative ionization for treatment of winter depression. Archives of GeneralPsychiatry. 55: 875-882.

Texas Department of Mental Health (2003). Texas Medication Algorithm Project.http://www.mhmr.state.tx.us/centraloffice/medicaldirector/TMAPtoc.html.

Thase, M.E., Greenhouse, J.B., Frank, E., Reynolds, C.F. 3rd., Pilkonis, P.A., Hurley, K.,Grochocinski, V., & Kupfer, D.J. (1997). Treatment of major depression withpsychotherapy or psychotherapy-pharmacotherapy combinations. Archives ofGeneral Psychiatry. 54: 1009-1015.

Trivedi, M.H., & Klieber, B.A., (2001). Algorithm for the treatment of chronic depres-sion. Journal of Clinical Psychiatry. 62(Suppl 6): 22-29.

Whisman, M.A., & Bruce, M.L. (1999). Marital dissatisfaction and incidence of majordepressive episode in a community sample. Journal of Abnormal Psychology. 108:674-678.

Whisman, M.A., & Uebelacker, L.A. (1999). Integrating couple therapy with individ-ual therapies and antidepressant medications in the treatment of depression. Clini-cal Psychology: Science and Practice. 6(4): 415-429.

Whisman, M.A. (2001). The association between depression and marital dissatisfac-tion. In S. R. H. Beach (Ed.), Marital and family processes in depression: A scien-tific foundation for clinical practice (pp. 3-24). Washington, D.C.: AmericanPsychological Association.

Yager, J. (1992). Mood disorders and marital and family problems. In: American Psy-chiatric Press Review of Psychiatry. Vol. 11 Edited by: Tasman, A. and Riba, M.B.Washington, D.C.: American Psychiatric Press. 477-493.

Yapko, M. (1999). Hand me down blues: How to stop depression from spreading infamilies. New York: St. Martin’s Press.Zimmerman, M., Posternak, M.A., andChelminski, I. (2002) Symptom severity and exclusion from antidepressant effi-cacy trials. Journal of Clinical Psychopharmacology. 22 (6): 610-614.

doi:10.1300/J085v17n03_03


Dow

nloa

ded

by [

RM

IT U

nive

rsity

] at

03:

24 2

4 A

ugus

t 201

4

Documents

Pharmacologie Treatment of Depression